Antipsychotic

An antipsychotic (or neuroleptic) is a tranquilizing psychiatric medication primarily used to manage psychosis (including delusions or hallucinations, as well as disordered thought), particularly in schizophrenia and bipolar disorder.

Mechanism of action
All antipsychotic drugs tend to block D2 receptors in the dopamine pathways of the brain. This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. It is the blockade of dopamine receptors in this pathway that is thought to control psychotic experiences.

Structural effects
Many studies now indicate that chronic treatment with antipsychotics affects the brain at a structural level, for example increasing the volume of the basal ganglia (especially the caudate nucleus), and reducing cortical grey matter volume in different brain areas. The effects may differ for typical versus atypical antipsychotics and may interact with different stages of disorders. Death of neurons in the cerebral cortex, especially in women, has been linked to the use of both typical and atypical antipsychotics for individuals withAlzheimers.

Side effects
Antipsychotics are associated with a range of side effects. It is well-recognized that many people stop taking them (around two-thirds even in controlled drug trials) due in part to adverse effects. Extrapyramidal reactions include acute dystonias, akathisia,parkinsonism (rigidity and tremor), tardive dyskinesia, tachycardia, hypotension, impotence, lethargy, seizures, intense dreams or nightmares, and hyperprolactinaemia. Side effects from antipsychotics can be managed by a number of different drugs. For example,anticholinergics are often used to alleviate the motor side effects of antipsychotics. Some of the side-effects will appear after the drug has been used only for a long time. Following are details concerning some of the side effects of antipsychotics:    Antipsychotics, particularly atypicals, appear to cause diabetes mellitus and fatal diabetic ketoacidosis, especially (in US studies) inAfrican Americans. Antipsychotics may cause pancreatitis. The atypical antipsychotics (especially olanzapine and clozapine) seem to (due to occupancy of the histamine receptor) cause weight gain more commonly than the typical antipsychotics. The well-documented metabolic side effects associated with weight gain include diabetes, which can be life-threatening. Antipsychotics increase the likelihood of a fatal heart attack, with the risk of death increasing with dose and the length of time on the drug. Clozapine also has a risk of inducing agranulocytosis, a potentially dangerous reduction in the number of white blood cells in the body. Because of this risk, patients prescribed clozapine may need to have regular blood checks to catch the condition early if it does occur, so the patient is in no danger. One of the more serious of these side effects is tardive dyskinesia, in which the sufferer may show repetitive, involuntary, purposeless movements (that are permanent and have no cure) often of the lips, face, legs, or torso. It is believed that there is a greater risk of developing tardive

 

dyskinesia with the older, typical antipsychotic drugs, although the newer antipsychotics are now also known to cause this disorder.  A potentially serious side effect of many antipsychotics is that they tend to lower an individual's seizure threshold. Chlorpromazine and clozapine, in particular, have a relatively high seizurogenic potential. Fluphenazine, haloperidol, pimozide and risperidone exhibit a relatively low risk. Caution should be exercised in individuals that have a history of seizurogenic conditions such as epilepsy, orbrain damage. Neuroleptic malignant syndrome, in which the drugs appear to cause the temperature regulation centers to fail, resulting in a medical emergency, as the patient's temperature suddenly increases to dangerous levels. Dysphoria. Drug-induced parkinsonism due to dopamine D2 receptor blockade may mimic idiopathic parkinsonism. The typical antipsychotics are more prone to cause this, compared to the atypical antipsychotics. Sexual dysfunction, which may rarely continue after withdrawal, similar to Post-SSRI sexual dysfunction (PSSD). Dystonia, a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. Hyperprolactinaemia. The breasts may enlarge and discharge milk, in both men and women due to abnormally-high levels of prolactinin the blood. Prolactin secretion in the pituitary is normally suppressed by dopamine. Drugs that block the effects of dopamine at the pituitary or deplete dopamine stores in the brain may cause the pituitary to secrete prolactin. There is evidence that exposure may cause demyelinating disease in laboratory animals. Following controversy over possible increased mortality (death) related to antipsychotics in individuals with dementia, warnings have been added to packaging.

 

  

 

Some people suffer few apparent side effects from taking antipsychotic medication, whereas others may have serious adverse effects. Some side effects, such as subtle cognitive problems, may go unnoticed. There is a possibility that the risk of tardive dyskinesia can be reduced by combining the antipsychotics with diphenhydramine orbenzatropine, although this remains to be established. Central nervous system damage is also associated with irreversible tardive akathisia and/or tardive dysphrenia.

Common antipsychotics
Commonly used antipsychotic medications are listed below by drug group. Trade names appear in parentheses.

First generation antipsychotics

Main article: Typical antipsychotic

Butyrophenones
Main article: Butyrophenones   Haloperidol (Haldol, Serenace) Droperidol (Droleptan)

Phenothiazines
Main article: Phenothiazines           Chlorpromazine (Thorazine, Largactil) Fluphenazine (Prolixin) - Available in decanoate (long-acting) form Perphenazine (Trilafon) Prochlorperazine (Compazine) Thioridazine (Mellaril, Melleril) Trifluoperazine (Stelazine) Promazine Triflupromazine (Vesprin) Levomepromazine (Nozinan) Promethazine (Phenergan)

Thioxanthenes
Main article: Thioxanthenes      Chlorprothixene (Cloxan, Taractan, Truxal) Clopenthixol (Sordinol) Flupenthixol (Depixol, Fluanxol) Thiothixene (Navane) Zuclopenthixol (Cisordinol, Clopixol, Acuphase)

Second generation antipsychotics

Main article: Atypical antipsychotic    Clozapine (Clozaril) of agranulocytosis. Requires weekly to biweekly complete blood count due including to risk

Olanzapine (Zyprexa) - Used to treat psychotic disorders acute manic episodes, and maintenance of bipolar disorder

schizophrenia,

Risperidone (Risperdal) -Divided dosing is recommended until initial titration is completed, at which time the drug can be administered once daily. Used off-label to treat Tourette syndrome and anxiety disorder. Quetiapine (Seroquel) - Used primarily to treat bipolar disorder and schizophrenia, and "off-label" to treat chronic insomnia andrestless legs syndrome; it is a powerful sedative. Ziprasidone (Geodon) - Approved in 2004 to treat bipolar disorder. Side-effects include a prolonged QT interval in the heart, which can be dangerous for patients with heart disease or those taking other drugs that prolong the QT interval. Amisulpride (Solian) - Selective dopamine antagonist. Higher doses (greater than 400 mg) act upon post-synaptic dopamine receptors resulting in a reduction in the positive symptoms of schizophrenia, such as psychosis. Lower doses, however, act upon dopamine autoreceptors, resulting in increased dopamine transmission, improving the negative symptoms of schizophrenia. Lower doses of amisulpride have also been shown to have antidepressant and anxiolytic effects in non-schizophrenic patients, leading to its use in dysthymia and social phobias. Amisulpride has not been approved for use by the Food and Drug Administration in the United States. Asenapine (Saphris) is a 5-HT2A- and D2-receptor antagonist under development for the treatment of schizophrenia and acute mania associated with bipolar disorder.

 

   

Paliperidone (Invega) - Derivative of risperidone that was approved in 2006. Iloperidone (Fanapt) - Approved by the FDA on May 6, 2009. Zotepine (Nipolept, Losizopilon, Lodopin, Setous)- An atypical antipsychotic indicated for acute and chronic schizophrenia. It was approved in Japan circa 1982 and Germany in 1990. Sertindole (Serdolect, and Serlect in Mexico). Sertindole was developed by the Danish pharmaceutical company H. Lundbeck. Like the other atypical antipsychotics, it is believed to have antagonist activity at dopamine and serotonin receptors in the brain. Lurasidone (Latuda), a recently FDA approved once daily antipsychotic with a favorable efficacy and safety profile.

Third generation antipsychotics

 Aripiprazole (Abilify) - Mechanism of action is thought to reduce susceptibility to metabolic symptoms seen in some other atypical antipsychotics. The extent to which these effects differ from other atypical antipsychotics is debated. Partial agonists of dopamine.

Other options
 Cannabidiol is one of the main components of Cannabis sativa. Cannabidiol differs from the active drug in cannabis,tetrahydrocannabinol, in that cannabidiol lacks the typical mind altering and recreational effects. One study has suggested that cannabidiol may be as effective as atypical antipsychotics in treating schizophrenia. Some further research has supported these results, and found fewer side effects with cannabidiol than with amisulpride. Tetrabenazine is similar in function to antipsychotic drugs, though is not, in general, considered an antipsychotic itself. Its main usefulness is the treatment of hyperkinetic movement disorders such as Huntington's disease and Tourette syndrome, rather than for conditions such as schizophrenia. Also, rather than having the potential to cause tardive dyskinesia, which most antipsychotics have, tetrabenazine can be an effective treatment for the condition. Metabotropic glutamate receptor 2 agonism has been seen as a promising strategy in the development of novel antipsychotics. When tested in patients, the research substance LY2140023 yielded promising results and had few side effects. The active metabolite of this prodrug targets the brain glutamate receptors mGluR2/3 rather than dopamine receptors. Glycine transporter 1 inhibition. RG1678 has been shown in phase 2 clinical trials to be selectively effective for the negative symptoms of schizophrenia. A placebo-controlled trial has suggested that adding L-theanine, an amino acid found in green tea and available as supplement, to ongoing antipsychotic medication may be helpful in reducing some symptoms of schizophrenia.