ANTIPSYCHOTIC DRUGS

Martin trba, PharmD., PhD.

Associate professor

2012

Psychotic disorders (psychosis):

are severe mental disorders that cause abnormal thinking and
perceptions.

Classification of psychotic disorders

Schizophrenia see below
Schizoaffective disorder disorder of both thought and
mood

Delusional disorder incl. paranoid psychosis

Substance-induced psychotic disorder use/withdrawal
of amphetamines, cocaine, alcohol, LSD, psilocybe

Psychotic disorder due to a medical condition

(organic psychosis) - disturbances caused by head injury or
tumor

others

SCHIZOPHRENIA

Definition:

Chronic (relapsing and remitting) disorder of though

characterised by acute psychotic episodes
periods of impaired psychosocial functionality and residual
symptoms in between

Typical feature is a loss of touch with reality

Life-time prevalence 1% of population

Onset in adolescence/early adulthood

Etiology unclear

significant genetic component

neurodevelopmental theory aberrant intrauterine brain
development (infections, hypoxia?) abnormal neuronal shape,
position and connections

Highly disabling strong medical, social and economical

implications

SCHIZOPHRENIA -PATHOPHYSIOLOGY

Morphological changes

brain asymmetry with decreased cortical/hyppocampal size and

increased ventricular size

Neurotransmitter changes

theories were derived from pharmacological observations

unfortunately no detail understanding to the neurochemistry

Dopamine theory central and most important one, it will

Glutamate theory

be discussed further in detail

Psychotic-like symptoms induced by administrations of NMDA-antagonists

(ketamine and phencyclidine
Reduction of glutamatergic and increased dopaminergic neurotransmission
impairment of gating fucntion of GABA neurons

Serotonin theory

schizophrenia-like symptoms induced by LSD,psilocybine

many atypical antipsychotics block also 5-HT receptors (! 5-HT2A)

DOPAMINE THEORY:
DOPAMINERGIC SYSTEMS IN CNS
Dopamine tract Innervation Function

D-antagonist
effects

Mesolimbic

Limbic areas
(amygdala)

Arousal, memory,
stimulus processing,
behavior, spontaneity,
motivation,
assertively, selfconfidence

Mesocortical

Cortex
frontal and
prefrontal

Communication,
cognition, social
functions and stress
response

Nigro-striatal

Caudate nucl.,
Putamen

Extrapyramidal
system and movement
coordination

Movement
disorders

Tuberoinfundibular

Pituitary
gland

Prolactin secretion
regulation

Hyperprolactinea
mia, galactorhea,
gynecomastia

Psychosis relief

Psychosis relief
Akathisia?

DOPAMINE THEORY OF SCHIZOPHRENIA

Symptoms of schizophrenia - hyperactivity of dopaminergic

pathways in mesolimbic/mesocortical system

Psychotic symptoms and related behavioural changes can be

Induced by
Drugs causing dopamine release e.g., amphetamines
D-agonists (e.g., bromocryptine) and dopamine precursors (like L-DOPA)
Inhibited by
Drugs blocking dopamine storage (e.g., reserpine)
D-antagonists

Dopamine receptors D1 type (D1 and D5) and D2-type (D2, D3, D4)

D2-receptors
Are evidently involved
correlation between D2-antagonistic effects and antipsychotic action
Clinical response in occupancy of 60-80% of D2 receptors
for atypical drugs 30-50% is enough

Some theories suggest

overactivation of D2 receptors in subcortical regions (positive
symptoms)
Deficient activation of D1 receptors (negative symptoms)

SYMPTOM CLUSTERS IN SCHIZOPHRENIA

Positive symptoms
Delusions (fixed false beliefs, often paranoid/conspirative in nature)
Hallucinations (usually hearing of voices, typically spurring)
Incoherent thought (disconnection - loosing of associations, inability of logical
analysis of the situation, ambivalence contradictory thoughts)

Suspiciousness, hostility and potentially aggression

Disorganized speech
Stereotype/abnormal movements
Negative symptoms
Affective flattening poor emotional experience
Anhedonia loss of the capacity to experience pleasure
Avolition - lack of desire, drive, or motivation to pursue goals
Withdrawal from social contacts
Cognitive symptomes

Impaired attention, working memory and executive function

Clinical picture may vary considerably, especially according to the positive/negative

symptoms balance

GOALS AND MEANS OF TREATMENT

Goals
To suppress any acute psychotic episode
To prevent relapses and progression of the disease
To restore/keep the psychosocial functionality (family, job and social
networks)
Therapy
should be complex
is not causal
Pharmacologic the mainstay of the treatment
Common mechanism of action: D2-antagonism
Additional mechanisms: antagonism on 5-HT2A/C. 1, M, H1,
Adverse effects
Therapeutic effects

PHARMACOTHERAPY OF SCHISOPHRENIA
GENERAL ASPECTS

Response in 70% of patients

Negative symptoms respond much less than positive symptoms

improved in atypical drugs

The full antipsychotic effect deserve weeks (3-4 weeks).

30% are treatment resistant forms = big clinical issue!!!

only non-specific sedative and aggression controlling effects

can be induced immediately

Monotherapy is preferable

combinations only in resistant forms

PHARMACOTHERAPY OF SCHISOPHRENIA
GENERAL ASPECTS

Long-term treatment

is usually initiated with newer atypical drugs

Compliance often big issue, i.m. injection (acute episode) or

depot i.m. forms (to avoid chronic non-compliance)

Dose is usually gradually titrated, adverse effects should be closely

monitored
Typical antipsychotics

useful in acute psychotic episode with strong aggression

(sedative effects, injectable forms are available)

PHARMACOKINETICS OF ANTIPSYCHOTICS

Route of administration
oral or by i.m. injection
once or twice a day.

Generally highly lipophilic drugs

highly bound on plasma proteins

large distribution into the tissues (high Vd), risk of accumulation
T1/2 of most antipsychotics

CL depends entirely on hepatic biotransformation

is long (15-30 hours)

mostly CYP 450-dependent (exception ziprasidone)

genetic polymorphisms (e.g., in CYP 2D6 - substrates risperidon)

Slow- release (depot) preparations

flupentixol decanoat, fluphenazine decanoat

active drug is esterified with heptanoic or decanoic acid
dissolved in oil.
Given as an i.m. inj., the drug acts for 2-4 weeks.

Classification of antipsychotic drugs:

I. typical antipsychotics
a) basal (sedative):
- chlorpromazine (typical example, a phenothiazine structure)
- chlorprotixene, thioridazine

b) incisive:
- haloperidol (typical example, a butyrophenone structure)
- fluphenazine, flupenthixol, clopenthixol

II. atypical antipsychotics:

a) Multi Acting Receptor Targeted Antipsychotics (MARTA)
- olanzapine, zotepin, quetiapine, clozapine
D1/2, 5-HT2A, , H1, M and receptor antagonists

b) Dopamine and serotonin receptor antagonists

- risperidone, ziprasidone, aripiprazole
c) D2-selective antagonists
- sulpiride, amisulpiride

CLASSIFICATION OF ANTIPSYCHOTICS

Incisive vs. sedative (typical) antipsychotics

Incisive - more potent and selective D2-antagonits than sedative (basal)

drugs
Incisive drugs are more effective
however, they induce significant problems with extrapyramidal adverse effects
Sedative drugs are weaker D2-antagonists, but block also H1, 1, M (which

explain sedative effects as well as some adverse effects)

Atypical vs. typical antipsychotics

Atypical drugs
less extrapyramidal complications
Have improved efficacy against negative symptoms
Might be useful in treatment-resistant group of patients
(especially clozapine)
Difference in overal efficacy ?

Adverse effects - A- type (dose dependent)

I. Extrapyramidal motor disturbances
- result from D2 blockade in the nigrostriatal pathways

- more frequent in typical (especially incisive) antipsychotics

Acute (reversible)
Parkinson-like symptoms (further details on next seminar)

Tremor
Rigidity
Bradykinesia/akinesia:

Acute dystonias
- severe muscle spasms, very painful (occur within initial 24-96h)
Orofacial muscles (e.g., blepharospasm - eye lid spasm, oculogyric crisis
turning of eye bulbi upward),
Neck muscle spasms (torticollis wry neck)
Tongue protrusion
Can be life-threatening pharyngeal-laryngeal forms

Akathasia
motor restlessness (restless leg syndrome)
inner restlessness

Treatment: benzodiazepines, beta-blockers

ADVERSE EFFECTS - A- TYPE (DOSE DEPENDENT)

I. Extrapyramidal motor disturbances

Slowly developing (often irreversible)

Tardive dyskinesia
involuntary movements in face/tongue and limbs
appearing after months or years of antipsychotic
treatment.
Includes: tongue thrusting, rolling and fly catching,
Chewing and rabbit lip syndrome (impaired speech, eating)
Grimassing, blinking + choreiform movements of extremities
(caused by up-regulation of D-receptors in striatum?)

Mechanisms of EPS
Dopamine (-)

cholinergic
pathway (+)
S. NIGRA

CORPUS
STRIATUM

GABA (-)

Adverse effects A -type

II. Decreased seizure threshold
- in predisposed persons may induce seizures (convulsions)!!!
- mainly in high doses

III. Sedation and cognitive deficit

- occurs with many antipsychotics
- antihistamine (H1) activity significantly contributes to this effects
(especially sedative typical drugs but also others)

IV. Antimuscarinic activity

- blurring of vision
- increased intraocular pressure (glaucoma!)
- dry mouth and eyes
- constipation
- urinary retention

Adverse effects A -type

V. Cardiovascular adverse reactions
- Orthostatic hypotension - -adrenoreceptors blockade
- Drug induced QT syndrome (e.g., thioridazine)

VI. Weight gain + dyslipidemia

- probably related to 5-HT blockade and apetite stimulation

VII. Diabetes
- atypical, esp. olanzapine and clozapine

Adverse effects
B type unpredictable

- neuroleptic malignant syndrome

Muscle rigidity, rapid rise in body temp. and mental confusion,
instable blood pressure and tachycardia.
Death rate 10-20% (renal or cardiovascular failure)
Discontinuation of therapy
Supportive care is essential (cooling!).
It is more frequent with typical antipsychotics.

- jaundice (with older drugs, mainly phenothiazines)

Usually mild cholestatic hepatitis (obstructive origin), disappears quickly
when the drug is stopped

- leukopenia and agranulocytosis

rare but potentially fatal complication occurring in clozapine its use requires
regular monitoring of blood cell counts

ADVERSE EFFECTS
OTHERS
- urticarial skin reactions
mainly phenothiazines
- depositions

- in skin in complex with melanine

gray discolorations of skin and excessive UV light sensitivity
- in cornea/lens (vision disturbances)

SELECTED TYPICAL DRUGS

Chlorpromazine
1st classic neuroleptic drug, inexpensive
Strong autonomic effects (blocks also ,M, H1)
Route: p.o., i.m., i.v.
Ind.:
schizophrenia (against positive symptoms)
Bipolar disorder (against mania)
Not to be used: in patients with dementia, treated by IMAO
Slow discontinuation after longer treatment
Be careful about combination with: sedative drugs, QT-prolonging drugs,
hypotensives

Haloperidol
Prototype incisive neuroleptic drug
Butyrophenone (not phenothiazine)
- Ind.:
Schizophrenia (both acute and chronic)
Korsakov syndrome (in alcoholics acute amnesia, confusion, delusions,
apathy)
Delusional disorders (like paranoid disorders)
Psychomotoric calm-down
Antiemetics
-

Less vegetative symptoms, more extrapyramidal symptoms

SELECTED ATYPICAL DRUGS

Olanzapine

MARTA much less antiD2 and more anti5-HT2A

IND

Schizophrenia
Manic phase of bipolar disorder (acute treatment and prophylaxis)

Superior to haloperidol in overall efficacy in schizophrenia

Good response of positive and negative symptoms
Response in partial resistance and failure of other atypical drug
Adverse reactions: body weight gain, dyslipidemia, diabetes (monitoring!), slight
sedationminimal problems with EPS

Clozapine
Developed in 70s, but not introduced into clinical practice

Adverse effect: leukopenia and agranulocytosis (monitoring),

epileptic seizures, anticholinergic effects,

The only drug clearly effective in pharmacoresistant forms of disease!!!

Very good response in negative symptoms
Drug of 3rd choice due to the safety concerns