What are antipsychotics

Antipsychotic medications, also called just antipsychotics, are medicines usually recommended as the first treatment for psychosis. Antipsychotics work by blocking the effect of dopamine, a chemical that transmits messages in the brain. However, they’re not suitable or effective for everyone, as side effects can affect people differently. In particular, antipsychotics will be monitored closely in people who also have epilepsy, a condition that causes seizures or fits.

People who have cardiovascular disease – conditions that affect the heart, blood vessels, or circulation, such as heart disease – will also be closely monitored.

Psychosis is an illness that makes it hard to tell what is real and what isn’t. Sometimes you might get psychosis if you already have illnesses such as schizophrenia, bipolar disorder or severe depression. It might cause you to have confused thinking, delusions (where you believe things that aren’t real) or paranoia (unjustified suspicion or mistrust of others) or hallucinations (where you see, hear, feel, smell or taste things that are not actually there). Antipsychotic medications can help reduce these symptoms, or sometimes even get rid of them.

Antipsychotic medications sometimes work better if you also use psychological therapy (psychotherapy such as cognitive behavioral therapy [CBT], given by a psychiatrist or psychologist) and community support.

Antipsychotics can usually reduce feelings of anxiety within a few hours of use, but they may take several days or weeks to reduce psychotic symptoms, such as hallucinations or delusional thoughts.

Antipsychotics can be taken by mouth (orally) or given as an injection. There are several slow-release antipsychotics, where you only need one injection every two to six weeks.

The antipsychotic medications are usually classified into conventional and atypical antipsychotics, based upon relative risks for extrapyramidal side effects that are greater with the older, conventional agents. Antipsychotics are also referred to as first and second generation antipscyhotic agents.

The initial antipsychotic medications introduced into clinical practice were the phenothiazines (first generation antipsychotics), but they have been largely replaced in recent years by the atypical antipsychotics or second generation antipsychotics.

First-generation antipsychotics / Typical antipsychotics

First-generation antipsychotics are dopamine receptor antagonists and are known as typical antipsychotics ¹. First-generation antipsychotics include phenothiazines (trifluoperazine, perphenazine, prochlorperazine, acetophenazine, triflupromazine, mesoridazine), butyrophenones (Haloperidol), thioxanthenes (thiothixene, chlorprothixene), dibenzoxazepines (loxapine), dihydroindole (molindone), and diphenylbutylpiperidines (pimozide) ².

First generation antipsychotics (typical antipsychotics)

• Phenothiazines
  • Chlorpromazine, Fluphenazine, Perphenazine, Prochlorperazine, Thioridazine, Trifluoperazine
• Other
  • Haloperidol, Lithium, Loxapine, Molindone, Pimozide

Second-generation antipsychotics / Atypical antipsychotics

Second-generation antipsychotics are serotonin-dopamine antagonists and are also known as atypical antipsychotics. The US Food and Drug Administration (FDA) has approved 12 atypical antipsychotics as of the year 2016. They are risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, lurasidone, iloperidone, cariprazine, brexpiprazole, and clozapine ³.

Clozapine is the drug of choice when the patient has failed multiple trials of standard antipsychotic therapies ¹. Clozapine is also useful in the treatment of tardive dyskinesia. Indications for the use of clozapine include treatment-resistant mania, severe psychotic features, obsessive-compulsive disorder, pervasive developmental disorders, childhood autism, Parkinson disease, Huntington disease and suicidal patient with schizophrenia or schizoaffective disorder.

Second generation antipsychotics (atypical antipsychotics)

• Aripiprazole,
• Asenapine,
• Brexpiprazole,
• Cariprazine,
• Clozapine,
• Iloperidone,
• Lurasidone,
• Olanzapine,
• Paliperidone,
• Pimavanserin,
• Quetiapine,
• Risperidone,
• Ziprasidone

How do antipsychotics work?

First-Generation Antipsychotics

The first-generation antipsychotics work by inhibiting dopaminergic neurotransmission. They are most effective when they block about 72% of the D2 dopamine receptors in the brain. They also have noradrenergic, cholinergic, and histaminergic blocking action.

All first-generation antipsychotics are available and can be administered in oral form. Except for thioridazine, pimozide, and molindone, all other first-generation antipsychotics can also be given parenterally. Haloperidol and fluphenazine can be given in long-acting depot parenteral form.

Second-Generation Antipsychotics

Second-generation antipsychotics work by blocking D2 dopamine receptors as well as serotonin receptor antagonist action. 5-HT2A subtype of serotonin receptor is most commonly involved.

Second-generation antipsychotics can be administered in oral or parenteral forms. Risperidone, olanzapine, aripiprazole, and paliperidone are available as extended release or long-acting injectable forms. Clozapine, asenapine, and olanzapine are available in the sublingual formulation.

Antipsychotic medications uses

Primary uses of antipsychotics

1. Schizophrenia and Schizoaffective disorders: First and second-generation antipsychotics (except clozapine) are indicated for the treatment of an acute episode of psychoses as well as maintenance therapy of schizophrenia and schizoaffective disorders. First generation antipsychotics are better for treating positive symptoms of hallucinations, delusions, among others. They also decrease the risk of a repeat episode of psychosis. Second-generation antipsychotics treat both positive symptoms and negative symptoms like withdrawal, ambivalence, among others and are known to reduce relapse rates.
2. Acute Mania: First-generation antipsychotics are effective in the treatment of acute mania with psychotic symptoms. All second-generation antipsychotics except clozapine can also be used as a treatment of symptoms of acute mania. Antipsychotics are used with mood stabilizers like lithium, valproic acid, or carbamazepine initially and then after symptoms have been stabilized can be gradually decreased and withdrawn.
3. Major Depressive Disorder with Psychotic features: First or second-generation antipsychotic along with an antidepressant is the treatment of choice for depression with psychotic features. Olanzapine and fluoxetine as combination therapy has been FDA approved for treatment-resistant depression.
4. Delusional Disorder: First-generation antipsychotics are indicated in the treatment of delusional disorder as well as paranoia associated with personality disorders.
5. Severe Agitation: Severely agitated, irritable, hostile and hyperactive patients can be treated with a short-term course of first-generation antipsychotics irrespective of the etiology of the behavior disturbance. Second-generation antipsychotics can also be used for treating acute agitation. Antipsychotics can also be used in children with severe autism exhibiting behavioral disturbances though repeatedly giving antipsychotics is not preferred. Risperidone and olanzapine are used to control aggression in children.
6. Tourette Disorder: Haloperidol and pimozide are the antipsychotics most commonly used for this syndrome. Tourette disorder is an off-label indication for second-generation antipsychotics.
7. Borderline Personality Disorder: This type of personality disorder can have symptoms of psychosis and paranoia. Both first and second-generation antipsychotics are used for the treatment of these symptoms.
8. Dementia and Delirium: A low dose of high potency first-generation antipsychotic like haloperidol is recommended for treatment of agitation in delirium and dementia. It is important to use caution in elderly patients as the antimuscarinic effects can cause significant adverse effects in this population. Second-generation antipsychotics can also be used for treating behavioral disturbances in dementia. Off-Label use of second-generation antipsychotics is acquired immunodeficiency syndrome-related dementia.
9. Substance-induced psychotic disorder: In cases of severe psychosis secondary to substance use, antipsychotics can be used to control agitation symptoms. Caution is to be exercised when using first-generation antipsychotics in alcohol withdrawal and phencyclidine intoxication.
10. Childhood Schizophrenia: Recent studies have shown the benefit of clozapine in treating early onset schizophrenia.

Other indications

Huntington disease, Parkinson disease, Lesch-Nyhan syndrome, pervasive developmental disorder are some other conditions where antipsychotics can be used though it is not the primary drug of choice.

Antipsychotics contraindications

First-generation antipsychotics are contraindicated in the following situations:

• History of severe allergy
• Use of central nervous system (CNS) depressants like barbiturates, benzodiazepines, opioids
• With anticholinergic medication like scopolamine or use of phencyclidine.
• Severe cardiac abnormalities
• History of seizure disorder
• Narrow-angle glaucoma or prostatic hypertrophy
• History of or ongoing tardive dyskinesia

Atypical antipsychotics (second-generation antipsychotics) carry the black box warning of increased incidence of stroke in elderly patients with dementia. It is recommended to avoid the use of second-generation antipsychotics along with other drugs that prolong the QTc interval.

Antipsychotics should be avoided during pregnancy especially in the first trimester and should be used only if the benefits outweigh the risks of treatment. Antipsychotics are secreted in breast milk, and it is advised to avoid breastfeeding.

Antipsychotic medications

There are two main types of antipsychotic medications:

1. Typical antipsychotics (first-generation antipsychotics) are an older type of medicine that has been used for many years
2. Atypical antipsychotics (second-generation antipsychotics) are newer medicines.

Atypical antipsychotics (second-generation antipsychotics) are used most often, but some people prefer the older medications. It’s best to talk about your options with your doctor, to find out what works best for you.

Most antipsychotics are tablets, which you need to take every day. Others are given by injection (called ‘depot’ medication). These release medicine into the body slowly over several weeks. Some people prefer injections so they don’t need to remember to take their tablets.

Typical antipsychotics (first-generation antipsychotics)

• Phenothiazines
  • Chlorpromazine, Fluphenazine, Perphenazine, Prochlorperazine, Thioridazine, Trifluoperazine
• Other
  • Haloperidol, Lithium, Loxapine, Molindone, Pimozide

Chlorpromazine

Chlorpromazine is a phenothiazine that was once the most commonly prescribed antipsychotic agent, but that is now rarely used. Current indications include psychotic disorders, schizophrenia, nausea and vomiting, acute intermittent porphyria and intractable hiccups. Chlorpromazine can cause mild and transient serum enzyme elevations and is also a well known cause of clinically apparent acute and chronic cholestatic liver injury.

Chlorpromazine is a tricyclic aliphatic phenothiazine which acts by postsynaptic inhibition of dopamine receptors. Chlorpromazine has other peripheral and central nervous system effects, producing both alpha adrenergic stimulation and blocking histamine- and serotonin-mediated effects. Chlorpromazine is indicated for the therapy of acute and chronic psychosis and for nausea and intractable hiccups. Chlorpromazine was approved for use in the United States in 1957 and was formerly the most commonly prescribed antipsychotic medication, being the prototypic, standard neuroleptic agent against which other antipsychotic agents were tested. In recent years, chlorpromazine has been replaced in large part by the atypical antipsychotics, which have fewer extrapyramidal and hepatic side effects.

Chlorpromazine is available in multiple generic forms as tablets of 10, 25, 50, 100 and 200 mg, as extended release capsules of 200 and 300 mg, and as syrup in various concentrations. Parenteral forms are also available. Chlorpromazine was formerly available under the brand names Thorazine and Largactil. The typical maintenance dose of chlorpromazine is 100 to 200 mg daily.

Chlorpromazine common side effects include drowsiness, dizziness, headache, blurred vision, dry mouth, constipation, tremor, restlessness, muscle spasms and weight gain.

Fluphenazine

Fluphenazine is a phenothiazine antipsychotic agent which is no longer in common use. Fluphenazine was formerly a commonly prescribed antipsychotic medication, but in recent years has been replaced in large part by the atypical antipsychotics, which have fewer extrapyramidal side effects. Fluphenazine is currently used as parentral therapy of psychosis and is available generically in solution for depot injection.

Fluphenazine is a tricyclic aliphatic phenothiazine which acts by postsynaptic inhibition of dopamine receptors. Fluphenazine has other peripheral and central nervous system effects, producing both alpha adrenergic stimulation and blocking histamine- and serotonin-mediated effects. Fluphenazine was approved in the United States in 1972 for use in the therapy of acute and chronic psychosis.

Fluphenazine was previously available under the brand name Prolixin. The typical maintenance dose in adults in 12.5 to 25 mg im or sc every 3 to 6 weeks.

Fluphenazine common side effects include drowsiness, dizziness, headache, blurred vision, dry mouth, constipation, tremor, restlessness, muscle spasms and weight gain. Rare but potentially severe adverse effects include suicidal thoughts or behaviors, neuroleptic malignant syndrome and tardive dyskinesia.

Perphenazine

Perphenazine is a phenothiazine antipsychotic agent, now rarely used in clinical practice. Perphenazine is indicated for the therapy of acute and psychosis and is also used for management of nausea and vomiting.

Perphenazine is a piperazine phenothiazine derivative which acts by postsynaptic inhibition of dopamine receptors. Perphenazine has other peripheral and central nervous system effects, producing both alpha adrenergic stimulation and blocking histamine- and serotonin-mediated effects. Perphenazine was approved for use in the United States in 1957 and was formerly a commonly prescribed antipsychotic, but in recent years, has been replaced in large part by the atypical antipsychotics, which have fewer extrapyramidal side effects.

Perphenazine is available in generic forms as tablets of 2, 4, 8 and 16 mg and previously under the brand name of Trilafon. Oral solutions are also available. Typical doses used to treat schizopheria are 4 to 16 mg two to four times daily, attempting to reduce the dose as soon as possible to a minimum.

Perphenazine common side effects include drowsiness, dizziness, headache, blurred vision, dry mouth, constipation, tremor, restlessness, muscle spasms and weight gain.

Prochlorperazine

Prochlorperazine is a phenothiazine used primarily as an antiemetic agent.

Prochlorperazine is a tricyclic aliphatic phenothiazine which acts by postsynaptic inhibition of dopamine receptors. Prochlorperazine has other peripheral and central nervous system effects, producing both alpha adrenergic stimulation and blocking histamine- and serotonin-mediated effects. Prochlorperazine is indicated primarily for the therapy of nausea and vomiting. Prochlorperazine also has antianxiety and antipsychotic effects, but is used less commonly for these indications compared to the major phenothiazines such as chlorpromazine, fluphenazine, perphenazine, thioridazine and trifluoperazine. Prochlorperazine was approved for use in the United States in 1956 and is still widely used in therapy of nausea and vomiting.

Prochlorperazine is available in generic forms as tablets of 5, 10 and 25 mg, in long acting capsules of 15 mg, as an oral solution of 5 mg/ 5 mL, as suppositories of 2.5, 5 and 25 mg, and in parenteral forms. Prochlorperazine is also available under the brand names of Compazine and Compro. Typical doses for nausea are 5 to 10 mg three to four times daily.

Prochlorperazine common side effects are similar to other phenothiazines and include drowsiness, dizziness, headache, blurred vision, dry mouth, constipation, tremor, restlessness, muscle spasms and weight gain.

Thioridazine

Thioridazine is a phenothiazine antipsychotic agent that is no longer in common use. Thioridazine is indicated for the therapy of acute and chronic psychosis. Use of thioridazine is also restricted because of its propensity to cause prolongation of the QTc interval and increased risk of sudden death.

Thioridazine is a piperazine phenothiazine derivative which acts by postsynaptic inhibition of dopamine receptors. Thioridazine has other peripheral and central nervous system effects, producing both alpha adrenergic stimulation and blocking histamine- and serotonin-mediated effects. Thioridazine was approved for use in the United States in 1978 and was formerly a commonly prescribed antipsychotic medication, but in recent years has been replaced in large part by the atypical antipsychotics, which have fewer extrapyramidal side effects.

Thioridazine is available as tablets of 10, 25, 50 and 100 mg in generic forms and previously under the brand name Mellaril. The usual recommended dose in adults is 50 to 100 mg three times daily, increasing based upon effect and tolerance to a maximum of 800 mg daily.

Thioridazine common side effects include drowsiness, dizziness, headache, blurred vision, dry mouth, constipation, tremor, restlessness, muscle spasms and weight gain.

Trifluoperazine

Trifluoperazine is a phenothiazine and antipsychotic agent that no longer commonly used in clinical practice. Trifluoperazine is indicated for the therapy of acute and chronic psychosis and rarely for nonpsychotic anxiety.

Trifluoperazine is a piperazine phenothiazine derivative which acts by postsynaptic inhibition of dopamine receptors. Trifluoperazine has other peripheral and central nervous system effects, producing both alpha adrenergic stimulation and blocking histamine- and serotonin-mediated effects. Trifluoperazine was approved for use in the United States in 1959 and was formerly a commonly prescribed antipsychotic medication, but has been replaced in recent years in large part by the atypical antipsychotics, which have fewer extrapyramidal side effects.

Trifluoperazine is available as tablets of 1, 2, 5 and 10 mg in generic forms and formerly under the brand name of Stelazine. Oral solutions and parenteral formulations are also available. The typical recommended dose in adults in 1 to 2 mg twice daily, increasing as needed to a maximum of 6 mg daily.

Trifluoperazine common side effects include drowsiness, dizziness, headache, blurred vision, dry mouth, constipation, tremor, restlessness, muscle spasms and weight gain.

Atypical antipsychotics (second-generation antipsychotics)

• Aripiprazole,
• Asenapine,
• Brexpiprazole,
• Cariprazine,
• Clozapine,
• Iloperidone,
• Lurasidone,
• Olanzapine,
• Paliperidone,
• Pimavanserin,
• Quetiapine,
• Risperidone,
• Ziprasidone

Aripiprazole

Aripiprazole is an atypical antipsychotic used in the treatment of schizophrenia and bipolar illness. Aripiprazole is indicated for the therapy of schizophrenia and as either monotherapy or adjunctive therapy for manic and mixed episodes in bipolar disorder, irritability associated with autistic disorder, and as adjunctive treatment with antidepressants for major depressive disorder. Aripiprazole is also indicated for treatment of Tourette disorder.

Aripiprazole is a partial agonist for dopamine type 2 (D2) and serotonin (5-HT1A) receptors and has antagonist activity against serotonin 5HT2A receptors. It was approved for use in the United States in 2002 and is widely used with almost 9 million prescriptions filled yearly.

Aripiprazole is available as tablets of 2, 5, 10, 15, 20 and 30 mg generically and under the brand name Abilify. Aripiprazole is also available as an oral solution (1 mg/mL), as orally disintegrating tablets (10 and 15 mg) and as a solution for intramuscular injection (7.5 mg/mL). The typical initial dose for adults is 10 to 15 mg daily, increasing to a maximum of 30 mg daily. In addition, an extended release formulation of aripiprazole has been developed and approved for use in schizophrenia. This formulation is given in a dose of 400 mg intramuscularly once monthly and is available under the brand name Abilify Maintenna.

Aripiprazole is generally well tolerated, but side effects can include restlessness, sedation, tremor, extrapyramidal symptoms, dizziness, blurred vision, headache, fatigue and nausea. Weight gain is uncommon. Rare, but potentially severe adverse events include suicidal ideation and behaviors, neuroleptic malignant syndrome, cerebrovascular adverse events in the elderly with dementia, hypersensitivity reactions, and body weight gain with complications of dyslipidemia and diabetes.

Asenapine

Asenapine is a second generation (atypical) antipsychotic agent that is taken sublingually and used in the treatment of schizophrenia and manic or mixed episodes associated with bipolar 1 disorder.

Asenapine is a second generation antipsychotic agent which appears to act as a dopamine type 2 (D2) and serotonin (5-HT)-2A receptor antagonist. It is a somewhat unique antipsychotic agent that has a tetracyclic structure similar to that of mirtazapine, and it is administered as a sublingual tablet, being poorly absorbed by the oral route. Several randomized controlled trials have shown that sublingual asenapine improves symptoms of schizophrenia with effects comparable to risperidone and olanzapine. It also has beneficial activity in acute manic and mixed episodes associated with bipolar 1 disorder. Asenapine was approved for use in the United States in 2009 and is available in sublingual tablets of 2.5, 5 and 10 mg under the brand name Saphris. The typical maintenance dose in adults is 2.5 to 10 mg twice daily.

Asenapine common side effects of include dizziness, somnolence, fatigue, nausea, anxiety, restlessness (akathisia) and weight gain. Rare, but potentially severe adverse reactions (mentioned in most antipsychotic and antidepressant product labels) include tardive dyskinesia, major neurologic events, neuroleptic malignant syndrome, orthostatic hypotension, seizures, neutropenia, hypersensitivity reactions, prolongation of the QTc interval and suicidal ideation or behavior.

Brexpiprazole

Brexpiprazole is an atypical antipsychotic used in the treatment of schizophrenia and major depressive disorders. Brexpiprazole was approved for use in the United States in 2015 as therapy for schizophrenia and as adjunctive therapy with antidepressants for major depressive disorders.

Brexpiprazole is a second generation (atypical) antipsychotic agent that is similar in structure and mechanism of action to aripiprazole. These two agents are believed to act as partial antagonists of dopamine type 2 (D2) and serotonin (5-HT)-2A receptors and partial agonists of serotonin 5-HT-1A receptors. In several randomized controlled trials, therapy with brexpiprazole was associated with a lessening of symptoms of schizophrenia and improvement in depression symptom scores in comparison to placebo treatment.

Brexpiprazole is available as tablets of 0.25, 0.5, 1, 2, 3 and 4 mg under the brand name Rexulti. The standard maintenance dose for schizophrenia in adults is 2 to 4 mg daily. The dose for as an adjunctive therapy for major depression is usually less.

Brexpiprazole common side effects include restlessness (akathisia), sedation, tremor, dizziness, blurred vision, fatigue, headaches, nausea and weight gain. Rare, but potential severe adverse reactions (mentioned in most antipsychotic product labels) include tardive dyskinesia, major neurologic events, neuroleptic malignant syndrome, orthostatic hypotension, seizures and neutropenia.

Cariprazine

Cariprazine is an atypical antipsychotic used in the treatment of schizophrenia and manic or mixed episodes of bipolar disorder. Cariprazine was approved for these indications in the United States in 2015 and is available in capsules of 1.5, 3, 4.5 and 6 mg under the brand name Vraylar.

Cariprazine  is an atypical antipsychotic which appears to act as a partial agonist of dopamine type 2 (D2) and 3 (D3) receptors. The D2 and D3 receptors have been identified as targets for therapy of schizophrenia where they appear to be overstimulated. Cariprazine also may have some degree of activity against selected serotonin receptors (5-HT1A). In short term clinical trials, cariprazine was shown to improve symptoms in patients with schizophrenia and manic or mixed episodes of bipolar I disorder.

Cariprazine recommended initial dose is 1.5 mg once daily, with subsequent dose increases based upon efficacy and tolerance to 3 to 6 mg daily.

Cariprazine common side effects include dizziness, sedation, somnolence, nausea, weight gain, restlessness, tremor, akathisia and extrapyramidal symptoms. More serious adverse events can include cerebrovascular events such as transient ischemic attacks, particularly in the elderly with dementia, neurologic malignant syndrome, marked weight gain, dyslipidemia, diabetes, and orthostatic hypotension.

Clozapine

Clozapine was the first atypical antipsychotic approved for treatment of schizophrenia. Because it is associated with severe and potentially fatal side effects (agranulocytosis), its use is restricted to refractory schizophrenia, and monitoring during therapy is required.

Clozapine is an atypical antipsychotic medication that appears to act both as a dopamine (D) and serotonin (5-HT2) receptor antagonist. Clozapine was introduced into clinical practice in 1971, but subsequently withdrawn in 1975 after reports of fatal agranulocytosis with its use. Nevertheless, because of its potent activity, clozapine was approved for restricted use in refractory schizophrenia in the United States in 1989 and only with surveillance using close monitoring of complete blood counts. As a result, use of clozapine has been limited.

Clozapine is available as tablets of 25 and 100 mg in generic forms and under the brand names of Clozaril. The dosage of clozapine varies greatly, from 25 to as much as 900 mg daily based upon clinical response and tolerability.

Clozapine common side effects include sedation, tremors, drooling, dizziness, headache, hypotension and syncope, dry mouth, constipation, and weight gain. Uncommon, but potential severe side effects include severe neutropenia, agranulocytosis, orthostatic hypotension and syncope, falls, seizures, cardiomyopathy, prolongation of the QTc interval, diabetes, dyslipidemia, weight gain and neuroleptic malignant syndrome.

Iloperidone

Iloperidone is a second generation (atypical) antipsychotic agent that is used for treatment of schizophrenia. Iloperidone was approved for use in schizophrenia in the United States in 2010. Several randomized controlled trials have shown that iloperidone improves symptoms of schizophrenia with effects comparable to risperidone and ziprasidone.

Iloperidone is a second generation antipsychotic agent which appears to act as a dopamine type 2 (D2) and serotonin (5-HT)-2A receptor antagonist whose structure and mechanism of action are similar to risperidone.

Iloperidone is available as tablets of 1, 2, 4, 6, 8, 10 and 12 mg under the brand name Fanapt. The typical maintenance dose in adults is 6 to 12 mg twice daily.

Iloperidone common side effects of include dizziness, dry mouth, somnolence, fatigue, nasal congestion, anxiety, restlessness (akathisia) and weight gain. Ilioperidone therapy is also associated with postural hypotension and prolongation of the QTc interval. Rare, but potentially severe adverse reactions (mentioned in most antipsychotic and antidepressant product labels) include tardive dyskinesia, major neurologic events, neuroleptic malignant syndrome, orthostatic hypotension, seizures and neutropenia.

Lurasidone

Lurasidone is a second generation (atypical) antipsychotic agent that is used in the treatment of schizophrenia. Several randomized controlled trials have shown that lurasidone improves symptoms of schizophrenia and it was approved for this indication and for depressive episodes associated with bipolar disorder in the United States in 2010.

Lurasidone is a second generation antipsychotic agent which appears to act as a dopamine type 2 (D2) and serotonin (5-HT)-2A receptor antagonist in a manner similar to risperidone.

Lurasidone is available as tablets of 20, 40, 80 and 120 mg under the brand name Latuda. The typical maintenance dose in adults is 80 to 160 mg daily.

Lurasidone common side effects include somnolence, fatigue, restlessness (akathisia), anxiety, headache, dizziness, constipation, increased appetite, weight gain, orthostatic hypotension and nasopharyngitis. Rare, but potential severe adverse reactions (mentioned in most antipsychotic and antidepressant product labels) include tardive dyskinesia, major neurologic events, neuroleptic malignant syndrome, orthostatic hypotension, seizures, neutropenia, elevations in serum prolactin levels, and suicidal thoughts and behaviors.

Olanzapine

Olanzapine is an atypical antipsychotic that is used currently in the treatment of schizophrenia and bipolar illness. Olanzapine was approved for use in schizophrenia in the United States in 1996 and continues to be used for this indication. Olanzapine is also used in mood disturbances of bipolar 1 disorder and in combination with other agents for treatment of resistant depression in adults.

Olanzapine is a thienobenzodiazepine derivative which appears to act as a dopamine (D1-4) and serotonic (5-HT2A/2C and 5-HT6) receptor antagonist.

Olanzapine is available as tablets of 2.5, 5, 7.5, 10, 15 and 20 mg generically and under the brand name Zyprexa; formulations for parenteral use and orally disintegrating tablets are also available, as are fixed combinations with antidepressants such as fluoxetine (Symbyax and generics). A typical dose regimen is 5 to 20 mg daily, starting with a low dose and increasing cautiously.

Olanzapine common side effects include sedation, increased appetite, weight gain, constipation, orthostatic hypotension, dizziness, dry mouth, weakness and akathisia (restlessness).

Paliperidone

Paliperidone is a second generation (atypical) antipsychotic agent that is available in both oral and long acting parenteral forms and is used in the treatment of schizophrenia. Oral formulations of paliperidone were approved for use in the United States in 2006 as treatment for schizophrenia and schizoaffective disorder, as extended release tablets of 1.5, 3, 6 and 9 mg under the brand name Invega. Subsequently, parenteral formulations of paliperidone palmitate were developed that could be administered every one or three months. These palmitate formulations are given intramuscularly in varying doses and are available under the brand names Invega Sustenna and Invega Trinzia.

Paliperidone is a second generation antipsychotic agent which appears to act as a dopamine type 2 (D2) and serotonin (5-HT)-2A receptor antagonist and is similar in structure and mechanism of action to risperidone. Indeed, paliperidone is the primary active metabolite of risperidone, its chemical name being 9-hydroxyrisperidone. Several randomized controlled trials have shown that oral paliperidone improves symptoms of schizophrenia and is comparable in effect to risperidone and ziprasidone.

Paliperidone common side effects of paliperidone include dizziness, dry mouth, somnolence, fatigue, nasal congestion, anxiety, restlessness and weight gain. Paliperidone therapy is also associated with postural hypotension and prolongation of the QTc interval. The intramuscular formulations also can cause local injection site and hypersensitivity reactions. Rare, but potential severe adverse reactions (mentioned in most antipsychotic and antidepressant product labels) include tardive dyskinesia, major neurologic events, neuroleptic malignant syndrome, orthostatic hypotension, seizures and neutropenia.

Pimavanserin

Pimavanserin is an atypical antipsychotic used in the treatment of hallucinations and psychosis in patients with Parkinson disease.

Pimavanserin is non-dopaminergic atypical antipsychotic agent that appears to act as a selective inverse agonist of the serotonin (5-HT) 2A receptor. It has little or no activity against the 5-HT2B and 2C receptors which may account for its relative lack of adverse effects. The absence of dopamine receptor activity suggested that pimavanserin would be appropriate for patients with Parkinson disease psychosis which is usually resistant to the atypical antipsychotic medications and can be worsened by inhibition of dopaminergic transmission. Clinical studies demonstrated its effectiveness in Parkinson disease psychosis and it was approved for this use in the United States in 2016.

Pimavanserin is available in tablets of 17 mg under the brand name Nuplazid. The typical dose is 34 mg once daily.

Pimavanserin common side effects include somnolence, headache, confusion, hallucinations, and peripheral edema. Rare, but potentially serious adverse events include prolongation of the QT interval and increased risk of death in elderly patients with dementia related psychosis.

Quetiapine

Quetiapine is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorder. Quetiapine is indicated for the treatment of schizophrenia and as either monotherapy or adjunctive therapy for acute manic episodes or as maintenance therapy in bipolar I disorder. It is also used in treatment of depressive episodes associated with bipolar I or II disorde and for major depressive disorders in combination with antidepressants. Quetiapine was approved for use in the United States in 1997 and is still widely used.

Quetiapine is an atypical antipsychotic and dibenzodiazepine derivative which appears to act as a dopamine (D1-4) and serotonin (5-HT2) receptor antagonist. It also may have activity against histamine and alpha adrenergic receptors.

Quetiapine is available as tablets of 25, 50, 100, 200, 300 and 400 mg under the brand name Seroquel. Typical doses vary from 300 to 800 mg daily given in two divided doses. Extended release forms are also available for once daily dosing.

Quetiapine common side effects include dizziness, sedation, somnolence, dry mouth, constipation, weakness, postural hypotension, increased appetite and weight gain. Rare, but potentially severe adverse events include neuroleptic malignant syndrome, tardive dyskinesia, severe dyslipidemia, diabetes, weight gain, hypotension, bone marrow suppression and cataracts.

Risperidone

Risperidone is an atypical antipsychotic that is used widely in the treatment of mania and schizophrenia. Risperidone is also used for management of irritability with autistic disorder in children and adolescents. Risperidone was approved for use in the United States in 1993 and it is still widely used.

Risperidone is a benzisoxazole derivative which appears to act as a dopamine type 2 (D2) and serotonin (5-HT2) receptor antagonist. Risperidone is indicated for treatment of schizophrenia and as monotherapy or combination therapy for acute manic or mixed episodes of bipolar I disorder in adults.

Risperidone is available as tablets of 0.25, 0.5, 1, 2, 3 and 4 mg generically and under the brand name of Risperdal. Oral solutions for pediatric use are available as are orally disintegrating tablets and formulations for parenteral administration. The typical initial dose in adults is 1 mg once or twice daily, with increase in dose to as high as 8 mg daily based upon indications, efficacy and tolerance.

Risperidone common side effects include somnolence, fatigue, restlessness, dizziness, dry mouth, increased saliva, constipation, increased appetite and weight gain. Rare, but potentially severe adverse events include cerebrovascular events, tardive dyskinesia, neuroleptic malignant syndrome, orthostatic hypotension, suicidal ideation and behavior, seizures, diabetes and agranulocytosis.

Ziprasidone

Ziprasidone is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorder. Ziprasidone is indicated for the therapy of schizophrenia and as either monotherapy or adjunctive therapy for acute manic episodes and maintenance therapy for manic and mixed episodes in bipolar disorder. Ziprasidone was approved for use in the United States in 2001 and is widely used.

Ziprasidone is a benzisothiazolyl piperazine-type atypical antipsychotic that appears to act as a dopamine type 2 (D2) and serotonin (5-HT2) receptor antagonist. It also has moderate activity against α-adrenergic and histamine receptors.

Ziprasidone is available as capsules of 20, 40, 60 and 80 mg generically and under the brand name Geodon. It is also available as an oral suspension and as a solution for intramuscular injection. The typical initial dose is 20 mg twice daily, which can be increased to a maximum of 100 mg twice daily.

Ziprasidone common side effects include somnolence, dizziness, restlessness, fatigue, headache, nausea, dyspepsia, anorexia, dry mouth and blurred vision. Weight gain is uncommon and extrapyramidal symptoms occur in about 5% of patients.

Antipsychotics side effects

Antipsychotics can have side effects, although not everyone will experience them and their severity will differ from person to person.

Antipsychotics side effects can include:

• drowsiness or feeling sleepy
• shaking and trembling
• weight gain
• restlessness
• muscle twitches and spasms – where your muscles shorten tightly and painfully
• blurred vision
• dizziness
• constipation
• loss of sex drive (libido)
• dry mouth
• nausea or indigestion

Tell your doctor or mental health worker if you have side effects that are becoming particularly troublesome. There may be an alternative antipsychotic medicine you can take that causes less side effects.

Never stop taking medication prescribed for you unless advised to do so by a qualified healthcare professional responsible for your care.

Suddenly stopping prescription medication could trigger a return of your symptoms (relapse). When it’s time for you to stop taking your medication, it will be done gradually.

First-generation antipsychotics side effects

First-generation antipsychotics are associated with significant extrapyramidal side effects. Anticholinergic adverse effects like dry mouth, constipation, urinary retention are common with low potency dopamine receptor antagonists like chlorpromazine, thioridazine. The action of H1 histamine block by the dopamine receptor antagonists causes sedation. Chlorpromazine is the most sedating while fluphenazine, haloperidol, and pimozide are less sedating. Dopamine receptor antagonists also lower seizure threshold and chlorpromazine and thioridazine are more epileptogenic than others. Haloperidol can cause abnormal heart rhythm, ventricular arrhythmia, torsades de pointes and even sudden death if injected intravenously. Other dopamine receptor antagonists cause prolongation of OTc interval, prolonged atrial and ventricular contraction and other cardiac conduction abnormalities. Thioridazine has a black box warning for sudden cardiac death. Low-potency dopamine receptor antagonist like chlorpromazine, thioridazine commonly cause orthostatic hypotension. This adverse effect caused by alpha-adrenergic block is usually seen initially when treatment is started and patients often develop a tolerance. It is important to avoid treating the hypotension with Epinephrine. Leukopenia, thrombocytopenia and blood dyscrasia are rare side effects of treatment with dopamine receptor antagonists. Increased serum prolactin levels along with galactorrhea, breast enlargement, amenorrhea, impotence in men and anorgasmia in women are known adverse effects due to the action of the dopamine receptor block in the tuberoinfundibular tract. Allergic dermatitis and photosensitivity can occur with chlorpromazine. Chlorpromazine is also associated with blue-gray skin discoloration and benign pigmentation of the lens and cornea. Thioridazine can cause retinal pigmentation which can continue even after the drug is discontinued ⁴.

Neuroleptic malignant syndrome is a rare but fatal adverse effect that can occur at any time during treatment with first-generation antipsychotics. The onset of symptoms is over 24 to 72 hours with increased temperature, severe muscular rigidity, confusion, agitation, elevation in white blood cell count, elevated creatinine phosphokinase levels, elevated liver enzymes, myoglobinuria and acute renal failure. The antipsychotic should be immediately discontinued and dantrolene 0.8 to 2.5 mg/kg every 6 hours up to 10 mg per day is the drug of choice. Adequate hydration, cooling and close monitoring of vital signs and serum electrolytes should be done. Though the risk of neuroleptic malignant syndrome is more with first-generation antipsychotics, second-generation antipsychotics are also known to cause this adverse effect.

Atypical antipsychotics side effects

Atypical antipsychotics or second-generation antipsychotics have a decreased risk of extrapyramidal side effects as compared to first-generation antipsychotics. Serotonin-dopamine antagonists are associated with significant weight gain and development of metabolic syndrome. The FDA recommends monitoring personal and family history of diabetes, dyslipidemia, weight, and height, waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile for all patients.

• Risperidone is associated with dizziness, anxiety, sedation, and extrapyramidal side effects.
• Paliperidone can cause temperature sensitivity to hot or cold temperatures and Qtc prolongation.
• Olanzapine has been associated with most frequently with weight gain, increased appetite, and somnolence. Quetiapine is the least likely to cause extrapyramidal side effects.
• The most common side effects of quetiapine are somnolence, orthostatic hypotension, and dizziness.
• Ziprasidone has almost no weight gain but can cause prolongation of QTc.
• Aripiprazole is the most common side effect of agitation, headache, and akathisia-like restlessness.
• Asenapine can cause an increase in serum prolactin levels, weight gain, and prolongation of QTc. Clozapine can cause hypersalivation, tachycardia, hypotension and anticholinergic side effects.
• Clozapine is unusual in that it suppresses dyskinesia. Clozapine cause agranulocytosis, leukopenia and requires monitoring of white blood cells and absolute neutrophil count.The FDA guidelines indicate monitoring absolute neutrophil count weekly for the first 6 months and if normal can be monitored every 2 weeks after that. Treatment with clozapine should be discontinued if absolute neutrophil count drops below 1000 cells per cubic millimeter or below 500 cell per cubic millimeter in those with benign ethnic neutropenia. Clozapine can also cause the rare side effect of cardiomyopathy and myocarditis.

Larger doses of all antipsychotics are associated with a higher incidence of adverse effects.

References

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4. Ross E, Barnett R, Tudhope R, Vasudev K. Can We Improve Physical Health Monitoring for Patients Taking Antipsychotics on a Mental Health Inpatient Unit? J Clin Psychopharmacol. 2018 Oct;38(5):447-453