FOREWORD

The editors of the 12th edition of The Ashburn Clinic Drug Manual take pleasure in presenting this updated edition.

Since the publication of the 11th edition in 1993, there have been a significant number of new psychopharmacological agents available for the treatment of psychiatric disorders.

The most significant developments have been in the production of new antidepressants and new antipsychotics. The new generation antipsychotics Risperidone, Olanzapine, Quetiapine and Clozapine have all brought significant benefits to selected patients.

The new antidepressants, which include the SSRIs, Nefazodone and the reversible MAOIs have rapidly found a place in the treatment of a wide variety of depressive and anxiety disorders. Whilst possibly not as effective as the old trycyclic antidepressants in the treatment of severe melancholic depression, they appear to be more acceptable to patients suffering more moderate forms of depression and a variety of anxiety disorders.

Psychiatric disorders impose a very large cost burden upon the wider community and there is a great need to ensure that barriers to access to these effective treatments are kept as low as possible, especially in these times of escalating health care costs where effective outpatient care is considerably less expensive than inpatient care.

Prescribers must exercise care to ensure that these recently available and relatively expensive pharmaceuticals are used only when clearly indicated. Patients and doctors alike need to avoid the risk of seduction by the idea that normal human unhappiness and worry can be ameliorated with a pill. We have a growing problem with drug and substance abuse in out society, and as prescribers need to take a lead in defining attitudes, using medications judiciously and only as an integrated part of a complete assessment management plan. Social and psychological factors must always be taken into consideration in the overall treatment of psychiatric disorders.

It is hoped that this 12th edition will provide help and information to those seeking to maximize the wise prescription of medicative treatment.

DR STEPHANIE du FRESNE

DR JOHN ADAMS

PROFESSOR TREVOR SILVERSTONE

Chapter 1

THE ANTIPSYCHOTIC DRUGS

Use and Classification

Indications 1 2 3 Acute psychosis, including mania. Maintenance treatment of schizophrenia. Acute and chronic organic psychosis, especially if there is agitation, restlessness or confusion. 4 Also used in lower doses in anxiety disorder and more disturbed periods of personality disorders. This usage is less well established, and the disadvantages of side-effects may outweigh the benefits.

Effects The antipsychotic drugs are most effective in controlling the positive symptoms of schizophrenia (thought disorder, hallucinations and delusions). This, in turn, generally leads to a reductions in psychotic agitation and, to a lesser extent, schizophrenic apathy and withdrawal . They do not act primarily by sedation. Patients must be warned that these drugs potentiate alcohol and some sedatives. Drowsiness may limit driving and the operation of heavy machinery, especially early in treatment.

It is now recommended that patients, particularly younger patients, who show early signs of a possible schizophrenic illness are treated with an antipsychotic drug as soon as possible. It is hoped that such early intervention will reduce the likelihood of more chronic symptoms developing.

Classification of antipsychotic drugs

All the effective antipsychotic compounds share the pharmacological property of blocking dopamine D2 receptors in the limbic system of the brain and it is generally believed that it is this which underlies their clinical efficacy. Where they differ from one another is in the nature and site of other receptors they act on. The older antipsychotic drugs, that is those introduced into clinical practice before 1990, are often referred to as typical antipsychotics. They bind to dopamine receptors in both the limbic system and the striatal areas; the latter giving rise to extrapyramidal symptoms (EPS) such as parkinsonism and akathisia (see below). Newer antipsychotics, most of which block serotonin 5-HT2 receptors in addition to D2 receptors, are less prone to cause EPS or to cause a sustained rise in prolactin levels. This reduced propensity to cause EPS has led to them being referred to as atypical antipsychotics. Although this term has been applied in a largely arbitrary manner and is of limited scientific value, it has gained such widespread currency that that it is probably here to stay for some time.

I. Typical antipsychotics

(a) Phenothiazines The discovery that the phenothiazine derivative promethazine possessed sedative and antihistamine activity encouraged the synthesis of other compounds in this group. Chlorpromazine, synthesised in 1950, was soon found to have pronounced calmative effects in disturbed psychotic patients and was introduced into clinical practice in 1952. Since then it has come to be one of the two standard compounds against which other substances are compared (the other is haloperidol - see below).

Phenothiazines have a large number of pharmacological properties, and minor changes in their molecular structure can profoundly influence their therapeutic activity and the severity of unwanted effects, particularly the incidence of extrapyramidal reactions. All the drugs in this group have a phenothiazine nucleus with one of the following side-chains: (i) Aliphatic Chlorpromazine [Largactil]

(ii) Piperazine Trifluoperazine [Stelazine] (iii) Piperidine Thioridazine [Melleril] (b) Butyrophenones Haloperidol [Serenace, Haldol] (c) Thioxanthenes Flupenthixol [Fluanxol] (d) Diphenylbutylpiperidines Pimozide [Orap] (e) Dibenzoxazepines Loxepine [Loxapac]

The aliphatic and piperidine phenothiazines and dibenzoxazepines are low potency antipsychotics and need to be given in relatively high dosage; butyrophenones and diphenylbutylpiperidines are high potency drugs which are effective in smaller doses.

II. Atypical antipsychotics (a) Dibenzodiazepines Clozapine [Clozaril] (b) Benzisoxazoles Risperidone [Risperdal]

(c) Thienobenzodiazepines Olanzapine [Zyprexa] (d) Dibenzothiazepine Quetiapine [Seroquel]

Drug Selection All the antipsychotic drugs in common use (other than clozapine) are approximately equally effective in clinically equivalent doses. The major differences between them lie in their side-effect profile; this can be a determining factor in drug selection. For instance, in patients with vascular disease haloperidol may be preferred to a phenothiazine compound as it carries less risk of causing hypotension. On the other hand, the sedative action of phenothiazines, such as chlorpromazine, can be useful for patients who are disturbed during the night. Patients suffering from renal, hepatic or cardiac failure need special consideration in deciding dosages. Earlier claims that atypical antipsychotics were particularly effective in ameliorating the negative symptoms of schizophrenia have not, unfortunately, been substantiated.

It is generally considered good practice to use only one antipsychotic compound at a time if possible. There is no evidence that combinations of antipsychotic drugs improve efficacy. They can make dose adjustments in response to side effects more difficult as it may not be clear which of the drugs is responsible for a particular symptom. There is a wide variation in individual dose-responsiveness. Increasing the dose above the usual recommended therapeutic range does not usually lead to increased effectiveness. It should only be done after careful consideration, the reasons carefully documented, and close monitoring ensured. A better approach is to try an antipsychotic drug of a different group. When a patient has failed to respond to antipsychotic drugs of two pharmacological classes given in adequate dose for a sufficient length of time (two to three months) he/she can be described as drug-resistant. Clozapine (see below) may be effective in a substantial proportion of such patients and is worthy of consideration despite the increased risk of blood dyscrasia.

When starting treatment for the first time it is probably advisable to use a newer atypical antipsychotic as they are less likely to cause EPS and thereby prejudice compliance.

Continued Treatment In general, after one psychotic episode, medication is continued for 9-12 months before being slowly discontinued. If symptoms recur the medication should be immediately restarted and consideration given to long-term maintenance treatment with antipsychotic medication . In making a decision about maintenance treatment the risk of relapse needs to be weighed against the long-term risk of tardive dyskinesia (see below).

At least 50% of schizophrenic patients fail to comply with oral maintenance regimes and consequently relapse. In such cases, the use of one of the long-acting parenteral drugs may be indicated. When starting a depot neuroleptic (see below), it is usual to give a 'test dose' (eg: 6.25mg to 12.5mg fluphenazine decanoate). The patient is then observed for signs of adverse reaction over the next week. The dose of depot neuroleptics should be tailored to the individual patient. The maintenance medication of chronic patients should be reviewed regularly, and kept below the minimum effective dose. Antipsychotics can have a protective effect for schizophrenic patients returning to a stressful or critical environment and increased stress, eg: starting work, may necessitate a temporary increase in dose.

Side Effects and their Treatment 1 Drowsiness is common, and caution needs to be exercised in driving or handling complex machinery when starting treatment with an antipsychotic drug. Dosage adjustment with advice to take the medication before retiring for the night is usually all that is required. Switching to a less sedative compound, such as haloperidol, may be helpful.

2 Autonomic Side-effects: (a) Postural hypotension Patients should be warned of the possibility of dizziness on rising If treatment is started with high doses the patient may need to be kept in bed to avoid falls. Immediate treatment is by lying down, with the feet elevated.

The drug should be changed to one less likely to cause this side-effect (e.g. perphenazine, haloperidol). (b) Anticholinergic effects Dry mouth, blurred vision, constipation, urinary retention, mydriasis. Anticholinergic (atropinic) psychosis may occur (treatment page 31).

3. Extrapyramidal effects (EPS) occur in up to 40 per cent of patients treated with typical antipsychotic drugs. Among the phenothiazines they are more common with those compounds having a piperazine side-chain. They are equally frequent with thioxanthine, butyrophenone and diphenylbutylpiperidine derivatives but less with drugs which have an intrinsic anticholinergic activity, such as thioridazine. Atypical antipsychotics, such as clozapine, olanzapine and quetiepine are less prone to be associated with extrapyramidal symptoms because of their associated 5-HT2 receptor blocking action, which is thought to counter the effects of dopaminergic blockade in the striatum. Risperidone, although classified as an atypical antipsychotic, does have a potential to cause EPS, particularly at higher doses. (a) Acute dystonia is an involuntary contraction of skeletal muscles most frequently occurring in the head and neck, giving rise to what is often called an 'oculogyric crisis'. It begins with a fixed stare which then gives way to a turning upwards of the eyes, followed by hyperextension of the neck and opening of the mouth. The attack may last several hours before subsiding spontaneously and can be a very distressing experience. It occurs in some 2 to 10 per cent of patients treated with antipsychotic drugs, usually appearing within a day or two of starting treatment, being commoner in younger male.

(b) Parkinsonism mimics idiopathic parkinsonism very closely, with a stiffening of the limbs, lack of facial expression, a characteristic coarse tremor of the hands and head at rest, plus sialorrhoea and seborrhoea. The mask-like facies, stiffness and motor retardation may be mistaken for schizophrenic apathy. Parkinsonism has been observed in 20 to 40 per cent of patients receiving antipsychotic drugs and is dose-related. Typically it begins within a week or two after starting treatment, being commoner in older patients, especially elderly females. (c) Akathisia is a condition characterised by motor restlessness, a subjective feeling of tension and an inability to tolerate inactivity which gives rise to restless movement. Milder cases present mainly with subjective feelings of inner restlessness, especially referable to the legs. As the condition progresses motor symptoms become evident. Patients typically rock from foot to foot, or walk on the spot when standing and show a coarse tremor of the feet. They may even feel compelled to get up from their chair and walk about. It occurs in some 20 per cent of patients receiving antipsychotic drugs, and comes on within the first few weeks of treatment. (d) Tardive dyskinesia is a chronic syndrome of hyperkinetic involuntary movements which often begins repetitive movements of the lips and tongue, going on to involve the face, jaw and neck, and even the trunk, arms and hands. There would appear to be two distinguishable subtypes. The first, and by far the most common, is referred to as the buccolinguo-masticatory (BLM) syndrome. It ranges from infrequent lateral movements of the jaw

together with puckering and pouting of the lips and slight tongue movements which distend the cheek, to a clinical picture dominated by unceasing movements of the lower face associated with frequent mouth opening and protrusion of the tongue. In the truncal type the limbs and trunk display choreiform movements and myoclonic jerks. Tardive dyskinesia, mainly of the BLM type, has been reported in 10 to 30 per cent of patients suffering from chronic schizophrenia and is commoner in the elderly. It is rarely seen before treatment with one or more antipsychotic drugs has been continuously administered for at least 6 months, and is uncommon before 4 or 5 years. There appears to be an association with previous EPS, as tardive dyskinesia occurs more frequently in patients who have exhibited parkinsonian symptoms or akathisia. Although generally suspected as being a consequence of prolonged antipsychotic drug treatment, stopping treatment may well lead to a sharp exacerbation of the symptoms; and in some patients they are observed for the first time on stopping antipsychotic drugs. Of the many and complex risk factors studied for the development of Tardive Dyskinesia, increasing age and higher neuroleptic dose have the clearest associations. The risk of developing irreversible dyskinesia is such that efforts must be made to use the minimal effective dosage of drugs and for as short a time as possible. It may be masked by high doses of antipsychotic drugs and first appear on reduction or withdrawal of the drug. If possible, antipsychotic drugs should be reduced or withdrawn, and there is usually a gradual, though often incomplete improvement in the dyskinetic

symptoms. Drugs which may be helpful include the dopamine depleting compound tetrabenazine (Nitoman), or GABA agonists such as benzodiazepines or baclofen.

4. Neuroleptic Malignant Syndrome (NMS) is a rare but potentially fatal complication of neuroleptic treatment. The hallmarks of the disorder are hyperthermia, autonomic nervous system dysfunction, and severe extrapyramidal signs. Altered consciousness, and abnormal laboratory investigations such as raised leukocyte count, liver enzymes and creatinine kinase levels, may be present. In a proportion of cases the syndrome continues on to muscle break down (rhabdomyolysis), renal failure and death. This is a medical emergency and urgent treatment is required. Severely psychiatrically ill, medically ill, and those on large doses, are seen as being particularly at risk, especially where there is dehydration. Recommended management includes a thorough search for other causes of fever, stopping neuroleptic drugs, and vigorous supportive measures with particular attention to electrolytes and hydration. Active steps should be taken to reduce body temperature by cooling. The muscle relaxant drug dantrolene and the centrally acting dopamine receptor agonist bromocriptine both appear to reduce recovery time. Cautious reintroduction of antipsychotic drug treatment after an interval of 2-3 weeks can usually be undertaken without a recurrence of NMS.

Skin (a) Allergic rash may appear in the first few weeks. Treat with an antihistamine and change to a different antipsychotic.

(b) Photosensitivity can be a problem in summer, especially with fair skinned patients. Patients should be warned to avoid excessive exposure, and advised to use a barrier cream. As this is most common with chlorpromazine a change to another antipsychotic drug may be necessary. (c) Oculocutaneous pigmentation is seen in patients treated chronically on high doses of phenothiazines. It is a blue-grey discolouration of exposed skin and may be associated with pigment deposits in the cornea, lens and retina. Treatment is by substituting a high-potency drug , but the pigment may take many months to fade.

Cholestatic Jaundice is a rare complication of treatment with phenothiazines, particularly chlorpromazine. The drug should be stopped and liver function tests and a blood screen performed. It is an allergic phenomenon occurring 1-5 weeks after starting the drug, and completely reversible.

6 Convulsions Chlorpromazine, haloperidol and other typical antipsychotics lower the seizure threshold, but epilepsy is not a contraindication to its use. Fits usually occur only with very high doses, and if necessary an anticonvulsant can be added.

Endocrine changes can occur secondary to the rise in prolactin caused by the typical antipsychotics. In women, menstruation may become irregular and, rarely, lactation may occur. Male patients may develop impotence. When changing to an

atypical antipsychotic drug, female patients should be warned about the increased fertility that may accompany this , and take appropriate contraceptive measures.

Leukopenia and/or agranulocytosis occurs in approximately 1% of patients treated with clozapine. Regular monitoring of the blood count of patients taking clozapine is mandatory; weekly for the first 8-12 weeks, monthly thereafter. Treatment should be stopped at any significant fall in the white count. As far as other antipsychotic drugs are concerned such blood dyscrasias are very rare

Cardiovascular effects Prolonged ventricular repolarisation can be found commonly in patients on phenothiazines, and in particular Thioridazine. The significance of these ECG changes remains unclear.

10 Weight gain Weight gain, often amounting to frank obesity, is disturbingly common among patients receiving long-term treatment with antipsychotic drugs, especially patients treated with phenothiazine compounds such as fluphenazine, and certain atypicals such as clozapine and olanzapine. The pathogenesis of this weight gain is not known, but many patients report a marked increase in hunger and an increased consumption of sugar-containing foods, possibly a consequence of 5-HT2 receptor blockade. When weight gain becomes troublesome a low-calorie diet should be instituted.

CLINICAL APPLICATIONS OF ANTIPSYCHOTIC DRUGS (a) PHENOTHIAZINES (i) ALIPHATIC SIDE CHAIN

Chlorpromazine (Largactil) This is the prototype of the phenothiazines, used in all the conditions listed as indications for antipsychotic medication. It is among the more sedative of the phenothiazines and is prone to cause postural hypotension. It carries a higher risk of cholestatic jaundice than other antipsychotics. Its use in anxiety disorders is not advisable as it may result in dysphoric mood and it may also lead to extrapyramidal symptoms.

Dosage 10, 25, 50 and 100mg tablets, syrup 25mg/5ml, injection 50mg/2ml in 2ml ampoules. Suppository 100mg, suspension 100mg in 5ml.

Chlorpromazine is painful and locally irritating as an injection. If used, injection sites must be rotated. In acute psychoses, the initial dose is 400-600 mg/day in divided doses, increasing until symptoms are controlled, then gradually reducing to a maintenance dose of 100-400 mg daily. It is seldom necessary or beneficial to exceed 900 mg daily.

In elderly patients it is wiser to start with smaller doses, as they may be more sensitive to the side effects eg: 25 mg q.i.d. Patients who suffer from daytime drowsiness, or insomnia, maybe given the major dose in the evening.

Other aliphatic side chain phenothiazines Methotrimeprazine (Nozinan) Related to promethazine with which it shares an antihistamine action. It has marked sedative effects which makes it particularly useful in psychotic patients who have significant sleep disturbance. Indications: Useful for controlling anxiety in alcoholics and excited schizophrenics. Also used in pain management.

Dosage:

Tablets Injection

25, 100mg 25 mg/ml

Initial dosage 25 mg daily in mild cases, in severe cases 75 mg daily increasing cautiously to a maximum of 600 mg daily. It may cause marked hypotension.

Side effects: As for chlorpromazine, but extrapyramidal effects are rare. Frequently upsets visual accommodation.

(ii)

PIPERAZINE SIDE CHAIN

Fluphenazine Indications: As for chlorpromazine. Usually given as the depot preparation fluphenazine decoanate where it is useful for longer-term maintenance treatment, particularly in patients non-compliant with oral medication. Side effect: More extrapyramidal side effects than chlorpromazine, but fewer autonomic side-effects and little drowsiness. Jaundice, photosensitivity and agranulocytosis do not occur, though leucopaenia has been reported rarely.

Fluphenazine Decanoate (Modecate) Indications: Chronic schizophrenia. Duration of effect 2-4 weeks.

Dosage:

Injection

0.5 ml ampoules containing 12.5 mg 1 ml ampoules containing 25 mg

Concentrate

1 ml ampoules containing l00 mg

Usual dosage 12.5 mg-25 mg (rarely up to 100 mg), every 2- 4 weeks. The peak serum level is reached after 36 hours. Patients are often aware of when the drug 'wears off' and hence the necessary frequency of injections.

Side effects: Extrapyramidal side-effects, particularly in the first few days after an injection, when anti-parkinsonian drugs may be required. Lethargy and drowsiness may occur in the first few days. Occasionally depressive reactions, with risk of suicide, occur

in schizophrenic patients begun on fluphenazine decanoate, so careful supervision is necessary.

Trifluoperazine (Stelazine) Indications: As for chlorpromazine. May be more useful for withdrawn patients as it is less sedatives.

Dosage:

Tablets

1, 2, 5 mg. capsule 15 mg

Liquid Forte 5 mg/5 ml Injection 1 mg in l ml

Initial dose 5-10mg/day; increases up to 20 mg/day occasionally needed. 5 mg is approximately equivalent to 100 mg chlorpromazine.

Side effects: As for chlorpromazine, but less sedation, hypo-tension or anticholinergic effects. Extrapyramidal symptoms are more common.

Prochlorperazine (Stemetil, Antinaus) This drug is little used in psychiatry being more useful as an anti-emetic, especially in migraine.

iii)

PIPERIDINE SIDE CHAIN

Thioridazine (Melleril, Aldazine) Indications: As for chlorpromazine. May be useful in nonpsychotic disorders, especially as an adjunct in the treatment of agitated depression.

Dosage:

Tablets

10, 25, 50, 100 mg, 200 mg 'Retard'

Solution Suspension

30 mg/ml 3% 50 mg/5 ml 1%

Psychotics 100-800 mg daily, other patients 25-50 mg t.d.s. Geriatric patients, organic psychosis - begin with 10mg t.d.s .

Side effects: As for chlorpromazine but less sedative and much less likely to cause hypotension or extrapyramidal symptoms, so often better tolerated. Must not be used in prolonged high dosage (over 400 mg/day) as it has been reported to cause retinal pigmentation with irreversible damage to vision. Sometimes produces ejaculatory retardation or retrograde ejaculation.

Pericyazine (Neulactil) Indications: As for chlorpromazine. Its marked sedative effects may be useful in inhibiting aggression, impulsive acting-out behaviour and severe tension and anxiety states.

Dosage:

Tablets Syrup

2.5, 10 mg 2.5 mg/5 ml Forte syrup 10 mg/5 ml

For behaviour disorders use 5 to 20mg daily, for psychoses 20 to 60 mg daily.

Side effects: As for chlorpromazine, but jaundice and agranulocytosis not reported.

Pipothiazine decoanate (Piportil) Indications: Chronic schizophrenia. A long acting injectable phenothiazine, duration of action 3-6 weeks.

Dosage:

50 mg/ml, 1 ml and 2 ml ampoules Usual dosage 50-100 mg every 3-6 weeks (Generally given every 4 weeks), recommended maximum 200 mg every 4 weeks.

Side effects: Extrapyramidal reactions are the most frequent. Occasionally depression and orthostatic hypotension may occur.

(b) OTHER TYPICAL ANTIPSYCHOTIC DRUGS (i) BUTYROPHENONES

Haloperidol (Serenace) Indications: As for chlorpromazine. Useful in the treatment of excited schizophrenic states, mania and organic psychoses and acute psychoses in medically ill patients. Worth trying in patients with Gilles de la Tourette's Syndrome, severe tics. spasmodic torticollis and stuttering. Use in low dosage in anxiety not recommended as limited by extrapyramidal side-effects. Haloperidol potentiates the effects of analgesics so may be useful in treating severe pain

Dosage:

Tablets Injection Liquid

0.5, 1.5 and 5 mg: 5 mg in 1 ml 2 mg/ml.

2 mg haloperidol is approximately equivalent to 100 mg chlorpromazine.

For the treatment of an acute psychotic episode haloperidol in doses greater than 10mg has been shown to have no corresponding therapeutic advantage. Even lower doses may be effective. Haloperidol is not particularly sedating - if required a sedative may be added (page 59) or another antipsychotic such as chlorpromazine used instead (not as well as). Haloperidol has a high incidence of parkinsonian side-effects; these are usually readily controlled by the anti-parkinsonian drugs. The oral dose for patients who have been on an I.M. regime is 1/2-2 times the 24 hour total with 1/3 of the dose given at night. Usual

maintenance oral doses are 3-12 mg daily. 1 mg/day may occasionally be helpful for patients with anxiety disorders.

Side effects: No hepatic or leucopaenic effects, little drowsiness, no hypotension, anticholinergic effects or photosensitivity. Occasional excessive salivation, sweating and hyperpyrexia have been reported. The combination of haloperidol and lithium has been reported to be associated with an acute encephalopathy, though this seems to be very rare. Extrapyramidal reactions are common, even at low doses and adolescents are particularly susceptible. Haloperidol is only slowly eliminated from the brain, with residual side-effects continuing for many days. Thus antiparkinsonian drug should be continued for a week or more after the drug is stopped.

Haloperidol decanoate (Haldol) Indications: Long-acting depot haloperidol for the maintenance treatment of chronic psychoses.

Dosage:

50mg/ml, 1ml and 5ml.

Given 4-weekly. 50-100mg for mild symptomatology, 150- 200mg for moderate symptomatology. The daily dose of oral haloperidol x 10 - 20 = the approximate monthly dose of haloperidol decanoate.

Droperidol (Droleptan) A short-acting butyrophenone with rapid onset. It is similar to, but more sedative then, haloperidol. Used mainly in the management of disturbed patients. Dosage: Tablets Injection 10 mg 2.5mg/ml 10 mg/2 ml

Neuroleptic dose orally 10-25 mg daily. Injection 5-25 mg I.M. 4-6 hourly.

(ii)

THIOXANTHENE DERIVATIVES

Thiothixene (Navane, Thixit) Indications: As for chlorpromazine, but has little sedative effect and may be particularly beneficial in the withdrawn patient.

Dosage:

Tablets Injection

2 mg, 10 mg 4 mg in 2 ml

Usual dosage 10 mg mane, increasing if needed up to 60 mg daily. 5 mg is approximately equivalent to 100 mg chlorpromazine. Thiothixene has been used for parenteral regimes for the control of acutely disturbed patients, the usual dosage being 8 mg initially (range 4-20 mg), repeated hourly. However, a more sedative drug is often more useful.

Side effects: As for chlorpromazine, but hepatic and erythropoietic effects not reported. No photosensitivity. Patients who are anxious or excitable may find that thiothixenes relatively activating effect increases their agitation, and trifluoperazine or another more sedative drug may be more appopropriate.

Zuclopenthixol acetate (Clopixol acuphase) A single injection of 50-150mg produces a rapid reduction in psychotic symptoms which persists for over 72 hours. Useful in emergency treatment.

Flupenthixol decanoate (Depixol) Indications: Maintenance treatment of chronic schizophrenics, especially those who are withdrawn or apathetic. It has also been reported to have an antidepressant action.

Dosage:

Depot injections

20 mg/ml, 100mg/ml

20-100 mg over 2-4 weeks, up to a maximum of 100 mg weekly, by deep l M. injection.

Side effects: As for thiothixene. Extrapyramidal side effects are the most common. Antiparkinsonian medication may be required, especially in the first few days after injection. Is said to cause less depression of mood than fluphenazine.

(iii)

DIPHENYLBUTYLPIPERIDINES

Pimozide (Orap) Indications: Chronic schizophrenia. A more specific D2 blocker, reputed to have greater impact on negative symptoms. Not as useful for acute phases. Said to have specific effects in monodelusional psychosis.

Dosage:

Tablets

2 mg, 10mg

Initial dose is 2 mg mane increasing up to 10 mg if necessary. The maximum dose should not exceed 20mg/day. Increases in dose should be made in doses of 2-4mg/day, at weekly intervals. Because of its relatively long half-life of 50 hours it may not need to be given more frequently than once every 3-4 days.

Side effects: Remarkably free of extrapyramidal side effects. There may be prolongation of the QT interval on the ECG. It is recommended that an ECG be performed before treatment and periodically during treatment. If ECG changes occur, treatment should be reviewed and dosage reduced. Pimozide is contraindicated in patients with a history of cardiac arrhythmias or congenital prolonged QT intervals.

(iv)

DIBENZOXAZEPINES

Loxapine (Loxapac) Indications: Management of psychotic disorders. Effective with acute and chronic symptomatology in schizophrenia. May also be useful in the management of aggressive behaviour disorders, including in the elderly. Has some 5-HT2 blocking action and therefore might be more properly be classified as an atypical antipsychotic.

Dosage:

Capsule

50mg

Orally, give in divided doses twice daily. Initial dose 50mg once daily, increasing over 7-10 days until there is effective control. Usual therapeutic range 50mg to 100mg per day.

Side effects: Extrapyramidal effects occur. Use with extreme caution in patients with a history of convulsive disorders.

(c) ATYPICAL ANTIPSYCHOTIC DRUGS (i) DIBENZODIAZEPINES

Clozapine (Clozaril) Indications: Clozapine has weak dopamine D2 receptor blocking activity, but blocks D1, 5-HT2 and NA alpha2 autoreceptors. It produces rapid and marked sedation, and has strong antipsychotic effects. Due to potentially serious side effects (below), the use of clozapine should be reserved for schizophrenic patients resistant to standard treatment.

(see above), up to 50% of whom can improve with clozapine. It is the only available antipsychotic in which efficacy in otherwise drug-resistant patients has been convincingly demonstrated.

Dosage:

Tablets

25mg and l00mg

Initial recommended dose is 25mg to 50mg per day gradually increasing to 300mg per day in divided doses over 14-21days. Usual therapeutic dose range 300-600mg per day. Recommended maximum dose 900mg/day. Maintenance dose 150-300mg/ day.

Side Effects:

WARNING: Because of the association of clozapine with a fall in the

white blood cell count (leucopenia), in some 5% of patients, which can go on to potentially fatal agranulocytosis in up to 1%, patients should have normal leucocyte counts before therapy. The risk of leucopenia is increased in the elderly. On starting treatment close monitoring is required, with weekly leucocyte counts for the first 18 weeks of treatment, and monthly counts thereafter. In addition, clozapine should not be used in association with any other medicines likely to cause leucopaenia. At any sign of infection a further white cell count should be done as soon as possible and clozapine stopped if it has fallen.

During the first period of treatment, transient autonomic side effects such as increased salivation and a rise in body temperature may occur. Clozapine produces few extrapyramidal re-actions. Weight gain, often leading to clinical obesity, can prove a

problem. This may lead to poor compliance and increase the risk of non-insulin dependent diabetes.

(ii)

BENZISOXAZOLES

Risperidone (Risperdal) Indications: In the initial treatment of first-episode schizophrenia and as an alternative treatment for patients unable to tolerate typical antipsychotics because of side-effects. Blocks D2 and 5-HT2 receptors.

Dosage:

Tablets Solution

1, 2, 3, 4 mg 1 mg/ml

For psychosis start at 2mg daily, increase to 4-6mg daily. Geriatric patients start with 0.25mg twice daily. Adjust no more frequently than every other day up to the optimal dosage of 0.5mg twice daily. Maximum dose 1mg bd.

Side Effects: Although less prone to cause EPS than haloperidol, EPS do occur at higher doses. It can produce sedation and orthostatic hypotension.

(iii)

THIENOBENZODIAZEPINES

Olanzapine (Zyprexa) Indications: In the treatment of acute schizophrenia and the prevention of relapse. It bocks a wide variety of receptors with high 5-HT2 : D2 ratio. It may be more effective

than risperidone, but if true, this has to be weighed against its greater propensity to cause weight gain.

Dosage:

Tablets

2.5, 5, 10 mg.

Initial recommended dose is 5-10mg daily, increasing to 10-20mg per day according to clinical response.

Side Effects: The main side effects are sedation and weight gain.

(iv)

DIBENZOTHIAZEPINES

Quetiapine (Seroquel) Chemically related to clozapine but with far less risk of leucopenia. Has a wide spectrum of pharmacological actions, blocking D2 and 5-HT2 receptors plus an action on histaminergic and adrenergic receptors. As effective in schizophrenia as standard antipsychotics but with a significantly lower incidence of extrapyramidal side effects.

Dosage:

Tablets

25 mg, 100mg, 200mg

Doses should be increased gradually over several days, starting with 25mg and progressing to 300-450mg daily using a starter pack. Women of child-bearing age,

switching from a typical antipsychotic to quetiapine, should be warned that their fertility may be increased as it does not cause the same rise in prolactin levels.

Side Effects: Headache, somnolence and dizziness are the most common.

Anti-Parkinsonian Drugs

Extrapyramidal side effects often occur with the typical antipsychotic drugs (see above) and to some degree with risperidone. The first step is to adjust the dose to the lowest effective dose. Another strategy is to switch to another, atypical antipsychotic ( see above). However, as it is often necessary to continue medication with a depot (typical) antipsychotic in patients above the threshold of extrapyramidal manifestations, antiparkinsonian drugs may be given to control these side-effects. With these precautions anti-parkinsonian drugs have a place in the treatment of extrapyramidal side-effects of antipsychotic drugs. The prophylactic administration of anti-parkinsonian drugs when the antipsychotic medication is begun, and before any extrapyramidal side-effects have appeared, remains controversial. Certainly a high proportion of patients may gradually come off anti-parkinsonian drugs after 2 to 3 months, whilst still taking the previous dose of tranquilliser. Elderly females are less likely to be able to do so. On the whole it is probably best to use these drugs only when extrapyramidal side-effects appear.

Extrapyramidal effects, especially akathisia, can be particularly distressing; it may be misinterpreted as an increase in psychotic activity. It is wise to warn patients (and their relatives) of these side effects and to give a small quantity of an anti-parkinsonian drug to be used if needed. Some patients on depot anti-psychotics find that they need antiparkinsonian drugs the first week or so following an injection.

As most of the anti-parkinsonian drugs are anti-cholinergic agents (see below) there is a risk of summation when prescribed with anti-psychotic drugs with similar side-effects (eg trifluoperazine). This can rarely result in a toxic psychosis which, if it occurs, may be treated with physostigmine.

Anticholinergic Anti-parkinsonian Drugs There is little clinically significant difference between the drugs in this group. They can all adversely affect memory in the elderly. They should be used at as low a dose as possible and for the shortest possible time. They have been suspected of having a mild euphoriant effect which has led to misuse by some patients. They have no place in the treatment of tardive dyskinesia, may even exacerbate it.

Benztropine mesylate (Cogentin) An anticholinergic with antihistamine properties. Dosage: Tablets Injection 2 mg 2 mg/2 ml I.V. or I.M.

Usual dose 1 to 3 tablets daily.

Orphenadrine (Disipal)

Dosage:

Tablets Injection

50 mg (Disipal), 100 mg 60 mg (Norflex)

Usual dose 100 to 300 mg daily, in divided doses.

Procyclidine (Kemadrin)

Dosage:

Tablets

S mg

Usual dose 7.5-60 mg daily.

Others Promethazine (Phenergan)

Dosage:

Tablets Injection

10 mg and 25 mg 25 mg/ml

Usual dose 25 mg q.i.d. It has mild antipsychotic anti-emetic and anti-histamine effects. It is a phenothiazine which paradoxically acts also as an anti-parkinsonian drug. Its sedative effect and its ready availability by injection make it useful for the acutely disturbed patient with extra-pyramidal symptoms.

Amantadine (Symmetrel)

Dosage:

Capsules

100 mg

Usual dose 200 mg daily. This drug can be quite useful for a patient who is otherwise resistant to treatment for drug-induced parkinsonism and may be better tolerated in the elderly.

Propranolol (Angilol, Cardinol) A beta adrenergic recptor blocking drug reported to be effective in reducing akathisia.

Dosage:

Tablets

10 mg, 40 mg, 160 mg

Initial dose of 40 mg twice daily, increasing to 160 mg daily.

Chapter 2

DRUG TREATMENT OF MAJOR AFFECTIVE DISORDERS

a) b)

Antidepressants Drugs used in Mania and Mood stabilisers

(a) ANTIDEPRESSANTS i) General

The affective disorders, also referred to as mood disorders, are those conditions in which there is alteration of mood to such a degree as to cause serious distress or disruption of normal life. The mood may be abnormally elevated as in mania, or lowered as in depression. Depression may either be a symptom of reaction to adverse circumstances, or an illness in its own right. When the change in mood is severe and persistent it falls into the category of major depressive episode (MDE), which usually warrants treatment with an antidepressant drug.

MDE are believed to be related to changes in neurochemical pathways within the brain, particularly those associated with noradrenaline and/or serotonin. The currently available antidepressant drugs all act by enhancing neurotransmission in one or other, or both, of these pathways which arise from groups of specialised neurones located in the brainstem and are widely disseminated to areas of the cerebral cortex in the frontal and temporal lobes.

Antidepressants can classified according to their pharmacological action within these pathways: 1) Inhibition of reuptake of monoamines into the presynaptic neurones (monoamine reuptake inhibitors [MARI]) a) Non-selective inhibitors of monamine (serotonin and noradrenaline) reuptake b) Selective serotonin reuptake inhibitors (SSRI) c) Selective noradrenaline reuptake inhibitors (NARI) 2) Stimulation of presynaptic autoreceptors 3) Inhibition of the enzyme, monamine oxidase, which inactivates monoamines in the brain (monamine oxidase inhibitors [MAOI])

There is little significant difference between the various groups of antidepressant drugs in their overall efficacy; in most clinical trials about 60-65% patients respond to some degree although less than 50% achieve full remission within the 6-8 weeks of most trials. Some subcategories of depression respond to particular types of antidepressants better than others. For example, the non-selective MARI are thought to be more effective than SSRI in patients with the more severe, melancholic type, and MAOI better in atypical depression with reversed vegetative symptoms (ie hypersomnia and hyperphagia). Recent studies suggest that, whatever the particular mechanism whereby monamine neurotransmission is enhanced, they all increase the level of neuroprotective proteins within the forebrain and limbic system. This is also true for ECT.

Principles of Use: Optimal use of anti-depressant drug therapy involves the basic requirements of having the right diagnosis, the right drug and the right dose. More than forty years of clinical experience have substantiated Kuhn's original observation that it is when 'vital' signs of depression are present - lassitude, feelings of depression and inhibition, a slowing down and difficulty in thinking and acting, of internal tension and the inability to feel pleasure the whole picture subject to diurnal fluctuations with exacerbation in the morning' that drug therapy is likely to be effective. Additional symptoms in major depression are sleep and appetite disturbance, impaired concentration, feelings of guilt and worthlessness, suicidal thoughts and impulses. Although this rule is not universally reliable, and there may be a place for a therapeutic trial in the absence of an endogenous pattern, it remains the surest guide to appropriate use. Antidepressants generally take 10 to 14 days before noticeable improvement occurs.

In the outpatient setting, many patients present with complaints of anxiety and often illdefined somatic symptoms rather than complaining of 'depressed mood', such patients should be questioned carefully about other symptoms of depression and if these are present, appropriate antidepressant treatment begun.

Many factors enter into the choice of which drug to choose first. None are absolute and perhaps the most important is that the physicians should first prescribe those drugs with which they are most familiar. The aim of treatment is to alleviate the depression and, as we have seen, for patients with a MDE of moderate severity, none of the antidepressants offer any real significant advantage in effectiveness. Drug choice is thus often more

affected by what the prescriber wishes to avoid in the way of side-effects, suicide risk, abuse potential or other special considerations. It should be noted that many

antidepressants are highly toxic to children and patients should be advised to store them safely at home. Patients also need advice about the use of alcohol and driving,

particularly while on a sedative antidepressant.

Some guidelines for treatment in selected patient groups are: 1 The Elderly Here depression is often complicated by the physiological effects of aging with reduced liver and renal function concurrent medical illness, other medications and degrees of mental confusion. Drug regimens should be kept simple and starting doses should be low (about half the recommended initial dose), increased slowly and with frequent monitoring of side effects. The use of SSRIs and moclobemide have increasingly been used for first line treatment due to their low toxicity and lack of anticholinergic side-effects. SSRIs may cause hyponatraeuria and serum sodium should be monitored in the elderly.

Patients with a high suicide potential When this is judged to be high, small quantities of an antidepressant drug with low toxicity, such as paroxetine, nefazedone, fluoxetine, or moclobemide should be prescribed initially.

Depression with anxiety Here, the SSRI may have an advantage

Obsessional Symptoms with Depression SSRIs and Clomipramine have been found to be useful in OCD and may offer an advantage.

Severe depressions with psychotic features Treatment with a combination of antidepressant and antipsychotic is often required. With amelioration of the underlying depression the antipsychotic can usually be tapered off.

Resistant depression There are a number of strategies which help patients who fail to respond within 4-6 weeks to treatment with an antidepressant at the recommended dose : (a) Increase the dose to within the limits of tolerability (b) Switch to an antidepressant of a different pharmacological class (c) Try a combination of antidepressants but, remember, the simultaneous prescription of an SSRI and a TCA can lead to elevated plasma levels of the TCA with resultant toxicity (d) Add lithium. This has been shown to improve about a third of patients with resistant depression in clinical trials. It requires careful monitoring of the plasma level of lithium (e) Add thyroid hormone. This requires monitoring of thyroid status, as, in the first instance, the addition of thyroid leads to feedback inhibition of endogenous thyroid production.

i) Non-selective inhibitors of monoamine reuptake

A. Inhibitors of serotonin and noardrenergic reuptake. a) Tricyclic antidepressants (TCA)

Imipramine, the first compound found to effective in the treatment of MDE was introduced into clinical practice almost 50 years ago. Following this a number of other TCA have appeared (see below). None seems be more effective than imipramine. Where they differ is in their side-effect profile. As with other antidepressants, some 60-65% of patients respond over a period of 2-3 weeks. The first drugs in this group to be introduced into clinical practice, imipramine and amitriptyline while effective, are prone to cause pronounced anticholinergic side effects such as dryness of the mouth, constipation, difficulty in micturition which can lead to urinary retention in men with prostatic hypertension and difficulty in visual accommodation. Other untoward effects include postural hypotension and excessive sweating. Amitryptyline causes weight gain, secondary to its appetite-stimulating effect. More dangerous, especially in overdose or in patients with a pre-existing heart disease, are the cardiotoxic properties which some of these drugs possess. Amitriptyline is the most likely to cause problems in this respect; it is not uncommon to find a prolongation of the Q-T interval, which can proceed to a frank dysrhythmia or ventricular tachycardia, which in cases of overdose occasionally progresses to fatal ventricular fibrillation. In the elderly, congestive cardiac failure is not uncommon. In addition to these autonomic and cardiac effects, the tricyclics are epileptogenic and may precipitate epileptic seizures, especially in those who are predisposed. In view of all these possible side effects, tricyclic (MARI) drugs should be used most cautiously in patients with glaucoma, prostatism, chronic heart disease and epilepsy. Furthermore, overdose with TCAs leads to loss of consciousness in 1-3 hours with

catastrophic fall in blood pressure, cardiac arrhythmias. epileptic seizures and death if not adequately treated. Because of the dangers associated with overdose and the frequency of untoward side effects TCA have been largely superseded by SSRI as the first line treatment for a MDE.

Amitriptyline is discussed as the prototype together with its side effects and their treatment. Individual drugs and their differences are discussed later.

Amitriptyline (Amitrip, Tryptanol)

Indications: Major depressive episode. It is especially suitable for the agitated depressive as it has a tranquillising and sedative action as well.

Tablets Capsules Syrup

10, 25, 50 mg 75 mg 10 mg/5 ml

Dosage: Initial dose of 50mg nocte, increasing to a total daily dose of 150 mg. If necessary, dose may be increased to 300mg daily.

Side effects and their treatment

Medical contra-indications: The usual cautions regarding renal and hepatic disease apply. Tricyclics are best avoided in patients suffering from prostatic hypertrophy as acute retention may be induced.

Considerable care must be taken when giving tricyclics to patients with known cardiac disease because of their tendency to either produce or aggravate arrhythmias, a fact which is often overlooked or ignored. Doxepin is the choice in these patients if a TCA is to be used but generally a SSRI would be chosen first.

Anti-cholinergic side effects: These are extremely common and the patient is best forewarned of them. Dryness of mouth, constipation and blurring of vision are the most frequent. They may be irksome, but the patient is far more likely to tolerate them if the possibility is known and it is pointed out that they are a harbinger of relief from depression and likely to resolve in a few weeks. Toxic Psychosis, although uncommon, is important as it is a serious condition, often misdiagnosed as D.T.'s, severe psychosis or organic brain syndrome and is poorly treated, despite a specific remedy (physostigmine, (see page.), being available. Manifestations of these side- effects, together with additional suggestions for alleviation are:

(a) Postural hypotension: This is common in the first few weeks of treatment and blood pressure usually returns to normal in a month. The patient should be advised to get slowly out of bed or up from chairs and to avoid standing in one position for too long. Hot baths are best avoided. This can be especially troublesome in the elderly.

(b) Blurred vision: If pilocarpine eye drops are ineffective and the dose of tricyclic cannot be reduced, compensatory glasses may rarely be needed.

(c) Dryness of the mouth: This is very common. Sucking peppermints or other confectionery is not advisable as it leads to tooth decay. Swabbing the gums with glycerine two or three times a day is useful.

(d) Constipation: This often improves as depression is alleviated. A decrease in frequency of bowel motions does not usually matter and the patient should be assured of this. Bulk laxatives may be helpful.

(e) Paralytic ileus: This is rare but serious. The drug should, of course, be stopped and the patient admitted to hospital for appropriate treatment.

(f) Sexual dysfunction: Impotence and delayed ejaculation are reported occasionally. Normal function returns in a few months. Occasionally an alternative drug may be needed.

(g) Excessive sweating: Flushing with marked sweating is not uncommon. There is no satisfactory treatment apart from stopping the drug.

(h) Toxic psychosis (Atropine psychosis, anticholinergic psychosis): This presents as an acute brain syndrome, with marked visual hallucinations, flushed skin, dry mouth and thirst and rapid pulse. ('Red as a beet, dry as a stone, blind as a bat and mad as a hatter.') It may be reversed rapidly by intravenous or intramuscular physostigmine 2 mg. This is a pro-cholinergic drug which passes the blood brain barrier. The offending drug must be stopped and if the condition is due to over-dosage, (see page for the management of overdoses) a stomach wash-out performed. The physostigmine usually needs to be repeated about every 2-3 hours, depending on the mental condition of the patient. Other rough guides to the efficacy of treatment are pulse and salivation rate. The psychosis may need to be treated for several days.

Tremors, muscle twitching, hyper-reflexia and extra pyramidal symptoms: Often a fine tremor of the hands is found. The more gross motor manifestations are uncommon and frequently do not respond to anti-parkinsonian drugs. The tricyclic should he reduced if possible.

Euphoria and mania: This may be managed by ceasing the anti-depressant. Such patients are probably bipolar and lithium treatment should be seriously considered. A major tranquilliser may be temporarily useful.

Seizures: The seizure threshold is lowered and epileptic patients may need increased doses of anti-convulsants.

Oedema: Unusual forms of oedema are occasionally seen. Diuretics are usually effective.

Weight gain: This may be due to the appetite being improved as the depression lifts. Simple dietary restrictions are advised. Anorexiant drugs are not indicated. If a problem, consider changing to fluoxetine, paroxetine, clomipramine or moclobemide. Weight Gain - Often a feature of older TCAs and a major cause of noncompliance in young women. SSRIs with Clomipramine have either nil or negative effects on weight. In the patient who has lost a lot of weight as a consequence of their depression, Doxepin often encourages weight restoration.

Paraesthesias: Uncommon, may be treated with Vitamin B complex tablets I b.d.

Jaundice, liver damage and agranulocytosis: Isolated reports have appeared, but these side effects are exceedingly rare.

Imipramine (Imipramin)

Indications: As for amitriptyline. It is useful in treating juvenile enuresis. Said to cause less confusion in the elderly.

Tablets Capsules

10, 25 mg 50 mg sustained release

Dosage: In depression 100 to 300 mg daily may be needed. For enuresis 25-75 mg nocte is given.

Side effects: As for amitriptyline, but less sedative and less weight gain. Rarely itching, rashes and photosensitivities may occur.

Clomipramine (Anafranil, Clopress) [Retail pharmacy specialist]. Has a greater inhibitory effect on serotonin reuptake than other TCA which probably underlies its usefulness in OCD.

Indications: As for amitriptyline. It is also useful in phobic and obsessional disorders. Specialist endorsement required.

Tablets

25 mg

Dosage Range: 100 to 300 mg daily.

Side effects: As for amitriptyline. Some patients suffer from headache and muscle aches after the first dose. This usually disappears after a couple of days, with continuance of

the drug. It should not be used in combined antidepressant treatment. A delay of 1 week is advised before using MAOIs.

Dothiepin (Prothiaden, Dopress)

Indications: As for amitriptyline.

Capsules Tablets

25 mg 75 mg

Dosage Range: 75 to 225 mg daily.

Side effects: As for amitriptyline, lower anti-cholinergic effects.

Doxepin (Sinequan, Anten)

Indications: As for amitriptyline. It also has an anxiolytic action helpful in the agitated patient. Encourages weight gain.

Capsules Tablets

10, 25, 50 and 75 mg 10, 25 and 50 mg

Dosage: As for amitriptyline.

Side effects: Similar to but less severe than amitriptyline. Less cardiotoxic than most tricyclics.

Nortriptyline (Allegron, Norpress)

Indications: As for amitriptyline. May be less sedative.

Tablets Liquid

10 mg and 25 mg 10 mg/5 ml

Dosage: Usual range 100 to 300 mg daily. Required doses may be less than for amitriptyline.

Side effects: As for amitriptyline.

Trimipramine (Surmontil, Tripress)

Indications: As for amitriptyline, but especially where sleep disturbance is a presenting symptom. Tablets Capsule 25 mg 25mg and 50 mg

Dosage: Doses as for amitriptyline, but more sedative. Said not to suppress REM sleep.

Maprotiline (Ludiomil) [Retail Pharmacy specialist]

Indications: A quadricyclic drug, as for amitriptyline.

Tablets

25 and 75 mg

Dosage: Usual range 75 to 200 mg daily.

Side effects: As for amitriptyline. In high dose has significant epileptigenic effect. Low cardiotoxicity.

Mianserin (Tolvon) [special authority only] Indications: a) Approval granted for treating depression only in those patients: - who have failed trials with other antidepressants and who have been maintained on Mianserim prior to 1993; or - with co-existent bladder neck obstruction or cardiovascular disease. b) Specialist must make application - psychiatrists only.

c)

Prescription must be written by a psychiatrist.

Tablets

10 mg and 30 mg

Dosage Range: 30 to 120 mg daily.

Side effects: Drowsiness may occur initial]y. Claimed to have little or no anticholinergic effects and little cardiotoxicity. White cell suppression has been reported in 1 in 1015,000, requires monitoring of blood count regularly.

(b) Non-tricyclic, dual-action reuptake inhibitors of seotonin and noradrenaline Venlafaxine (Effexor) [special conditions, specialist only] A potent inhibitor of serotonin and noradrenaline reuptake and a weak inhibitor of dopamine reuptake with no anticholinergic properties. Possible faster onset of action than other antidepressants.

Indications: Major depressive episode.

Dosage:

Tablets Sustained release

25, 37.5, 50, 75, 100mg 75mg

Dosage range: Starting dose 75mg/day in divided doses. Can be increased in increments of 75mg/day no more frequently than every 4 days, up to a maximum 350mg/day Side effects: Nausea and other gastrointestinal symptoms.

Mirtazepine (

Enhances central noradrenaline neurotransmission by blocking pre-synaptic alpha-2 autoreceptors and enhances serotoninergic neurotransmission by direct stimulation of serotonin neurones. As effective as other antidepressants, with possibly a faster onset of action.

Dosage:

Tablets

mg

Start at 15mg daily; can increase up to 45mg daily.

Side effects: Dry mouth, somnolence, an increase in appetite and weight gain are the most commonly reported side effects. Neutropenia has been reported and it is recommended that mirtazepine is stopped in any patient developing signs of infection with a low white blood cell count.

B. Inhibitors of noradrenaline and dopamine reuptake Buproprion (Wellbutrin) Related to the stimulant anorectic compound diethylproprion and has more stimulant activity other antidepressants. This presumed to be secondary to the enhancement of dopaminergic neurotransmission. Is prone to cause seizures.

Indications: Depression

Dosage:

Tablets

100mg

Commence with 100mg bd. Increase in 100mg steps not more frequently than every 3 days to a maximum of 150mg tid.

Side effects: Restlessness, insomnia and agitation. An increased risk of halucinations and/or delusions. Can precipitate mania in the predisposed. Weight loss.

ii)

Selective monamine reuptake inhibitors

a) Selective serotonin reuptake inhibitors (SSRI) Selective serotonin reuptake inhibitors (SSRI) are now generally accepted as the treatments of first choice in depression and anxiety-depression states. Their major advantages over the standard tricyclic MARI lie in their lower propensity to cause anticholinergic side-effects (dry mouth, constipation, postural hypotension) , and their

absence of cardiotoxicity which leads to greater safety in overdose. They are also less likely to cause impairment in psychomotor function, making them less prone to cause cognitive problems, particularly in the elderly. They are not more effective than the tricyclic MARI, nor do they act more quickly They tend to have a more simple dosage schedule, usually one single dose in the morning. This, along with fewer troublesome side effects, is said to improve compliance . Most are available for GP prescribing but some require specialist authorisation. In New Zealand, fluoxetine (Prozac), paroxetine (Aropax) and citalopran (Cipramil) are subsidised and available on GP prescription. Other SSRI, such as sertraline (Zoloft), attract no subsidy and can only be prescribed on a named patient basis.

Clinical opinion differs as to whether Nefazodone (Serzone) is a SSRI or not. It is chemically unrelated to the other SSRIs and exerts dual effects of serotonergic neurotransmission through blockade of serotonin type 2(5-HT2) receptors plus inhibition of serotonin re-uptake. As it has similar therapeutic effects to the SSRI PHARMAC lists Nefazodone under this category in the Pharmaceutical Schedule. Unlike other SSRI Nefazodone requires a twice daily dosage schedule because of its shorter half-life. It is available on specialist recommendation.

Patients may exhibit a specific response to the different SSRI; if there is a poor clinical response to the first trial of medication, it is certainly worth trying an alternative SSRI. There have been reports of patients having a dramatic improvement in mood, outlook and even according to some, a change in personality. This form of response is rare but has

certainly been observed and may be due to a longstanding dysthymic disorder which has responded to the SSRI.

Serotonin Syndrome: A syndrome which includes symptoms of tremor, myoclonus, diarrhoea, confusion, hypomania, agitation, hyper-reflexia, shivering, incoordination, fever and diaphoresis has been reported following treatment with all serotonin enhancing drugs. These include L-tryptophan, MAOI, SSRI and TCA, especially clomipramine. Because of their selective effect on serotonin the SSRI may have a higher incidence of serotonin syndrome. Its occurrence is rare but, when it occurs the medication should be immediately discontinued and appropriated supportive measures taken.

SSRI currently available in New Zealand are:

Fluoxetine (Prozac 20, Fluox, Lovan)

Indications: Fluoxetine is indicated for the treatment of depression and its associated anxiety. It has low incidence of the anticholinergic side-effects seen with TCAs and is apparently safe in over-doseage. It is of equal efficacy to the TCAs as an antidepressant and does not stimulate weight gain so is particularly useful in depressed patients with concurrent eating disorders. Useful in the elderly because of simple dosage schedule, low side effect profile and margin of safety. Tablet Capsules 20 mg 20mg.

Dosage: Usual dose is 20mg mane. If no response after 4 weeks may increase to 40mg mane. Probably no indication to go above 40mg daily although higher doses appear safe. Effective daily dose may be as low as 10mg. May be taken with or without food. Fluoxetine has been shown to be effective in the treatment of OCD and Bulimia Nervosa where the therapeutic dose is 60 mg mane. As the half life is long there is no need for divided doses.

Side Effects and Cautions: Whilst being almost totally free of anticholinergic, cardiovascular and antihistaminic side-effects, fluoxetine does have a side effect profile of its own. The most troublesome side effects are nausea, headache, nervousness, insomnia. These tend to be limited to the initial period of treatment but can be sufficiently troublesome to warrant discontinuation. Another common side effect, which is often not volunteered, is lowered sexual interest and reduced inability to reach orgasm.

Because of the long half-life of fluoxetine and its active metabolites five weeks should elapse between discontinuation of fluoxetine and commencement of a non-reversible MAOI. Combined use should be avoided. Caution should be exercised when using fluoxetine with a TCA or lithium as it has been known to significantly increase serum levels of these drugs. Hyponatremia can occur, particularly in the elderly.

If sleep disturbance is a persistent problem a small dose of a sedative TCA may be added at night (eg trimipramine 25 mg or amitriptyline 25 mg). The combined use of SSRIs

and TCAs has been criticised by some authorities who state these drugs should never by used together, however so long as one is aware the blood level of the TCA may be doubled by the SSRI the judicious combination as recommended above is clinically useful and apparently safe.

Historical note: Fluoxetine was released in the USA in December 1987 and rapidly became the most prescribed antidepressant drug because of its efficacy and low incidence of side effects. Widespread concern and much legal activity was stimulated by an article in the American Journal of Psychiatry (Feb 1990) suggesting that fluoxetine induced patients to become both suicidal and homicidal. To date investigations by the FDA and the CSM in Great Britain have not substantiated these claims and both organisations are continuing to support the safety of fluoxetine. On current evidence there is rarely need for concern on this score.

Paroxetine (Aropax) A selective serotonin reuptake inhibitor similar to fluoxetine but with a shorter half-life and a more powerful auxiolytic action. Useful in OCD and Panic Disorder.

Tablets

20 mg

Dosage:

Depression and Anxiety: usual dose 20 mg mane, upper limit 60 mg.

OCD: 40 mg mane but may need to increase to 60 mg mane. Can be taken on tid schedule if patient finds the post-dose sedation helpful. Panic Disorder, agoraphobia: 40 mg mane but usually necessary to increase to 60 mg daily. The mean half-life of paroxetine is 20 hrs.

Side effects:

Similar to fluoxetine but may cause some sedation. Can be troublesome

with regard to sexual function by inhibition of orgasm especially in males. Generally this side effect is not volunteered spontaneously and should be enquired about at follow up.

Paroxetine does not appear to increase serum lithium levels in the way that fluoxetine does.

Levels in breast milk are found to be similar to serum levels so should not be used or used with caution in breastfeeding mothers.

A withdrawal syndrome has been noted in a significant percentage of patients discontinuing paroxetine. It is usually mild and generally passes in a few days. Symptoms include nausea, flu like symptoms, a sensation of small electric shocks in the periphery, tremor and anxiety as well as a wide variety of other minor discomforts. Withdrawal symptoms can be lessened or avoided by tapering the dose to 10 mg for several weeks before discontinuing.

Citalopram (Cipramil) Citalopram is the most selective serotonin reuptake inhibitor (SSRI) yet described with no or minimal effect on noradrenelin, dopamine or gamma aminobutyric acid uptake. Tablets 20 mg

Dosage: 20 mg daily with increases at 2 - 3 week intervals to a maximum of 60 mg daily (40 mg daily in elderly). Citalopram is indicated for the treatment of depression. It has been found useful in the treatment of social phobia. As with other SSRIs it should not be used in combination with MAOIs. A 14 day washout period should be allowed for patients taking MAOIs previously and a 7 day period allowed between discontinuing citalopram and beginning MAOIs.

The side effect profile is similar to other SSRIs with nausea, somnolence, increased sweating headache and tremor being the most common.

Experience in overdose suggests a wide margin of safety.

Safety in pregnancy is not established. Citalopram is found in breast-milk in very low concentrations suggesting it may be useful in breastfeeding mothers if used with caution. The effects on the infant are not known.

Nefazodone (Serzone) [Retail pharmacy specialist] Has a double action on serotonin, both of which enhance serotoninergic neurotransmission: it is a relatively weak reuptake inhibitor and a powerful blocker of presynaptic 5-HT2 receptors

Tablets

50, 100, 200 mg

Dosage: Begin with dose of 50 - 100 mg bd increasing every 5 days by 100 - 200 mg to a maximum dose of 600 mg daily. Monitor therapeutic response and side effects as dose increases. usual adult dose range 300 - 600 mg daily.

Serzone is recommended for the treatment of depression accompanied by anxiety and sleep disturbance.

Side effect profile is similar to the other SSRI with nausea andbeing the most common.

Experience of over-dosage suggests a high degree of safety.

Safety in pregnancy has not been established. Animal studies suggest some concentration in milk so should not be used in breastfeeding mothers.

b) Selective noradrenaline reuptake inhibitors (NaRI) Reboxetine ( ) Appears to be equal in efficacy to TCA and SSRI in the treatment of depression. It has no effects on serotonin or dopamine neurotransmission at clinically effective doses.

Dosage:

Tablets

mg

Start at 8mg daily in divided doses; can increase to 20mg

Side effects: Relatively few. Impotence and urinary hesitancy in men; a rise in heart rate with no accompanying ECG abnormalities has been noted in clinical trials but its clinical significance is uncertain.

iii)

Monoamine oxidase inhibitors (MAOI)

MAOI can be very effective in the treatment of so-called `atypical' or `neurotic' depression where the vegetative symptoms are frequently the obverse of those seen in the more typical depressive illness, with an increase rather than a decrease in appetite and sleep. Anxiety, hypochondriacal symptoms, lethargy and fatigue are prominent symptoms

In the past MAOI have been indicated for depressive illness that has not responded to an adequate trial of tricyclic drugs or that has previously responded well to MAO inhibitors.

Monamine oxidase is the enzyme responsible for the metabolism of tyramine contained in foods such as cheese, broad beans and meat extracts. When the action of this enzyme is blocked unmetabolised tyramine passes from the intestine into the blood stream where it can cause severe hypertensive reactions (cheese reaction). The reversible MAOI, moclobemide, allows much greater dietary freedom. MAOI may be helpful in clinical atypical depressions, obsessive-compulsive disorders, and phobic states. Tranylcypromine is discussed as the prototype of the non-reversible MAOIs and moclobemide is discussed as the prototype of the reversible MAOIs.

a) Non-reversible inhibitors of monamine oxidase Tranylcypromine (Parnate)

Indications: Depressive illness, may be useful in some obsessive-compulsive and phobic states.

Tablets

10 mg

Dosage: Commence with 10 mg morning gradually increasing if necessary up to 40 mg mane. It has a stimulant effect which may be useful in the retarded patient

Major Side Effects

(a) Hypertensive episode (cheese reaction): Patients must be warned against eating cheese and extracts of meat and yeast (Marmite and Vegemite). Broad beans are often listed but in fact it is only the pods that are dangerous. Alcohol is safe in moderation except Chianti. Drugs to be avoided are tricyclic antidepressants, sympathomimetics such as adrenaline, ephedrine, neosynephrine, amphetamine and its derivatives, and L-dopa. Cough and cold remedies and nasal sprays may be dangerous. Such a hypertensive reaction is a serious condition. It usually begins with a severe head- ache, pounding of the heart, sweating and often restlessness. In some cases this condition has led to subarachnoid haemorrhage and death.

All patients prescribed these drugs must be told in detail which foods they should not eat; usually they are given a card listing them at the time the drug is dispensed. Cough and cold remedies containing sympathomimetic constituents must also be avoided. Provided these simple precautions are taken there is little risk of untoward reaction.

Combining a tricyclic MARI with a MAOI does not bestow any significant therapeutic advantage in uncomplicated depression; furthermore, it increases the occurrence of weight gain, orthostatic hypotension and impotence. Fatal reactions have rarely occurred, usually in the context of an overdose. It is generally recommended that tricyclic MARI should not be

prescribed for at least 14 days after stopping treatment with MAOI. When given alone MAOI are prone to cause postural hypotension, sleep disturbance and weight gain. MAOI are not cardiotoxic, nor do they have any anticholinergic activity.

Immediate treatment of a hypertensive reaction involves giving intravenous phentolamine ('Rogitine'). I ampoule (10 mg) and repeat this in 10 minutes if the blood pressure has not returned to satisfactory limits. Treatment of a hypertensive crisis may need to continue for up to 24 hours if the offending substance is still being absorbed.

The use of phentolamine carries certain risks in itself and it should not be used outside of a well-equipped hospital situation unless absolutely necessary. A safer way of lowering the blood pressure rapidly is for the patient to take a 10mg nifedipine (Adalat) capsule which should be bitten and swallowed with a small quantity of water. This method does not carry the risk of hypotensive overshoot which can occur with phentolamine.

The dose may be repeated if necessary to achieve satisfactory blood pressure levels.

On very rare occasions other foods and drugs may cause a hypertensive reaction. It is therefore wise to describe the symptoms to the patient, and give a card specifying the drug used, outlining the forbidden foods and drugs, symptoms of a hypertensive crisis, and appropriate treatment. For further treatment see Overdoses, page 75.

(b) Hypotensive reaction: Pethidine (U.S. meperidine) and morphine can lead to severe hypotensive crisis (cardiovascular collapse). Cocaine derivatives, e.g., lignocaine or 'Xylocaine ' seem reasonably safe, as does pentazocine ('Fortral'). There is no need to avoid adrenaline in dental injections. For treatment see Overdoses, page 75.

Minor side effects: (usually dose related) Restlessness, insomnia, drowsiness, hypotension, lowering of seizure threshold. See the section on tricyclic side effects for treatment.

Phenelzine (Nardil)

Indications. As for tranylcypromine.

Tablets

15 mg

Dosage: 30-75 mg daily is the usual dose.

Side effects: As for tranylcypromine, but may cause anticholinergic effects. It does not have the stimulant action of tranylcypromine and is less likely to be associated with hypertensive crisis. A few patients complain of drowsiness, an equal number of insomnia and some of weight gain.

b) Reversible inhibitors of monoamine oxidase

Moclobemide (Aurorix) A reversible inhibitor of mono-amine oxidase type-A (RIMA). This allows much greater dietary freedom as the risk of a hypertensive reaction with tyramine-containing foods is much less.

Indications: Depressive illness, may offer special benefits in the elderly, patients with phobic disorders and panic disorder and for those at risk of overdose. Moclobemide does not impair vigilance and is not sedative.

Tablets

150mg, 300 mg

Dosage: Begin with initial dose of 100mg tds and increase if necessary to maximum of 600mg daily. (200mg tds or 300mg bd). Average adult dose 450mg daily. Do not increase dose until after one week from commencement as bio-availability increases throughout this time. No dose reduction needed in the elderly or those with renal impairment. Caution in cases of severe hepatic impairment.

Major Side Effects and Cautions Moclobemide is very well tolerated and has few side effects. Do not use in children or pregnant or nursing mothers, as no information is currently available for these situations. Animal studies do not indicate the likelihood of difficulties in pregnancy. Depressed patients with high levels of excitation or agitation should not be treated with Moclobemide unless an anxiolytic is used as well.

Treatment with Moclobemide does not necessitate dietary restrictions in patients with normal dietary habits.

The following transient effects have occasionally been observed: anxiety, blurred vision, dry mouth, gastrointestinal disturbance, nervousness, agitation, sleep disturbance, headache. These effects may be due to the underlying illness and none occurred with an increased frequency of more than 5% compared with placebo. Cimetidine prolongs the metabolism of Moclobemide, the usual dose of Moclobemide should be halved in patients taking cinmetidine.

Treatment with a TCA or other antidepressant can be initiated directly without a washout period when discontinuing Moclobemide treatment or vice versa. NB: Still a 2 week washout recommended for SSRI to Moclobemide transfer.

(vi) COMBINED M.A.O. INHIBITORS AND TRICYCLICS

In a few patients with depression resistant to either group of drugs given separately, improvement may occur if they are combined. This may also be effective in phobic and obsessive-compulsive conditions. The usual procedure is to give the MAO inhibitor in the morning and the tricyclic in the evening. Generally, both drugs are commenced at a low dosage at the same time, or the MAO inhibitor may be added to a tricyclic regime. Both drugs are increased within the usual range as necessary. It is best initiated by a specialist on an inpatient basis. Tranylcypromine should be avoided, as should clomipramine, in combined treatment.

When choosing an antidepressant however it is worth keeping in mind a recent analysis of the situation regarding antidepressants in Australia. Since the introduction of the new generation of antidepressants in the early 1990s there has been a threefold increase in cost of antidepressants for only a 7% increase in usage.

Mono-amine oxidase inhibitors (MAOIs) are an alternative and effective group of drugs which may have some specific indications although not as yet clearly defined. The major disadvantage to the use of MAOIs in the past has been the strict requirements to avoid tyramine containing foods and sympathomimetic medications such as many common cold remedies. The recent introduction of the reversible MAOI. moclobemide, has made this restriction unnecessary and has opened the way for MAOIs to be used preferentially in certain clinical situations. Also changing to and from TCAs to a MAOI can be done

more rapidly with moclobemide. If changing from a TCA to another MAOI, a three-day drug free period is needed. Changing from MAOI to a TCA requires a 10-day drug-free period. Inpatients with treatment resistant depression have been treated with a combination of MAOI and TCA but this needs to be carefully monitored and should not be attempted on an outpatient basis.

It is good practice to know one or two antidepressant drugs really well and to use them consistently. The newer drugs however widen the therapeutic range and have a place in the treatment of particular patient populations.

Antidepressants and Hypertension: Some antihypertensive drugs (and other medical drugs) may precipitate depression, e.g. reserpine, methyldopa, propranolol, clonidine and occasionally guanethidine. Conversely, the antidepressant drugs may seriously affect the treatment of high blood pressure. The MAO inhibitors may cause marked potentiation of the ganglion-blocking drugs. Tricyclics antagonise the action of the adrenergic neuroneblocking drugs and probably also methyldopa. It is possible that this effect is less marked with doxepin. As a general rule it is best to avoid the use of antidepressant drugs in patients on anti-hypertensive therapy (other than a diuretic). When a patient on antihypertensive therapy develops depression, this therapy must be reviewed and any possible offending drug replaced by a suitable substitute. Mianserin has been reported to have little or no interaction with the anti-hypertensive effects of clonidine and methyldopa.

BIPOLAR DISORDER The treatment of bipolar disorder can be considered under three headings: a) an acute manic episode; b) a depressive episode (bipolar depression); c) the prevention of recurrences.

a) MANIA The severely manic patient, with his non- stop activity, constant pressure of talk, bellicose self-confidence and inability to focus on any activity for more than a moment, requires urgent treatment, usually in hospital. In less severe cases treatment as an outpatient is often possible. Most published guidelines recommend starting treatment with a mood stabiliser (see below), but, in more severe cases it is usually necessary to use an antipsychotic drug in the first instance, as mood stabilisers such as lithium and valproate take longer to act, and are generally less effective in reducing the overall level of disturbance.

(i) Antipsychotic drugs As they act rapidly, the antipsychotic drugs are frequently used in the acute phase of mania but rarely in maintenance treatment thereafter. A regime that has been found useful in the management of the manic patient has been to start the antipsychotic drug at the same time as commencing treatment with a mood stabiliser such as lithium carbonate. Often the antipsychotic can be stopped after a few weeks and the mood stabiliser continued indefinitely in maintenance dosage. (See page for treatment of acute psychotic excitement).

Some patients, particularly those prone to recurrent episodes mania, and who are unreliable in their compliance, benefit from long-term treatment with a depot antipsychotic (see chapter ).

Haloperidol (see page..) is widely used for this purpose and has the advantage that it can be given as an injection to patient unwilling to take oral medication. However, a more sedative antipsychotic such a chlorpromazine or olanzapine (see page..) may be preferable if the patient is prepared to accept oral medication. When haloperidol is used in treating the acutely manic patient, it is very rarely necessary to exceed a maximum dose of 20mg in any 24hr period. This can be gradually decreased to as the symptoms settle.

ii) Mood stabilisers Mood stabilisers are drugs which have been shown to be effective in the treatment of an acute manic episode and have the potential to reduce the frequency of further episodes. They include lithium and a number of anticonvulsants, such as sodium valproate, carbamazepine, lamotrigine and gabapentin.

Lithium Lithium was the first drug to shown to be effective in the treatment of mania and the prevention of further episodes. This discovery in 1949, by John Cade of Melbourne, can be said to have ushered in the era of modern psychopharmacology.

Lithium carbonate (Lithicarb, Lithiomyl, Priadel)

Indications: It is most useful in the prophylaxis of recurrent affective disorders (see below), but it also has a calming effect in mania after a few days. It may be useful in schizo-affective psychosis, and is worth trying in combination with antidepressants in cases of refractory depression.

Dosage: Tablets: 250 mg and 400 mg Capsules: 250mg Slow release tablets (Priadel): 400mg

For control of acute mania 750 1250mg. may be needed during the first few days until improvement or side effects are noted. An antipsychotic such as haloperidol, chlorpromazine, methotrimeprazine, risperidone or olanzapine is often needed to calm the more excited patient before lithium takes its effect. Once controlled the dose is reduced to maintenance levels, ensuring the serum concentration remains between 0.5 and 0.9 mmol/l. Usually this requires a dose of 750 to 1,250 mg/day but the elderly may need as little as 500 mg/day. It is emphasised that the serum level and clinical state should determine the daily dose. A few patients, usually elderly, do well on serum levels lower than the usual range. Also, some, again usually the elderly, show toxic symptoms at therapeutic serum levels. After stabilisation, the entire maintenance dose can be taken at night, but if this produces undesirable side effects then twice-daily dosage is

warranted. Blood for lithium levels should be taken 12 hours after the night dose and before any morning tablets. Blood levels are usually taken at the end of the first week, then weekly for the first month, monthly for 3 months, 3 monthly for a year and then as often as it would appear indicated by past experience with the patient. It is wise to give the patient and a close relative a card warning about the signs and symptoms of toxicity.

250 mg and 400 mg tablets. For control of acute mania 750 1250mg. may be needed during the first few days until improvement or side effects are noted. An antipsychotic such as haloperidol, chlorpromazine, risperidone or olanzapine is often needed to calm the more excited patient before lithium takes its effect. Once controlled the dose is reduced to maintenance levels, ensuring the serum concentration remains between 0.5 and 0.9 mmol/l. Usually this requires a dose of 750 to 1,250 mg/day but the elderly may need as little as 500 mg/day. It is emphasised that the serum level and clinical state should determine the daily dose. A few patients, usually elderly, do well on serum levels lower than the usual range. Also, some, again usually the elderly, show toxic symptoms at therapeutic serum levels. After stabilisation, the entire maintenance dose can be taken at night, but if this produces undesirable side effects then twice-daily dosage is warranted. Blood for lithium levels should be taken 12 hours after the night dose and before any morning tablets. Blood levels are usually taken at the end of the first week, then weekly for the first month, monthly for 3 months, 3 monthly for a year and then as often as it would appear indicated by past experience with the patient. It is wise to give the patient and a close relative a card warning about the signs and symptoms of toxicity.

Contra-indications: None are absolute, but lithium should be given cautiously to those with renal or cardiac disease and those in concurrent diuretic treatment. It is wise to stop lithium treatment during acute renal infections.

Pregnancy: As a general rule lithium is not advised during pregnancy, particularly in the first trimester, as the risk of foetal malformation involving the cardiovascular system is greater in the children of women prescribed lithium during pregnancy than that of women not so exposed. Thus, if possible, pregnancy should be planned so that lithium can be stopped a week or two before conception and recommenced after the first trimester. Dosage often needs adjusting as renal clearance increases during pregnancy then returns to normal after birth. Lithium is excreted in breast milk producing a serum concentration half that of the mother in the infant, but has not produced toxicity. If a manic-depressive patient has been off lithium during pregnancy, it should be recommenced immediately post-partum as this is a high-risk period for relapse.

Preliminary tests: A baseline series of tests should be performed immediately prior to starting lithium. These are: electrolytes, urea, serum creatinine, thyroid function tests and an ECG in those over 40yrs.

Annual check-up: Renal function tests and thyroid function tests should done annually.

Side effects: Initial and harmless: Nausea, loose stools, fine tremor, thirst, polydipsia and polyuria.

Persistent but harmless. None of these conditions usually warrants the discontinuance of lithium. For polyuria and polydipsia the patient should be advised to drink plenty of fluid. Oedema of the face and ankles, do not use diuretics unless essential, as the sodium loss induced may lead to lithium toxicity. If a thiazide diuretic is used, the lithium dose should be reduced. Moderate weight gain can most suitably be controlled by avoiding sugar-containing drinks. A fine tremor of the hands is usually of little consequence, but if a source of embarrassment, a beta blocker, eg: propranolol 40 mg t.d.s. is helpful.

Long term. Hypothyroidism may occur, and is treated in the usual way with thyroid replacement. There is no need to cease lithium but a review of the patient's clinical state and need for lithium should be carried out.

Symptoms heralding intoxication. Vomiting and diarrhoea, coarse tremor of the hands, sudden onset of polydipsia and polyuria, sluggishness, sleepiness, vertigo and dysarthria. Neurological defects mimicking strokes may present and may not remit completely after treatment of toxicity. If toxicity is supected lithium should be stopped immediately and the serum level determined. Levels above 1.5 meq./l indicate impending toxicity. Serum levels are normally halved each day after the drug has been stopped. For treatment of severe toxicity see page .

Carbamazepine (Tegretol, Teril) . Indications: Clinical trials have produced evidence that carbamazepine has antimanic, and prophylactic effects in bipolar disorder especially in patients with mixed affective disorder those with a rapid cycling course who often are less responsive to lithium. Evidence would suggest lithium and carbamazepine may have a synergistic effect and may be tried in combination if either alone fails to produce satisfactory results.

Dosage: Tablets 200, 400mg; controlled release 200, 400mg

400-1600mg daily in divided doses. Start at low dose and increase gradually.

Side-effects: Dizziness, ataxia, gastrointestinal symptoms and drowsiness. Skin rash in up to 15%. The risk of blood dyscrasias warrant monitoring in the early stages

Sodium valproate (Epilim)

Indications: At least one controlled trial has shown it be as effective as lithium in acute mania but there is less evidence for its value in the prevention of recurrences.

Dosage:

Tablets 100, 200, 500mg

800 mg daily in 2 divided doses increasing by 200 - 400 mg every 2 - 3 days until symptoms come under control. A plasma level of 45-125mcg/ml is probably optimal. A

loading dose of up to 20mg/kg/day has been shown to produce a more rapid anti-manic action.

Side effects: These include sedation, headache, ataxia and gastrointestinal disturbances. Weight gain can be troublesome and total alopecia has been reported. Although valproate causes less risk of blood dyscrasia than carbamazepine, it is probably advisable to monitor the blood count in the early stages of treatment.

(c)

Benzodiazepines

This group of compounds can be valuable as adjunctive medication in the treatment of an acute manic episode. They help moderate disturbed behaviour and promote sleep. Clonazepam has found favour for this indication in New Zealand, although there is no evidence that it is more effective than other members of this group (see page..).

iv)

Prevention of relapse

Prevention of relapse is the major therapeutic challenge in the overall management of bipolar affective disorder. Most patients relapse at least once, many several times.

(a) Lithium In a large number of double-blind clinical trials lithium has been found consistently to be superior to placebo. Lithium is still recommended by most authorities as the drug of first choice for the long-term management of bipolar disorder. Once started it should probably be continued indefinitely. Most studies indicate that the optimal plasma level for

prophylaxis is 0.5-0.9mmol/l; a level below this is usually ineffective, one above is frequently accompanied by side effects which prejudice compliance. Between one third and one half of the patients prescribed lithium stop taking it against medical advice, accounting for approximately half of all relapses. Stopping lithium abruptly, even after several years successful prophylaxis, greatly increases the likelihood of a manic relapse occurring within the next 14-21 days. In approximately a third of patients continuous lithium fails to prevent relapse. Here, switching to alternative mood stabiliser (see below), or combining it with lithium may prove effective.

(b) Anticonvulsants Carbamazepine Controlled trials of carbamazepine have shown it to be as effective as lithium in the prophylaxis of bipolar disorder. In patients who relapse on lithium, and in those prone to rapid-cycling, the combination of carbamazepine and lithium may be more effective than either drug given alone.

Because carbamazepine causes liver enzyme induction, women taking an oral contraceptive should be advised to adopt an alternative contraceptive practice, at least during the first few weeks of treatment with carbamazepine. It can be teratogenic; a neural tube defect occurred in 1% of the offspring of mothers taking carbamzepine during pregnancy. There is evidence that folic acid can protect against this.

Sodium valproate Open studies have indicated that valproate may have a role in the prevention of manic episodes in bipolar patients but, as yet, there have been controlled trials confirming this. Valproate can be useful for those who do not respond to lithium or carbamazepine, or who cannot tolerate them. It appears particularly effective in patients with a rapid cyling pattern of illness. Patients who have failed to respond to treatment with either lithium or valproate given separately, may benefit from combining the two.

A 'foetal valproate syndrome', characterised by both major (mainly cardiac) and minor congenital malformations and by jitteriness, seizures and feeding problems in the infant, has been described in the offspring of epileptic mothers who took valproate during the first trimester of pregnancy. Spina bifida occurs in 1.3% of offspring, folic acid may prevent this.

Lamotrigine (Lamictal) Lamotrigine given as an add-on treatment can benefit patients who fail to remain well on other treatments. Its place in the maintenance treatment of bipolar disorder remains to be established.

Dosage:. Tablets 25, 50, 100mg

Need to build up slowly: 50mg daily for 2 weeks, 100mg daily for the next two weeks, o then increase by 100 mg daily every 1-2 weeks to reach a maintenance dose of 2-400mg daily given in divided doses.

Side effects and toxicity: The most serious is a skin rash with fever, facial oedema and lymphadenopathy (Stevens Johnson syndrome).

Gabapentin (Neurontin) This may help in the maintenance therapy of bipolar disorder when given as adjunctive therapy to patients who relapse on standard treatments.

Dosage: Capsules 300, 400mg Start at 300mg/day, build up slowly to 300mg bd.

Side effects: Dizzines, ataxia, somnolence, blurred vision.

(c) Antipsychotics Conventional antipsychotic drugs are widely used in the maintenance treatment of bipolar disorder, usually in combination with lithium. Depot neuroleptics given to patients with recurrent mania who are non-compliant with lithium or carbamazepine significantly reduce the frequency of manic episodes.

(d) Benzodiazepines As insomnia is a frequent harbinger of relapse, patients should be given a supply of diazepam, clonazepam or temazepam to take if they experience difficulty in sleeping and then advised to seek a clinical review. In patients subject to stressful events, treatment with clonazepam may help reduce the likelihood of relapse.

Chapter 3

HYPNOTICS AND ANXIOLYTICS

When treating sleep disturbance, it is important to remember:-

1 2

Insomnia is a symptom and not a disease. Careful enquiry as to sleeping habits and caffeine intake is essential, perhaps asking the patient to keep a sleep diary for a week to establish a base-line.

3 4 5

Depression is often the cause of insomnia. All hypnotics alter the E.E.G. pattern and normalization may take a long period. There is little clinical justification for giving hypnotics for more than a few days at a time and patients rapidly become dependent on hypnotics.

6 7

Adequate muscular relaxation training is much safer in chronic insomnia. Patients taking tranquillisers and tricyclic anti-depressants should be encouraged to take them at night.

Chloral hydrate and its derivatives are effective and are cheaper than their modern equivalents.

(a) BENZODIAZEPINES

For treatment of overdose see page .. and...

Apart from their use as hypnotics, the main use of benzodiazepines is in the symptomatic management of anxiety and stress-related conditions. Many controlled trials have shown their superiority over placebo and barbiturates in relieving these conditions. Although there seems to be little difference among benzodiazepines in terms of effectiveness, there are significant differences in speed of onset and duration of action. Diazepam is rapidly absorbed when taken orally, reaches the brain quickly and can therefore be used to give prompt relief of panic attacks. Given intravenously its action is particularly rapid although it is slowly and erratically absorbed after intramuscular injection. In contrast, Oxazepam is slowly absorbed and much slower in penetration Lorazepam is somewhere between these two in speed of action. Plasma half-lives for parent drug and active metabolite have been given in hours as:

Flurazepam Chlordiazepoxide Diazepam

50-100 50-100 50-100

Alprazolam Lorazepam Lormetazepam Clonazepam

12-15 9-16 8-12

Nitrazepam Flunitrazepam Bromazepam

18-34 25- 30 12- 20

Oxazepam Temazepam Triazolam

6- 8 5- 8 2- 3

Half-life times can be a guide to appropriate clinical use. A long half-life compound such as diazepam would be most appropriate for sustained anxiety, a short-life one such

as Lorazepam for episodic attacks. Oxazepam is short-acting but absorption is too slow for emergency use. Ideally a hypnotic should act rapidly, have a short half-life and not accumulate. Triazolam and Temazepam meet these requirements. The medium half-life compounds Nitrazepam and Flunitrazepam are suitable as hypnotics with continuing daytime anxiolytic action.

A note of caution is necessary in relation to the use of these drugs for anxiety secondary to depression. Whereas they may in these circumstances give immediate symptom relief, there is evidence that they can intensify depression and without treatment of the underlying condition, are really contraindicated in such circumstances. A possible exception to this is alprazolam which is reported to be effective in moderate depression. Clonazepam is widely used in the treatment of mania, although it is not clear that it has any great advantage over other benzodiazepine compounds.

Half-life times are also significant as regards withdrawal effects and dependence. If these drugs are given in large doses and then suddenly stopped there occurs a withdrawal syndrome with restlessness, anxiety and insomnia, sometimes leading to seizures. Symptoms of benzodiazepine withdrawal are the same as those of alcohol and barbiturate withdrawal except that they tend to be later in onset and more attenuated, depending on half- life duration. As awareness of the problems associated with benzodiazepine dependence becomes more widespread a syndrome of rebound withdrawal is being recognised more frequently. Patients who have taken short-acting benzodiazepines for long enough to become dependent and to develop tolerance (variable between individuals

and between different members of the benzodiazepine group) appear to have periods of rebound withdrawal anxiety between doses. This is rapidly relieved by taking another dose - thus reinforcing the dependency and falsely reconfirming for the patient that they suffer chronic anxiety. Persuading the patient to give up their medication is difficult. Moving to a longer acting benzodiazepine and then progressively reducing the dose may help, but withdrawal may often require inpatient admission. If this can be achieved the patient will often be astounded at how much better they feel once drug free for several weeks. Total cessation of withdrawal symptoms may take many months.

The danger of benzodiazepine dependence can be reduced by avoiding the long-term use of these drugs whenever possible and always gradually reducing the dose when stopping.

One further note of caution needs to be sounded. Benzodiazepines do have an adverse effect on cognitive function, particularly in the elderly, and cognitive impairment from long-term use is a possibility that always must be kept in mind.

(a) (1) Benzodiazepines used Primarily as Hypnotics

Flunitrazepam (Rohypnol): 2 mg tablets. Usual dose l to 2 tablets. More potent than its cogeners, suitable for the treatment of resistant insomnia. A frequent drug of abuse in the street.

Flurazepam (Dalmane): 15 and 30mg capsules. Closely related to, and little different from nitrazepam.

Loprazolam (Dormonoct): l mg tablets. Usual dose 0.5-1 mg.

Lormetazepam (Noctamid): 1 mgm tablets. Dose 1-2 mgm. Rapid and short action similar to Temazepam.

Midazolam (Hypnovel): 7.5 mg and 15 mg tablets. Usual dose 15 mg, with 7.5 mg for elderly and/or debilitated patients. Has rapid and short action.

Nitrazepam (Mogadon, Insoma 5, Nitepam, Nitrados): 5 mg tablets and capsules. Usual dose 1-2 tablets.

Temazepam (Euhypnos, Normison): 10 and 20 mgm capsules. Dose 10-30 mgm. Has rapid and short action.

Triazolam (Halcion): 0.125mg tablets. Usual dose 0.125-0.5mg. Recent concern about mental state changes on the higher dose range of Triazolam have prompted the Health Department to withdraw all but the 0.125 mg tablets. Doses should be kept to an absolute minimum.

(a) (2) Benzodiazepines Used Primarily in the Treatment of Anxiety

Alprazolam (Xanax):

Indications: Reported to have special application in the treatment of mixed anxiety/depressive states, and in neurotic depression. It should not be used in patients with psychomotor retardation, nor in patients whose diagnosis is of major (endogenous) depression, nor those with psychotic symptoms.

Dosage: 0.25 mg, 0.5 mg, 1.0 mg tablets.

Usual dose:

(a) Anxiety states - 0.5 to 4.0mg daily in divided doses.

(b) Neurotic Depression - 1.5 mg to 4.5 mg daily in divided doses.

Side Effects: Drowsiness, light-headedness, blurred vision, gastro-intestinal symptoms and autonomic manifestations. As with other benzodiazepines, can occasionally cause paradoxical stimulation and possible hostile outbursts. There is also evidence to indicate that Alprazolam may have a more severe withdrawal syndrome than some other benzodiazepines.

Bromazepam (Lexotan)

Indications: High potency benzodiazepine, indicated in the treatment of severe generalised anxiety. It has an intermediate length half-life.

Dosage:

1.5 mg, 3.0 mg, 6.0 mg tablets.

Usual dosage: Usual dosage:

Outpatients 1.5 to 3.0 mg t.d.s. Inpatients 6.0 to 12.0 mg b.d. to t.d.s.

Side effects: Well tolerated with usually little sedation. Fatigue and drowsiness may occur.

Chlordiazepoxide (Librium):

Indications: It is recommended for the short-term relief of anxiety and tension in neuroses.

Dosage:

Tablets Capsules

5, 10, and 25 mg 10 mg

In neuroses 5-10 mg t.d.s. is the usual dose.

Side effects: Dizziness, ataxia and drowsiness occur. Skin rashes, nausea, headaches, loss of libido, failure of ejaculation and constipation have been reported. Long term effects - see page 46.

Clonazepam (Rivotril)

Indications: Although marketed primarily as an anticonvulsant for use in epilepsy, because of its sedative action clonazepam is widely used in psychiatry as an adjunctive treatment in the management of manic episodes. It can also be effective in panic disorder.

Dosage: Tablets 0.5, 2mg

For agitation and/or anxiety 0.2-0.5mg prn up to 1.5mg daily

Diazepam (Valium, D-Pam Pro-Pam oral, Diazemuls inj):

Indications: It has been recommended for short-term treatment of anxiety and tension. It is used in epilepsy, probably being the drug of choice in status epilepticus.

Dosage:

Tablets Capsules

2. 5, and 10 mg 2 and 5 mg

Syrup Injection

2 mg/5 ml 10 mg/2 ml

Usual dose 6 to 40 mg daily in divided doses.

Side effects. Mild ataxia and drowsiness occur in excessive dosage. It has been shown that diazepam can precipitate serious depressive illness and that it can aggravate existing depression. Long-term effects - see page 46.

Lorazepam (Ativan, Lorapam):

Indications: Anxiety.

Dosage:

Tablets Sublingual tablet

0.5, 1 and 2.5 mg 1 mg

Usual range 1 mg b.d. to t.d.s.

Side effects: Drowsiness may occur initially. Ataxia and confusion have been reported in high dosage. Long term effects - see page 46.

Oxazepam (Serepax, Ox-Pam, Benzotran):

Indications: Said to reduce symptoms of anxiety and tension. Claimed to relieve anxiety in alcohol withdrawal.

Dosage:

Tablets

10. 15 and 30 mg

45-120 mg/day in divided doses.

(b) OTHER HYPNOTICS

Chloral Hydrate: 600-1,200 mg in syrup or 500 mg caps (Noctec). One or two tablets act rapidly. It is well tolerated by the elderly.

Chlormethiazole (Hemineurin) 300 mg capsules. 250 mg/5 ml syrup and 0.8 I/V infusion. This drug is well tolerated by the elderly and rapidly eliminated. Dependence may occur especially in alcoholics, for whom it is an excellent sedative in withdrawal states (see page 62). Deaths by overdose (combined with alcohol) have been reported. It is a short acting sedative with a half-life of less than four hours.

Zopiclone (Imovane): A cyclopyrrolone compound. 7.5 mg tablets. Adult dose 7.5 mg. (Range 3.75 mg to 15 mg). A short acting hypnotic with a half-life of 5 hours.

Induces and sustains sleep without reduction of REM sleep and with preservation of slow wave sleep.

Negligible residual effects and rebound insomnia not a feature. Most troublesome side effect appears to be unpleasant aftertaste. Dependence potential is said to be less pronounced than with the benzodiazepines. Is very well tolerated by most patients.

(c) OTHER ANXIOLYTICS Beta blockers Although primarily used in the treatment of hypertension, this group of drugs has anxiolytic properties. They are most effective in acute situational anxiety with somatic symptoms, as they do not produce drowsiness as found with the benzodiazepines. Skilled performance is unaffected. The usual dose is one of the smallest tablet size of any betablocker taken b.d. or t.d.s., the dose increased if necessary within wide limits. A history of asthma or cardiac failure contraindicates this treatment. Depression has occurred with propranolol.

Buspirone (Buspar) A non-benzodiazepine anxiolytic. Reported to have no CNS depressant effect, no apparent abuse liability, no withdrawal symptoms and few side effects. In the CNS it acts as a serotonin partial agonist and thus has similar properties to the serotonergic antidepressants, hence its antidepressant properties and slow onset of action. Has been

reported to have augmentation effect when used together with other antidepressants. Should not be used with MAOI's.

Dosage:

5 mg, 10 mg tablets.

Initial dose 5 mg t.d.s. Optimal daily dose 20 - 30 mg in divided doses. Slow onset of improvement of symptoms, noticeable after 7 - 10 days.

Side effects: Dizziness, headache, nervousness, and diarrhoea.

Hydroxyzine (Serecid) An antihistamine, related to the phenothiazines, which can be useful in some cases of anxiety.

Dosage:

Tablets 25, 50mg

25-50mg up to four times daily.

Side effects: Drowsiness

(d) CHOICE OF ANXIOLYTIC Unfortunately there is no ideal anti-anxiety drug. While benzodiazepines have been the mainstay of drug treatment in anxiety for decades, there has been a determined search for effective alternatives, largely because of the tendency of benzodiazepines to produce tolerance and dependence.

There are five distinct anxiety syndromes recognised in DSM-IV for which anxiolytic drugs have an important place in treatment. Drugs are best administered as part of a comprehensive treatment plan which includes psychological treatment. (Specific phobias are probably best treated exclusively with psychological treatment.)

(i) Generalised Anxiety Disorder (GAD) The recommended first-line treatment for GAD is with an SSRI antidepressant or an antidepressant with a dual action such as venlafaxine. Buspirone may be be tried if these prove ineffective. In an acute anxiety reaction, or an acute exacerbation of anxiety, short-term treatment with a benzodiazepine is likely to afford symptomatic relief.

(ii)

Panic Disorder

Tricyclic antidepressants (TCA), particularly imipramine have proved helpful, as have monoamine oxidase inhibitors (MAOI).

(iii)

Social phobia

MAOI, particularly moclobemide, and SSRI, have been shown to be superior to placebo in clinical trials. If the symptoms are limited to performing or speaking in public (performance anxiety) treatment with a beta-blocker should be tried first.

(iv)

Obsessive Compulsive Disorder (OCD)

A serotonin reuptake inhibitor (SSRI) such as paroxetine, or a tricyclic antidepressant (TCA) with pronounced serotoninergic reuptake inhibition, such as clomipramine, are the preferred first-line drugs.

(v)

Post-traumatic Stress Disorder (PTSD)

Here too, drug treatment should start with an SSRI or moclobemide.

Chapter 4

DRUG TREATMENT IN EPILEPSY

We wish to thank Dr G. D. Hammond-Tooke, Senior Lecturer in Medicine (Neurology) at the University of Otago for updating this chapter.

(a) GENERAL

Although drugs are helpful in epilepsy they are by no means the entire treatment. Attention must be paid to underlying causes, to avoidance or anticipation of precipitating factors, as well as to the personal and social aspects of having such a condition.

The general principles of drug treatment in epilepsy are: 1 Always attempt to control seizures using a single drug. Using more than one drug increases the risk of drug interactions and adverse effects, and there is no evidence that it provides better seizure control. On the contrary, clinical trials have shown that better control can be achieved with single drug treatment, properly monitored.

Choice of drug should be based on the seizure type. Use well-tried and less toxic drugs first, giving sufficient time for an adequate trial.

Therapy with phenytoin may be initiated with an appropriate maintenance dose or even with a loading dose, Carbamazepine, and most other anticonvulsants should be introduced gradually to minimise side effects, Anticonvulsants have a low therapeutic ratio so the dose required to reduce seizures is only slightly less than the toxic dose. Because of this, careful titration of dose is necessary.

Dosage intervals range from once daily (phenytoin, phenobarbitone, primidone) to three or four times a day in the case of carbamazepine, although the controlled release preparation of carbamazepine may be used twice a day.

Only when single drug options have been exhausted should one resort to combination regimens. Serum level monitoring is an important aid to effective drug, use particularly when response to treatment is poor, possible toxicity develops, other drug therapy is required or compliance is suspect. The target range of commonly used drugs should be used as a guide and careful clinical monitoring is preferable to rigid adherence to these values: Phenytoin 10-20 mg/l

Carbamazepine

5-8 mg/l

Sodium Valproate50-110 mg/l

Ethosuximide

40-80 mg/l

Anticonvulsants may cause impairment of cognitive function, and psychomotor changes in children. Phenytoin and phenobarbitone are particularly likely to do this, making carbamazepine and sodium valproate preferable choices in children.

Where there is psychosis or depression in association with epilepsy, which is not uncommonly so in temporal lobe epilepsy, there is the problem of anti-psychotic and antidepressant drugs lowering seizure threshold and also interfering with anticonvulsant serum levels. There is some evidence to suggest that newer anti-depressants maybe less epileptogenic.

b) DRUGS OF 1st CHOICE

Carbamazepine: 'Tegretol' (Geigy); Teril (Pacific);

Indications: Effective in partial and generalised tonic-clonic seizures. Also used in trigeminal neuralgia.

Dosage: Tablets: standard and controlled release; 200 and 400mg Syrup 100mg/5ml

Starting dose 100 mg twice daily, with slow increase until response is obtained. Maintenance range 400-2,000 mg per day. Dosage interval: twice daily with controlled release preparation; three to four times daily with standard preparation.

Side Effects: Anorexia, nausea, vomiting, headache, dizziness, drowsiness or visual disturbances may occur. Allergic skin rashes. Blood dyscrasias may occur in long-term therapy .

Phenytoin: 'Dilantin'

Indications: Effective in partial and generalised tonic-clonic seizures, and in tonic-clonic status epilepticus. Not effective in generalised absence attacks and may aggravate them.

Dosage:

Capsules: Tablets: Suspension:

30 and 100mg (infatab) 50mg 30mg/5ml, Forte suspension 100mg/5ml

Ampoules:

100mg/2ml and 250mg/5ml

Usual adult range:

200 to 400mg per day. mg/kg/day

Paediatric starting dose: Dosage interval:

nce or twice daily.

Side effects: Slurring of speech, double vision, incoordination and ataxia with, more rarely, swelling of lymph glands. Hyperplasia of the gums may be a problem in children. Occasionally hirsutism may warrant withdrawal.

Sodium valproate: 'Epilim' :

Indications: Primary generalised epilepsies, (including absence seizures), partial seizures, prophyllaxis of febrile convulsions.

Dosage:

Tablets: Syrup:

100mg, 200mg, 500mg 200mg/5ml

Starting dose: Maintenance range: Dosage interval:

200mg twice daily. 400 to 2,000mg daily. twice daily.

Side Effects: May potentiate sedative effects or other drugs. Gastro-intestinal side effects. Temporary hair loss, teratogenicity. Weight gain, and blood dyscrasias. Hepatotoxicity which can be fatal, mainly in children under the age of three years.

Ethosuximide: 'Zarontin' :

Indications. Absence seizures.

Dosage:

Capsules Syrup

250mg 250 mg/5ml

Range 500 to 1,500 mg daily.

Side Effects: Gastro-intestinal symptoms, drowsiness, leucopenia, and agranulocytosis can occur. Headaches, dizziness and psychiatric manifestations have also been reported.

(c) DRUGS OF 2nd CHOICE

Clonazepam: 'Rivotril' :

Indications: Myoclonic and generalized tonic-clonic seizures, status epilepticus.

Dosage:

Tablets Oral drops Ampoules

0.5 and 2 mg 2.5 mg/ml 1 mg/ml

Starting dose: Maintenance range: Dosage Interval:

0.5-1mg per day 2 to 8mg per day. three to four times a day.

Side Effects: Drowsiness, occasional behavioural changes including aggression.

Clobazam: 'Frisium' :

Indications: Adjunctive therapy in partial or generalised epilepsy and monotherapy in certain forms (Lennox-Gastaut and catamenial).

Dosage:

Tablets

10 mg

Starting dose: Maintenance range: Dosage interval:

10mg at night. 20-40mg daily once or twice a day.

Side effects: Similar to clonazepam. Drowsiness, dizziness and dryness of mouth have been reported.

Phenobarbitone (PSM), Phenobarbitone Sodium or Gardenal Sodium:

Indications: Effective in partial and generalised tonic-clonic, clonic and tonic seizures.

Dosage:

Tablets Injections

15, 30, 60mg 200mg/ml

Starting dose: Usual maintenance dose: Dosage interval:

30-60mg/day 6-240mg daily. once or twice daily.

Side Effects: Sedative effect limits its value. Children may be irritable, hyperkinetic and aggressive with it.

Primidone: 'Mysoline' (I.C.I.):

Indications: Effective against partial and generalised tonic- clonic seizures.

Dosage:

Tablets

250mg

Starting dose: Maintenance range: Dosage interval:

125-250mg per day 250- 1,500mg per day. once or twice a day.

Side effects. Nausea, vomiting, drowsiness, dizziness, ataxia. Very occasionally blood disorders have been described.

(d) ADJUVANTS

Acetazolamide: 'Diamox' :

Indications: Effective in both tonic-clonic and absence seizures. Tolerance develops quickly. Its intermittent use for seizures occurring before and during menstruation is often effective.

Dosage:

Tablets Capsule

250 mg 500 mg (sustained action)

Usual dose 250- 1,000 mg daily.

Side effects: High doses may cause drowsiness, fever, rashes and paraesthesiae. It should not be used in liver failure.

(e) NEW ANTI-EPILEPTIC DRUGS

In recent years new anti-epileptic drugs have become available. The following are registered in New Zealand for add on therapy, although it is likely that they will be used as monotherapy in the future. They are subject to restrictions because of their expense, and are funded only if prescribed by approved specialists.

Lamotrigine: Lamictal :

Action: Inhibits release of glutamate.

Indications: Add on treatment in any seizure type, especially primary generalized seizures and Lennox-Gastaut syndrome.

Dosage:

Tablets 25 mg, 50 mg, 100 mg.

Starting dose: day. Maintenance range: With valproic acid:

50 mg once daily for 2 weeks, then 50 mg twice a

200-400 mg/day in divided doses. 100-200 mg/day.

With enzyme inducing drugs: 500 mg/day.

Side effects: Skin rashes occur in about 3%. Other side effects are dizziness, diplopia and ataxia, blurred vision and somnolence.

Vigabatrin: Sabril:

Action: A GABA aminotransferase inhibitor.

Indications: Partial seizures with or without secondary generalization as add on treatment. It is not effective for absences or myoclonic seizures.

Dosage:

Tablets 500 mg

Starting dose: Maintenance range:

2 g/day 2-4 g/day

Side effects: These include drowsiness, dizziness and weight gain, irritability, headache, depression, confusion and psychosis. Intramyelinic oedema has been described in rats and dogs.

Gabapentin: Neurontin:

Indications: Add on treatment for resistant partial and secondary generalized tonicclonic seizures. Not effective for absences and myclonic seizures.

Dosage:

Tablets 300 mg, 400 mg.

Starting dose: 300 mg once daily; increase by 300 mg per day to 300 mg three times daily. Upper range: 2400 mg daily.

Side effects: The commonest side effects are sleepiness and unsteadiness, usually occurring in the first 2-3 weeks of treatment and resolving in two weeks or less. Other side effects are fatigue, headache, feeling sick and vomiting. Serious side-effects rarely occur.

(f) TREATMENT OF STATUS EPILEPTICUS

This is a medical emergency. The following is a suitable protocol:

1 2 3 4

Secure the airway, measure blood pressure and give oxygen. Take blood for glucose, and electrolytes. Give thiamine 100mg intravenously, followed by dextrose 25-50g. Slow intravenous injection of Diazepam 10mg. Be prepared to ventilate the patient if necessary.

If ineffective, infuse phenytoin 15mg/kg (maximum 1g) no faster than 50mg/minute, monitoring the blood pressure and ECG.

If seizures continue, use phenobarbitone 10mg/kg in children or 90-120mg in adults by slow intravenous injection over 10 minutes. Repeat, if necessary after 10-15 minutes.

7 8

Alternatively, paraldehyde 10ml intramuscularly may be tried. If the above is unsuccessful, a general anaesthetic should be administered.

It is essential to recommence or start maintenance therapy as soon as possible, by nasogastric tube, if necessary.

Chapter 5

SPECIAL DRUG REGIMES

(a) (b) (c) (d) (e) (f)

Acute psychotic excitement. Withdrawal regimes. Drugs used in personality disturbance. Attention deficit hyperactivity disorder. Drugs during pregnancy. Drugs during breastfeeding.

(a) ACUTE PSYCHOTIC EXCITEMENT

Occasionally, a patient at home or in hospital is so severely disturbed or excited that emergency control is necessary. This may be accomplished by using adequate doses of antipsychotics, combined where necessary with sedatives.

If oral preparations are able to be used, syrup forms are very useful. A suitable regime, for instance, is 100-200 mg chlorpromazine (or its equivalent) 6 hrly. Chlorpromazine has the added advantage of being quite sedative.

Injectable regimes may be necessary if more rapid action is required, or if there is doubt about whether the patient will take the medication. Suitable agents are Haloperidol 5-15 mg IV or IM, and Thiothixine 4-8 mg IM. Chlorpromazine 50- 100 mg IM may be used but the injection is locally irritating. A further alternative is Droperidol 10-15 mg IV or IM. Its action is similar to haloperidol, but has the added advantage in this situation of being more sedative.

Added sedation with a benzodiazepine compound such as diazepam or lorazepam may be needed to achieve full control Skilled clinical judgment is often needed to weigh up the dangers to the patient of uncontrolled psychosis against confusing the clinical picture with sedation or benzodiazepine-induced disinhibition. Diazepam 10-20 mgs orally is suitable (intramuscular diazepam should be avoided because of its poor distribution). Clonazepam 2 mg t.d.s. has been thought by some to have a specific antimanic effect, and therefore may be particularly useful in acutely disturbed manic patients.

A place may still occasionally exist here for the use of barbiturates; sodium amytal 250500 mg given slowly IV, or 200 mg orally is a potent sedative which may be useful. Chlormethiazole may be used orally as 192 mg capsules, 1 - 2, 6 hrly. In a hospital setting chlormethiazole 0.8% solution may be used IV 40-100 ml initially over 3-5 mins, then 500- 1,000 ml over the next 6-12 hrs to maintain a light sleep. . In the management of a sedated patient, close observation needs to be maintained, and vital signs should be noted regularly. Routine care of the unconscious patient should be given, and attention paid to fluid intake.

(b) WITHDRAWAL REGIMES

It is emphasised that the treatment of withdrawal states is only the beginning of a prolonged psychiatric programme.

Alcohol

Withdrawal from alcohol is a potentially life threatening condition particularly in those who have a high prolonged daily consumption (greater than 15 units per day), advanced dependency features e.g. regular morning drinking and a past history of complicated alcohol withdrawal. In all cases a detailed alcohol and drug history is a necessary precursor for management and this would include a physical examination for evidence of the stigmata of alcoholism such as enlarged liver, spider naevi, palmar erythema, malnutrition, alcohol on the breath, peripheral neuropathy, Wernicke-Korsakoffs syndrome, hypertension (30% contribution by alcohol), G-I problems etc.

There are two main types of withdrawal syndromes:

Minor Withdrawal

This occurs within hours of cessation of drinking and has the following symptoms and signs: restlessness, anxiety, nausea, insomnia, headache, tachycardia, hypotension, tremor. In approximately 15% of patients withdrawing from prolonged, high alcohol consumption generalised seizures occur most commonly within 48 hours after stopping drinking. Hallucinations may also occur in approximately a quarter of all cases and they usually have a visual and tactile nature (occasionally auditory).

Major Withdrawal (Delirium Tremens or DTs)

This occurs 48 to 72 hours after cessation of alcohol and should be considered as a medical emergency and has a mortality said to be in the range of 5% to 10% of all patients even if treated. The hallmark of DTs is an organic delirium with clouding of consciousness. Other symptoms and signs include severe agitation, sweating, fever and paranoid ideation. Generalized seizures and hallucinations may also occur as outlined above. Hospitalisation is recommended.

MANAGEMENT 1 General

In both minor and major types of withdrawal attention must be paid to hydration and metabolic parameters (particularly hypoglycaemia, hypomagnesaemia and

hypokalaemeia) as well as physical investigations looking for intercurrent illness (e.g. pneumonia) and other physical conditions associated with excess alcohol consumption (e.g. head injury).

Well lit, quiet surroundings generally lessen the distress of the patient. Vitamin B1 (thiamine) administered in all cases to prevent encephalopathies and may be either given I.M./I.V. Parenterovite 1 amp or orally 50 mg twice a day.

Benzodiazepines

Benzodiazepines are useful medications to treat the symptoms of withdrawal especially since they have anxiolytic and anti-seizure properties. In general the dose of benzodiazepine should be titrated to the severity of the withdrawal symptoms/signs. Studies have shown that lower doses are required with flexible regimes compared to fixed dosage regimes. Common benzodiazepines used include diazepam (Valium) 10 20 mg orally or slowly I.V. if vomiting, as a loading dose and reassess 2 hours later. Doses of up to 60 to 80 mg a day may be used initially and gradually titrated down over 7 to 10 days. Chlordiazepoxide (Librium) can be used in up to 100 mg per day or oxazepam (Serepax) 120 mg per day this benzodiazepine has a relatively short half life and no active metabolites. Chlormethiazole (Hemineurin) is still occasionally used in acute withdrawal states but there is special concern relating to respiratory depression and the rapid development of dependence its use is generally not recommended.

Complications

Generalized seizures are treated if they arise or if there is a past history of seizure activity during withdrawal. Phenytoin (Dilantin) in doses of 400 mg P.O. or I.V. stat with 100 mg 6 hourly for 5 days or sodium valproate (Epilim) 600 mg stat with 400 mg 8 hourly for 5 days. Severe agitation and hallucinations may also be treated with low dose haloperidol 2 5 mg 6 hourly orally or intramuscularly.

ADJUNCTS TO TREATMENT

Disulfiram (Antabuse)

This drug interferes with the oxidation of alcohol leading to the accumulation of acetaldehyde which produces the aversive disulfiram-alcohol interaction flushing, nausea, vomiting, tachycardia and anxiety. This reaction various in intensity and should only be used in patients who will adhere to the therapy and who have continued counselling support. It is contraindicated in those people who have significant hepatic renal and cardiac insufficiency and also in those with coexisting severe psychiatric conditions. Avoid in pregnancy.

The recommended dosage is now lower than used previously starting off with 100 to 200 mg daily. It should be understood that the aversive effects of disulfiram persist for 4

to 7 days from the last dose. At these lower dosages side-effects are generally uncommon but may include drowsiness, fatigue and a metallic taste. Rarely drug rashes, impotence, neuropathy, hepatotoxcity and organic brain syndromes may occur.

Calcium Carbimide (Dispan)

This acts in a similar manner to Disulfiram but the reactions are generally milder and it has a shorter duration of effects of 12 to 24 hours. The dosage regime is 50 mg twice daily.

Other medications

There is increasing evidence that the use of SSRIs (selective serotonin re-uptake inhibitors) e.g. fluoxetine (Prozac) and paroxetine (Aropax) may decrease the appetitive drive or craving for alcohol once the patient has stopped drinking. In studies overseas these drugs have been shown to be particularly effective in those alcohol dependent people who also have depressive symptoms. The usual dosage as used in depression is employed. Other medications currently not freely available in New Zealand are showing promise and these include naltrexone (an opioid antagonist) and acamprosate (acting on GABA). Both of these drugs have been shown to reduce relapse rate in dependent alcoholics and to decrease craving.

II

Benzodiazepines

This class of medications has recently been scheduled under the Controlled Drug Section of the Misuse of Drugs Act 1975. This places restrictions for prescribing to those patients who are dependent (only by gazetted drug clinic doctors or those doctors authorised in writing by a drug clinic doctor or doctors who have been gazetted for the purpose of drug treatment) and may only be prescribed for one month per prescription. In general there are few if any indications for long term prescribing of benzodiazepines to new patients. If a benzodiazepine is to be prescribed it is recommended that it is short term only and for a maximum continuous supply of 2 to 4 weeks. Benzodiazepine dependence is common and moderate to severe withdrawal symptoms are seen in approximately 40% of patients who have been on benzodiazepines for 6 months or more. Precipitation of major psychiatric condition or generalized seizures are two of the more serious effects of withdrawal from benzodiazepines. Other withdrawal effects include alterations in perceptions (hypersensitivity to light, noise, taste and smell), depersonalisation, rebound insomnia, flu-like illness, depression, muscular aches and pains, restlessness, anxiety/panic attacks, headaches and anergia. There are also a number of side-effects which become apparent on long term use of benzodiazepines and this includes a sense of dysphoria or detachment, sedation, hypotonia, disinhibition, menstrual and cognitive deficits.

Particular care should be exercised with the elderly due to their slower elimination of the drug and increased neuro-sensitivity.

After enlisting the cooperation of the patient a gradual withdrawal regime may be implemented. Do not stop the benzodiazepine abruptly. A rough rule of thumb the number of years on the benzodiazepine is the number of months it takes to withdraw; otherwise 4 12 weeks gradual tapering of dose. Other strategies include switching over a short acting benzodiazepine to a long acting one (e.g. diazepam) and/or the use of antidepressants (particularly sedative tricyclics) or propranolol (80 160 mg/day may lessen the severity of withdrawal symptoms. Psychological therapies and general support are essential.

In-patient withdrawal should be considered if major events occur (e.g. seizures or psychosis precipitated) or there are coexisting problems e.g. depression or previous outpatient withdrawal has failed.

III

Opioids

Having taken a detailed alcohol and drug history it is important to assess the use of other drugs (especially benzodiazepines and alcohol) as well as co-existing disorders (e.g. BAD, depression etc). A medical history, examination and investigations may reveal associated physical conditions e.g. hepatitis B & C, HIV/AIDS, endocarditis,

septicaemia, abscesses, STDs, pregnancy and poor nutritional status. Evidence for drug use sought intoxication (slurred speech, pin-point pupils, ataxia etc.), puncture wounds and observed (if possible) urine drug screens.

Treatment

A drug-free (abstinent) lifestyle is the primary goal. Methadone Maintenance Treatment (MMT), however has been established in the light of relative failure of abstinent regimes for long term drug users and is part of a harm reduction model which has been shown to improve health, diminish I.V. use and infectious conditions as well as overdose death. There are several components in MMT which promote effectiveness and these include adequate dose of methadone (50 150 mg/day), an adequate duration, positive attitudes from trained staff, engagement into counselling and services to deal with psychosocial dysfunction and coexisting disorders. Prescriptions of oral methadone (2mg/ml mixture) starts off usually at a dose of 10 30 mg (not higher than 40mg initially to prevent overdose) and reassessed after 4 hours with dose change as necessary. Stabilisation is said to occur if there is an absence of withdrawal symptoms and craving (hanging out) and there is no evidence of over medication (stoned). This process takes several days due to the long half-life of methadone and may require initial daily adjustments to dose. The methadone is initially consumed once a day at a designated pharmacy.

Methadone does have a number of side effects which are generally alleviated with dosage reduction and includes night sweats, constipation, decreased libido, lethargy, skin rashes, dental problems and of course dependence.

Withdrawal

Usually done as an outpatient with regular counselling/support. Dose reduction varies from 2 to 5 mg per week. Inpatient detoxification may be required for severe withdrawals or complicated poly-drug abusers with medical complications and may be rapid (see below). An opioid withdrawal syndrome includes restlessness, irritability, sweating, tremor, nightmares, agitation, muscle cramps, sleep disturbance, diarrhoea and a craving for the drug previously used.

If with an inpatient, then oral methadone mixture 15 mg is given 2 hourly until the withdrawal signs/symptoms dissipate. This total daily dose may then be reduced by 20% per day if a rapid detoxification is required.

Adjuncts in withdrawal

There are a number of medications used to try and relieve some of the withdrawal symptoms. The most commonly used include:

Clonidine, an alpha-adrenergic agonist, helps relieve some of the sympathetic overactivity associated with opioid withdrawal. Caution needs to be exercised with sedation and hypotension. It is now available in two forms as a tablet (75 150 microgram QID) and as a transdermal patch Catapres-TTS I (100microgm/day) and Catapres-TTS II (200microgm/day) applied weekly.

Quinine sulphate 300 mg QID for leg cramps.

Hyoscine: Buscopan 20mg QID for stomach cramps.

Loperamide: Imodium 2mg QID for diarrhoea.

Zopiclone: Imovane 7.5 15mg at bedtime (maximum duration is 2 weeks).

Other medications

LAAM: lambda alpha acetylmethadol a long acting synthetic opioid only taken every 2 days.

Buprenorphine: Temgesic gaining increasing use due to its relative safety in overdose and ease of withdrawal. This may also be combined with naloxone (an opioid antagonist, only active parenterally) to deter I.V. use and is available as Temgesic-nX

Naltrexone an oral analogue of naloxone used as an aid to an opioid- free life which has been used for rapid detoxification (not freely available in New Zealand).

Pregnancy and lactation

Recent research has reliably shown a better outcome for both foetus and mother if longterm opioid using women are stabilised on methadone at as low a dose as comfortably possible. Priority access to MMT is essential to engage in counselling and specialist obstetric/paediatric care. Methadone is not contra-indicated during breastfeeding.

(c) DRUGS USED IN PERSONALITY DISTURBANCES

The use of medications to control personality and behavioural disturbance should never be entered into lightly. Other psychiatric disorders such as depression, anxiety disorders and transient psychotic episodes may arise in association with personality disorder and should be treated accordingly. The use of addictive drugs should be avoided if there is the likelihood of abuse or dependency.

On some occasions, symptomatic control of acute anxiety or impulsiveness is necessary, and the use of a major tranquilliser in a low to moderate dose over a short period of time may be appropriate.

Cyproterone acetate or Androcur:

Indications: An anti-androgen for the treatment of severe hypersexuality and sexual deviation in males.

Dosage:

50mg tablets, 100mg/ml depot injection

Usual dose:

50mg twice daily, or IM 300mg every 10 to 14 days

(d) ATTENTION DEFICIT HYPERACTIVITY DISORDER:

The most commonly diagnosed behavioural syndrome in childhood estimated to affect between 3 and 5 percent of school age children. It cannot be said strongly enough that aetiology is unclear and this disorder requires very careful expert multidisciplinary assessment and diagnosis. Treatment is much more than the prescription of psychostimulants.

Nevertheless, medication and in particular, methylphenidate, has been shown to significantly reduce the core symptoms of ADHD and improve attention. Little data exists about effectiveness in adults. Trials to date are predominantly short term, and there is little data about long-term outcome. There are side effects to the medication and

potential dangers to the patient and society in over prescription. Side effects include decreased appetite, nausea, growth rate impairment, sleep disturbances, irritability, dysphoria and increases in tic disorders. Psychostimulants have clear abuse potential. There are potential interactions with several drugs including anticoagulants, anticonvulsants and antidepressants. Do not use in children under 6 years of age, as safety has not been established.

Methylphenidate or Ritalin:

Dosage: Usual dose:

10 mg tablets, 20 mg CR tablets Start with 5 mg once or twice daily, and increase by 5-10 mg weekly until effect observed.

Maximum dose:

60 mg daily

(e) DRUGS DURING PREGNANCY:

As with most drugs, psychotropic drugs are best avoided during pregnancy, especially during the first trimester. They should only be used when the indications are clear and commanding and benefits outweigh the possible risks.

Risks include teratogenicity, embryotoxicity, prematurity, and symptoms of toxicity or withdrawal in the foetus or neonate. These risks should be carefully assessed not only in treating pregnant women, but also with all patients who may become pregnant.

The exact risks are difficult to quantify. Information on the newer drugs especially is still being collected, and some of the existing information is unclear. In some there is insufficient information to declare that they are safe.

Disulfiram (Antabuse) is definitely contraindicated in pregnancy. Its use has been associated with congenital anomalies.

The use of lithium in the first trimester has been associated with defects particularly of the cardiovascular system. Lithium toxicity in the neonate has often been reported when lithium is used near term, including nephrogenic diabetes insipidus and thyroid depression with goitre. These toxic effects usually return to normal over a period of weeks. Renal clearance of lithium rises during pregnancy, and then rapidly declines to normal levels in the weeks after delivery. Lithium during pregnancy should be withheld until at least the 10th week if this is possible. There should be frequent measurement of serum levels and the dose titrated to the lowest possible clinically effective dose. Lithium should be given in divided doses to avoid high peak serum levels. At delivery consideration should be given to reducing the dose by up to 50% to avoid foetal toxicity.

Anticonvulsants unfortunately do not provide a safe alternative. Both carbamazepine and sodium valproate have been shown to have teratogenic potential. Again, first trimester use should be avoided where possible and folate supplementation should be used before and during pregnancy. Vitamin K1 has been recommended during the last weeks of pregnancy and for the neonate to avoid bleeding disorders. The serum level should be closely monitored. When anticonvulsants are being used for epilepsy, the risk of foetal malformations needs to be weighed against the risk to the mother and foetus if seizures are not controlled.

It would appear that major tranquillisers are relatively safe, although low potency phenothiazines have been associated with an increase in malformations. High potency agents in low doses are recommended by some. Little information exists on the newer agents, and therefore their use in pregnancy cannot be recommended.

In general, the antidepressants appear reasonably safe, although again little data exists for the newer agents including Fluoxetine, and therefore they cannot be recommended. The tricyclics have been the most studied, and reports of malformations do exist, though there does not seem to be a strong association in larger studies. Toxic effects sometimes from the anticholinergic action, and withdrawal effects in the newborn have been reported.

Minor tranquillisers such as Diazepam are suspect as studies have shown both an association with congenital anomalies and toxic effects in the newborn. It has been suggested that Lorazepam and Clonazepam do not accumulate to the same degree in the

foetus as Diazepam and may be safer during pregnancy. In general avoid if at all possible.

(f) DRUGS DURING BREAST-FEEDING:

Literature on the safety of psychotropic drugs during breast-feeding remains limited. A decision to use medications and continue breast-feeding requires the parents informed consent and assessment of the multiple factors involved, including the drug, the age of the infant and risk of non-treatment. Some general guidelines are to use low dose monotherapy, to use short acting drugs and time doses to give medicines after feeding, and to evaluate the risk factors of the specific drug. Always continuously evaluate the neonate for side effects.

Lithium levels in the infant may rise to 50% of the maternal concentration and therefore because of the risk of toxicity in the baby, mothers on lithium should only breast-feed with great caution and with frequent monitoring of the blood levels. Carbamazepine and sodium valproate are probably more compatible with breast-feeding. Both, however, pass into breast milk and carbamazepine has been associated with liver function abnormalities. Hepatotoxicity has been reported in young children treated with valproate, therefore it must be used in breast-feeding mothers with caution. Other anticonvulsants are probably safe although methaemoglobinaemia has been reported in the baby with phenytoin.

Antipsychotic drugs are in general probably safe. Drowsiness has been found in infants whose mothers are taking chlorpromazine. Haloperidol appears relatively safe. There is little data on the atypical antipsychotics to date. However, given the degree of passage of clozapine into breast milk and the potentially fatal agranulocytosis that could result, it should not be used in nursing mothers.

The use of tricyclic antidepressants seems safe, apart from doxepin where adverse reactions in the baby have been reported. SSRIs are also probably safe though data is still accumulating. A recent suggestion is that paroxetine may be safer than fluoxetine in lactating mothers as it passes less into breast milk. Moclobemide has minimal concentration in breast milk and may be a useful alternative.

Shorter half-life benzodiazepines are preferred, as the infant has a slow metabolism of these drugs and accumulation may occur. With diazepam, lethargy, weight loss and EEG changes have been reported in infants whose mothers were taking large doses, and it is recommended that lactating women take less than 10mg per day. Withdrawal symptoms may occur in the baby when breast-feeding is stopped, therefore weaning should be gradual.

Chapter 6

TREATMENT OF OVERDOSES OF PSYCHOTROPIC DRUGS

Although this section deals with the management of over-doses of the commonly used psychotropic drugs, it has been decided to include amphetamines, narcotic analgesics and L.S.D. Despite the fact that these drugs are rarely used in psychiatric practice, they are subject to abuse and therefore likely to be seen in either the general or the psychiatric hospital. We wish to thank Dr. M. Beasley, Research Fellow, National Toxicology Group - University of Otago Medical School for helping update this chapter.

Note: The National Poisons Information Centre Phone: Fax: Dunedin Dunedin (03) 474-7000 (03) 477-0509

is available for enquiries at any time of the day or night.

(a) FIRST AID

Assessment, with support where necessary, of airway, breathing and circulation is always the first priority. Clear the oropharynx, bring the tongue forward, and assess respiration. The degree of impaired consciousness and/or absent gag reflex are guides to the need for

intubation and/or assisted ventilation. In cases of marked respiratory depression where the full range of ingested agents is uncertain, give naloxone IV (0.4 - 2 mg in adults and 0.1 mg/kg in children) and also consider IV glucose. For hypotension, nonpharmacological treatments (elevation of lower extremities, IV fluid replacement) is often worth trying first.

(b) DECONTAMINATION

Activated charcoal is the mainstay of treatment. The standard dose is 50-100 grams (adults) and 1gm/kg (children). For large ingestions of highly toxic agents, give amounts at the upper range, or alternatively at ten times the estimated dose of drug ingested, whichever is the larger. Charcoal is currently available as Carbisorb (a pre-mixed aqueous suspension), containing 50 gm per 100 ml. Repeat dose charcoal is useful for slow-release formulations. It has also been shown to enhance the elimination of some medicines already absorbed into the body. These agents include phenobarbitone, carbamazepine and meprobamate. Charcoal can be taken orally, or given via nasogastric tube or orogastric tube postlavage. However, with a few exceptions (such as SR dosage forms), gastric lavage is now recommended only for patients presenting within one hour of ingestion and in a heavily drowsy or comatose state. In the latter case, airway protection is required prior to lavage. Syrup of ipecac is falling out of favour even in children and certainly should not be given for overdoses of CNS depressants or convulsants. Whole bowel irrigation is being used increasingly for toxic amounts of

agents not well adsorbed to charcoal, and as an adjunct to repeat dose charcoal for certain SR products.

SPECIFIC TREATMENTS

HYPNOSEDATIVES AND ANXIOLYTICS

(a)

Barbiturates. Toxic reactions generally begin at 1-2 hours and peak at 6-12

hours. Mild to moderate intoxication can include lethargy, slurred speech, confusion, ataxia, vertigo, nystagmus, headache. Respiratory depression occurs relatively early in coma. While cardio-respiratory arrest is less frequent than with shorter acting barbiturates, it remains a hazard. Both vasodilatation and depression of myocardial contractility can occur. Complications include cardiac failure, pneumonia, hypoglycaemia and hypothermia. The primary danger is depression of central control of respiration, and impaired circulation. Cardiac arrhythmias are uncommon. Significant toxicity may occur at 5 times the therapeutic hypnotic dose and severe effects at 10 times (ie 20 - 30 mg/kg) with potentially fatal adult doses being around 6gm or more for phenobarbitone but less for shorter-acting barbiturates.

Treatment Activated charcoal for significant ingestions. Precede with gastric lavage if seen within one hour of ingestion. Repeat dose charcoal can enhance clearance of phenobarbitone. Induction of an alkaline diuresis with intravenous bicarbonate is another option, but this is contraindicated in patients with markedly impaired renal output and/or requiring

vasopressor or inotropic support of the circulation. Give oxygen and artificial ventilation (intermittent positive pressure) if indicated. Estimate the serum barbiturate level if possible (as this helps in deciding the intensity of therapy). Bronchial toilet bronchoscopy and possible tracheostomy may be necessary. Haemodialysis is worthwhile in severe cases.

b) Benzodiazepines

Signs and Symptoms While the adverse effects from pure benzodiazepine overdose by ingestion are usually relatively mild, with CNS symptoms often limited to sedation, dysarthria, confusion, diplopia and ataxia; there are exceptions particularly with the short-acting agents. Coma with serious respiratory depression can occur with triazolam, temazepam, and midazolam, with fatalities being reported. With all classes there is greater risk with the very young and elderly and with alcohol co- ingestion, where respiratory depression is more likely. Recovery may be delayed for benzodiazepines with active metabolites, and withdrawal symptoms may occur. Severe cardiorespiratory symptoms often suggest coingested agents.

Treatment Decontamination for amounts ten times the single therapeutic dose is certainly indicated for the short acting class, and is a useful precaution for all agents. Activated charcoal preceded by gastric lavage for large ingestions seen early. Activated charcoal should be

given. Monitor respiration and level of consciousness. Assisted ventilation may be necessary. Flumazenil is helpful both diagnostically and therapeutically. but its brief action, cost and potential risk with certain co-ingested agents, (tri-cyclics, chloralhydrate, anti-convulsants) are drawbacks Many choose not to use it in the overdose situation and rely on supportive treatment.

(c) Buspirone

Signs and Symptoms Few consistent symptoms in overdose. In one reported case 250mg produced no symptoms in an adult, and early trials involved mean daily doses of up to 1,470mg without serious toxicity.

Treatment Charcoal for large ingestions. Further treatment symptomatic.

(d) Chloral hydrate

Signs and Symptoms Toxicity may occur at 30mg/kg and above. In overdose there is the rapid onset of ataxia, lethargy and coma within 1-2hrs. Pupils are initially miotic and later dilated. Ventricular arrhythmias may develop, as may respiratory depression.

Treatment Monitoring of respiratory and cardiovascular status is essential. Establish an IV line, give oxygen and place on cardiac monitor. If presenting within one hour, gastric lavage with airways protection. Give activated charcoal. For hypotension give IV fluids and alpha-agonists if necessary. Treat ventricular arrhythmias with lignocaine or B-blockers.

(e) Meprobamate

Signs and Symptoms Adult fatalities have occurred with around 12gms. Nystagmus, ataxia, hallucinations and convulsions may occur. In severe cases there may be hypotension, coma or respiratory depression.

Treatment Decontamination measures if possible within 4hrs for ingestion. Lavage may be useful for up to 12hrs. Follow with charcoal, repeat dose if necessary. Monitor for respiratory, CNS, circulatory and acid-base status.

(f) Zopiclone: Imovane Drowsiness, lethargy and ataxia may occur but no serious effects have been reported in the few overdose cases so far. First degree heart block has been reported in one case. Treatment involves decontamination for moderate to large doses and symptomatic support.

ANTIPSYCHOTIC AGENTS

a)

PHENOTHIAZINES

The aliphatic subclass (eg chlorpromazine) are considered the least toxic in overdose. The piperazine class (eg trifluoperazine) contains the most potent agents and extrapyramidal effects are more marked with this group although circulatory effects including hypotension are less common. The piperidine group (eg thioridazine) appears more cardiotoxic and most fatal outcomes are attributable to this class. However, some agents from each class have been strongly suspected as rare causes of cardiac deaths even at therapeutic doses.

Signs and Symptoms Many of the effects can be explained by various receptor blockade mechanisms operating. These include postural hypotension and reflex tachycardia (alpha-adrenergic), blurred vision, urinary retention (cholinergic-muscarinic), and sedation (H1-histamine). Extrapyramidal reactions are common and are partly due to dopamine (D2) receptor blockade which is also largely responsible for the therapeutic effect. Acute dystonic

reactions may be seen in about 10% of ingestions. Occasionally more direct cardiotoxicity occurs, generally signalled by ECG abnormalities such as prolongation of PR, QT, intervals and the QRS complex. Conduction delays are most marked with piperidines. There may be CNS depression with stupor or coma or convulsions. Rarely there may be a malignant-neuroleptic syndrome with severe extrapyramidal reactions, hyperthermia and risk of rhabdomyolysis.

Treatment a) General: Decontamination measures are indicated with ingestions over about 10mg/kg Chlorpromazine equivalents or where the dose is uncertain and/or there are significant symptoms. Decontamination may be effective for several hours postingestion due to anti-cholinergic properties. Charcoal, including a repeat dose is useful.

b) Specific: Hypotension - Usually responds to IV fluids and limb elevation. Alphaadrenergic agonists are the theoretical vasopressor agents of choice. Arrhythmias - Monitor and maintain acid-base and electrolyte balance. Lignocaine and phenytoin are the agents of choice for ventricular arrhythmias. Extrapyramidal reactions - for acute dystonic reactions, benztropine (2mg IM or IV) in adults and diphenhydramine (2mg/kg IV over several minutes) in children Malignant neuroleptic syndrome - dantrolene IV. Monitor acid-base balance, electrolytes, glucose and CPK.

b)

OTHER ANTIPSYCHOTIC AGENTS

BUTYROPHENONES (Haloperidol, Droperidol)

Similar effects to the phenothiazines. Muscle tremor, spasm or weakness, with sedation or coma in severe cases. Hypotension occurs, but ECG abnormalities are less common. Lowered seizure threshold. Treatment is similar to that of the phenothiazines.

DIBENZOXAZEPINES (Loxapine)

Convulsions are a risk (it is structurally related to amoxapine which is well known to cause seizures). Significant symptoms in adults have occurred with ingestions ranging between 800-2200mg. These include drowsiness, coma, hypotension, hyperthermia, rhabdomyolysis with renal failure. Cardiac arrhythmias are not common features.

DIPHENYLBUTYLPIPERIDINES (Pimozide)

There are few published cases of overdose. However 2 notified NZ cases (40mg, 80mg) suggest that the predictable effects of drowsiness and extra-pyramidal reactions can occur but may not be severe at these dosages.

THIOXANTHENES (Thiothixine, flupenthixol)

Mild CNS depression is the most common presentation. Orthostatic and/or diastolic hypotension. Extrapyramidal effects. Ventricular tachycardia, responding to lignocaine, has been described. One ingestion of 250mg was reported to be fatal.

OTHER (clozapine, tetrabenazine, risperidone)

Clozapine interacts with a subgroup of central dopaminergic receptors and in addition possesses potent sympatholytic, anticholinergic, antihistaminic and anti-serotoninergic properties. There is a risk of agranulocytosis with regular dosing. One review suggested that an overdose of 400mg in a previously untreated patient or a dose increment of 300mg or more in treated patients can cause serious, even life-threatening toxicity. Convulsions are well-recognised and pulmonary aspiration was a not infrequent complication in one series review. Extrapyramidal reactions are less common than with older, classical neuroleptics.

Treatment Decontamination is indicated for all but very low ingestions. Monitor level of consciousness, respiration, circulatory status and observe for evidence of aspiration pneumonia. Cardiac monitoring, or at least ECG, for at least 24 hours, especially if

tachycardia unexplained by hypotension, and observation of urinary output. Dopamine or noradrenalin are the preferred pressor/inotropic agents. It has been suggested that all comatose patients should be intubated and a chest radiograph taken on admission and again 24 hours later.

TRICYCLIC ANTIDEPRESSANTS

As there is a possibility of cardiac arrhythmias, including ventricular fibrillation, treatment is a matter of urgency.

Signs and Symptoms Usually appear within 4hrs of overdose. The clinical features are manifestations of a variety of toxic effects on the cardiovascular and nervous systems (CNS and autonomic) plus the respiratory system (often but not always secondary). They include anticholinergic effects such as dry mouth, mydriasis, blurred vision, sinus tachycardia, agitation or drowsiness. Myoclonic twitching and muscle rigidity may occur. Cardiovascular effects include sinus tachycardia and more seriously, impaired intracardiac conduction with ECG signs such as prolonged PR and QT intervals, widened QRS complex, and various arrhythmias including idioventricular rhythm, SV, nodal and ventricular tachycardia, and ventricular fibrillation. Hypotension, aggravated by arrhythmia or metabolic acidosis, is a risk along with hypokalemia. Coma or convulsions in severe cases.

Treatment Serious toxicity may occur with doses over 10mg/kg. Activated charcoal is indicated for ingestions of 5-7 mg/ kg or more. Precede with gastric lavage, at least in obtunded patients if seen within one hour of ingestion. This may be useful even up to 4hrs or more after ingestion of these drugs. With ingestions over 10mg/kg or where the patient is symptomatic, admit to an appropriate facility, eg: ICU. Place on an IV line and cardiac monitor. Assess cardiac rhythm, ECG, circulation including BP, and serum electrolytes and acid-base balance. Intravenous sodium bicarbonate is often useful providing a benefit over and above that associated with correction of acidosis. It is a mainstay of treatment. Hypotension may respond to IV fluids (eg: colloid) and leg elevation, but consider dopamine or dobutamine in refractory cases with CVP monitoring. Arrythmias may reverse with improvement of circulatory, acid-base and electrolyte status. Phenytoin or lignocaine may be effective in resistant cases. Give diazepam or phenytoin for convulsions.

For coma, physostigmine should be used only with extreme caution and symptomatic management with ventilatory support where indicated is preferred.

MONO-AMINE OXIDASE INHIBITORS

Inhibition of the MAO enzymes (A and/or B) results in elevated levels of serotonin, (nor)adrenalin and dopamine both in the brain and storage sites of the autonomic nervous system. However other toxic mechanisms may also be involved.

Signs and .Symptoms of Poisoning Ingestions over 2mg/kg are considered potentially very serious (excluding Moclobemide, see page ). Symptoms depend in part on dietary habits and concurrent medication (including previous MAOIs). The onset of symptoms is typically delayed 6 -12hrs, with maximum effects later. In mild cases, headache, flushing, sweating, palpitations, tremor and dilated pupils may be present. General sympathetic and neuromuscular excitability. In more serious cases there is CNS depression (replacing earlier agitation) and cardiovascular collapse with profound hypotension, pulmonary oedema and asystole.

Hyperpyrexia, severe muscle rigidity, rhabdomyolysis, coma, convulsions may occur. Various coingested agents can increase toxicity considerably, including some tricyclic antidepressants (those with inhibitory effects on serotonin re-uptake) and the SSRIs.

Treatment With excessive or symptomatic ingestions, place an IV line and monitor cardiovascular and respiratory function. Give oxygen. Gastric lavage should be undertaken if within 1hr of ingestion. Follow with activated charcoal.

For severe hypertension. IV phentolamine (20mg stat +- repeat in 10mins) or sodium nitroprusside may be the agents of choice. If hypotension develops, unresponsive to IV fluids, noradrenaline is recommended although ideally with haemodynamic monitoring. Monitor for hyperthermia and hypertonia, and observe for at least 24hrs. Physical cooling methods and paracetamol may be useful.

REVERSIBLE MAOI's (moclobemide)

Signs and symptoms Nausea and vomiting. Drowsiness, confusion or agitation. Hypotension occasionally. Either hypo- or hyperthermia. In one series depressed levels of consciousness and slight increases in blood pressure were seen at doses of 3000-4000mg, plus agitation, sinus tachycardia and mydriasis at higher doses, around 7000-8000mg. There is little risk of life-threatening cardiotoxicity or respiratory depression, even with somewhat higher amounts. The major concern relates to potential interactions, including with antidepressants that inhibit serotonin reuptake. Serious effects have been described with co-ingested sertraline.

Treatment Decontamination with charcoal for moderate to high ingestions. Further treatment symptomatic. With severe effects, consider possibility of coingested drugs. Avoid

concomitant use of clomipramine and other tricyclics which inhibit serotonin reuptake, as mixed overdoses can cause the potentially fatal serotonin syndrome. This can also be a risk with coingested SSRIs.

OTHER ANTIDEPRESSANTS

a) Amoxapine - Toxicity L.D. 100 is 30mg/kg

Signs and Symptoms There is a higher incidence of convulsions and this effect has been described with therapeutic usage also. There may be long-term neurological damage in overdose, possibly secondary to convulsions. Metabolic acidosis may occur as may respiratory depression and coma. There may be renal failure which in some cases is related to rhabdomyolysis possibly secondary to convulsions.

Treatment Activated charcoal for ingestions over 10mg/kg. Precede with gastric lavage if patient seen within one hour of ingestion and is in an obtunded state. Monitor and correct acidbase, fluid and electrolyte balance. Monitor CPK and urine for myoglobin if there are recurrent seizures. Diazepam, phenytoin or chlormethiazole may be effective for convulsions, but if these persist, intubation and neuromuscular blockade may be necessary. Physostigmine may be contraindicated.

b) Maprotiline

Signs and Symptoms Miosis, dry mouth, sinus, tachycardia, PR and QRS prolongation and bradycardia. In severe cases, hypotension, arrythmia and cardiac arrest. Coma and convulsions may occur, the latter more frequent than with tricyclics. Coma may persist for 24hrs.

Treatment Activated charcoal with ingestions over 5- 10mg/kg. Monitor circulatory, respiratory, CNS status and acid-base balance. For convulsions, diazepam may be effective, otherwise phenytoin; physostigmine is contraindicated.

c) Mianserin

Signs and Symptoms Drowsiness and hypotension. (There are few reports of more serious effects.) Sinus tachycardia or bradycardia may occur. Neutropenia or agranulocytosis is described with therapeutic use.

Treatment Activated charcoal with moderate ingestions. Further treatment is symptomatic.

d) SSRI's (paroxetine, fluoxetine, citalopram)

Symptoms are generally minor and of short duration, or may be absent. Drowsiness, tremor, tachycardia, nausea or vomiting have been noted. Various coingested agents can increase the toxic risks considerably. Serotonin syndrome can occur with coingestion of MAOIs. However a similar presentation has rarely been described with suspected pure SSRI ingestions, including sertraline in a child. Symptoms included prolonged hypertension, tremor, hyperthermia, flushing, hallucinations and coma. Serum levels of TCAs and lithium can be increased. The few fatalities reported mainly relate to mixed overdoses.

Treatment Activated charcoal. Monitor cardiovascular parameters and CNS functioning. Further treatment symptomatic. For the rare serious presentation, serotonin (5-HT) antagonists have been suggested; eg cyproheptadine in the context of mixed ingestions with MAOIs.

LITHIUM CARBONATE

Lithium is not plasma protein bound but distributes quite slowly into cells, with equilibrium taking several days or weeks. Therefore serum levels do not correlate very well with the severity of effects in acute, as opposed to chronic poisoning. In the latter situation adverse effects are common at the top of the therapeutic range. It is readily

filtered at the glomerulus and the (largely proximal) tubular reabsorption parallels that of sodium, and is affected by similar factors. Thus conditions such as sodium deficiency, dehydration or cardiac failure which decrease glomecular filtration rate and/or increase proximal tubular reabsorption of sodium and water will promote lithium retention. However, lithium itself can contribute to salt and water loss by impairing renal concentrating ability with resultant polyuria. Hence a vicious circle can develop where the increased reabsorption of lithium consequent on dehydration can exacerbate this condition. It is one cause of nephrogenic diabetes insipidus with fluid depletion and hyponatremia.

Early Signs and Symptoms of Toxicity Nausea, vomiting and diarrhoea are more common with acute poisoning, while renal effects are less significant than with chronic toxicity. The various CNS effects can be delayed unless ingestions are acute-on-chronic. Earliest manifestations include lethargy, coarse tremor of the hands, and polyuria with polydipsia, followed by dysarthria and ataxia. With larger doses the above symptoms become worse and are followed by impairment of consciousness leading to coma, convulsions and delirium. The neurologic signs may be asymmetric, giving the appearance of cerebral haemorrhage. Mechanisms are thought to include interference of ion channels involved in neurotransmission.

Treatment With one-off acute ingestions, decontamination options include gastric lavage if seen early enough, and/or whole bowel irrigation, especially if slow-release formulations are

involved. Gastric lavage may be useful up to 12hours with SR products.(Toxic one-off doses are said to be 40mg/kg or more but even just therapeutic amounts in chronic patients). Charcoal is only indicated for any co-ingested agents. With acute-on-chronic cases, stop the lithium and take the serum level. It has been suggested that all symptomatic chronic patients with levels over 1.5 - 2.0 mmol/l should be admitted. IV fluid replacement with normal saline. Screening ECG and continue to monitor ir abnormal. If the serum level is less than 4 meq/ I and the patient's condition reasonable and the serum level falling adequately, (ie: halving every 24 hours), then conservative measures are generally adequate. Check the lithium level 6 hourly to see it is falling adequately. Haemodialysis is the definitive treatment. It may be necessary at comparatively low serum levels in chronic poisoning depending on the clinical circumstances but in the acute case the indications are a level of higher than 4 meq/l and/or deteriorating clinical condition especially coma, convulsions or refractory hypotension. If not in circulatory failure and glomerular filtration is below normal the excretion rate of lithium may be increased by osmotic diuresis (urea or mannitol infusion) and alkalinisation by sodium lactate or bicarbonate. Diuretics are not advised. Half normal or other hypotonic solutions are recommended rather than normal saline to restore sodium and water balance. Signs of intoxication may last several weeks, even after there is no longer detectable lithium in the blood. Some neurologic impairment may be permanent.

AMPHETAMINES

Eg: Methedrine, 'Dexedrine', 'Durophet', 'Drinamyl' (dexamphetamine with amylobarbitone), numerous slang terms, eg: 'goof balls', 'purple hearts', 'speed', etc. Amphetamine (phenylisopropylamine) and its analogues stimulate adrenergic receptors both directly and indirectly (by causing release of noradrenalin), and inhibit both the degradation of catecholamines (through MAO inhibition) and their reuptake. The result is marked alpha- and beta- adrenergic stimulation as well as CNS stimulation.

Signs and Symptoms of Poisoning Initial intense stimulant effect, usually commencing within 30-60 minutes. Confusion, anxiety, delirium, hallucinations, profuse sweating, tachycardia. Severe effects include either increasing hypertension or arrhythmias with hypotension, marked hyperpyrexia, rhabdomyolysis, convulsions, coma, and circulatory collapse. With chronic abuse, psychosis with aggression can occur. Withdrawal symptoms are not usually severe. The toxic and lethal doses vary considerably both between specific drugs and individuals, with the degree of habituation an important factor. Death has been reported with as little as 1.5mg/kg of metamphetamine.

Treatment Activated charcoal, certainly with ingestions over 1mg/kg in non-tolerant patients. Habitual users can tolerate 5-8 gms amphetamine daily at least. Convulsions can be treated with diazepam, phenytoin or in extreme cases, phenobarbitol. Labetalol or nitroprusside and lignocaine have their advocates for hypertension/tachycardia and ventricular arrhythmias respectively. Dantrolene for severe muscular hyperactivity.

The amphetamines and fenfluramine are some of the few medications for which acid diuresis can enhance renal elimination. This regime involves use of either ascorbic acid (0.5- I .5 gm) or ammonium chloride 4 gm, every 4-6 hours orally, or a 1-2% solution IV; adjusting dose to maintain urinary pH at 5.5-6.5: monitoring also the serum K. Mannitol and frusemide may be used along with large volumes of fluids, until urine flow is 3-6 ml/kg/hr. The patient needs to be observed for pulmonary oedema and hypertension as well as renal function and thus the procedure is a specialist one. Amphetamine induced psychosis is most rationally treated with specific dopamine antagonists, such as the phenothiazines or butyrophenones. However chlorpromazine may result in a delayed but severe fall in blood pressure and haloperidol is preferred.

OPIOIDS

Opium, papaveretum, (Omnopon), morphine, heroin, codeine, methadone (Physeptone), amidone, pethidine (meperidine, Demerol) etc.

Signs and Symptoms of Poisoning The classic triad is miosis, coma and respiratory depression. However pinpoint pupils are not invariable; eg with lomotil (concomitant atropine) or superimposed hypoxia. CNS depression ranging from drowsiness to deep coma, with risk of aspiration. Bradypnoea or apnoea in severe cases. The blood pressure is initially well maintained, later anoxia

may cause hypotension. Agitation, convulsions, or arrhythmias are more likely with meperidine or propoxyphene. Hypothermia and pulmonary oedema are risks.

Assess and maintain airway. Oxygen and assisted ventilation may be necessary. For respiratory and CVS depression and coma give Naloxone IV. Doses may range from 0.01mg/kg -0.2mg/kg but in adults 0.4mg ( I ampoule) stat is a reasonable start. Repeat if necessary at 2-3 min intervals in the event of return of respiratory depression or coma. Maximum dose about 10mg. Bag-mask ventilation until naloxone has been given can often obviate the need for intubation in mild to moderate cases. Hypotension, arrhythmias and convulsions may require additional specific pharmacological treatment. Activated charcoal (preceded by gastric lavage in obtunded patients seen early) when the patient is stabilised. .

10

LYSERGIC ACID DIETHYLAMIDE (LSD)

LSD is an indoleamine structurally related to serotonin. Part of the action involves binding to 5HT receptors and inhibition of serotonergic neurotransmission. Minimally effective dose is about 25ug with hallucinogenesis over 100ug.

Symptoms and Findings Sympathomimetic effects are seen first, including mydriasis, tremor, pilo-erection, flushing, fever and hypertension. Also nausea, vomiting, salivation, hyperreflexia,

weakness and ataxia. Hallucinogenic effects are bizarre and highly variable, usually developing within 30-90 minutes. Complete loss of reality contact (derealisation) and loss of body image, plus visual illusions with changed perceptions of colours, shapes and distances. Acute panic reactions and impaired judgement. Peak effects typically at around 4 hours persisting for 12 hours or so. Convulsions have occurred rarely, along with coma, respiratory depression and hypotension in massive overdose.

Treatment Although the typical doses ingested are well under the estimated toxicologically lethal dose, early presentations should receive activated charcoal. Fatalities can occur secondary to effects on behaviour, eg. increasing the risk of trauma. Some of the most effective antagonists to both the psychic and autonomic effects of LSD are the phenothiazines, but hallucinogen intoxication may be aggravated, and there may be profound hypotension. Diazepam may therefore be the treatment of choice. Haloperidol has been suggested in non-responders. Observation and reassurance in a quiet setting. Cooling measures for fever. In severe toxicity, monitor for hypotension, convulsions, hyperthermia, muscle injury or associated trauma.