side effects of antipsychotics in a tabular form from standard resources
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antipsychotic medication side effects NHS extrapyramidal metabolic hyperprolactinaemia QT
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| System / adverse effect | Typical clinical features | Usual mechanism | Drugs with relatively higher risk / key points |
|---|---|---|---|
| Extrapyramidal symptoms (EPS) | Acute dystonia, parkinsonism, akathisia, tardive dyskinesia | Nigrostriatal D2 receptor blockade. Tardive dyskinesia is linked to dopamine-receptor supersensitivity after chronic blockade. | More likely with high-potency first-generation agents, especially haloperidol and fluphenazine; dose-related. Lower risk with clozapine and quetiapine. |
| Acute dystonia | Painful sustained muscle contractions: torticollis, jaw spasm, oculogyric crisis; rarely laryngospasm | D2 blockade in nigrostriatal pathway | Usually hours to days after starting/increasing dose; more frequent in young males and with high-potency FGAs. |
| Drug-induced parkinsonism | Tremor, rigidity, bradykinesia, masked facies, shuffling gait | D2 blockade | Often develops over days to weeks. |
| Akathisia | Subjective inner restlessness, pacing, inability to sit still; may be mistaken for agitation | D2 blockade | Can occur early. Recognize because it is distressing and may be associated with suicidal ideation. |
| Tardive dyskinesia | Late-onset, often persistent involuntary choreiform/athetoid movements: lip smacking, chewing, tongue protrusion, limb movements | Dopamine receptor supersensitivity | Risk rises with cumulative exposure, older age, and higher doses. |
| Neuroleptic malignant syndrome (NMS) | Hyperthermia, severe rigidity, altered consciousness, autonomic instability, elevated CK; medical emergency | Marked central dopamine blockade | Can occur with any antipsychotic, often after rapid dose escalation or parenteral high-potency drugs. Stop the drug and provide urgent hospital care. |
| Hyperprolactinaemia | Galactorrhoea, amenorrhoea/oligomenorrhoea, infertility, sexual dysfunction, gynecomastia; long-term bone loss risk | Tuberoinfundibular D2 blockade removes dopamine inhibition of prolactin release | Common with FGAs, risperidone, paliperidone and amisulpride. Aripiprazole, clozapine and quetiapine are relatively prolactin-sparing. |
| Weight gain and metabolic syndrome | Increased appetite, weight gain, central obesity, dyslipidaemia, insulin resistance, type 2 diabetes | Histamine H1 and serotonin 5-HT2C antagonism contribute | Particularly important with clozapine and olanzapine; monitor weight, waist circumference, glucose/HbA1c and lipids. |
| Sedation / cognitive slowing | Daytime drowsiness, reduced alertness, impaired concentration | H1 histamine receptor blockade, sometimes antimuscarinic effect | Higher with clozapine, olanzapine, quetiapine, chlorpromazine and other low-potency phenothiazines. |
| Anticholinergic effects | Dry mouth, blurred vision/loss of accommodation, constipation, urinary retention, tachycardia; confusion or delirium in susceptible patients | Muscarinic M1 blockade | More with low-potency FGAs, clozapine, olanzapine and quetiapine. Constipation with clozapine can become severe or life-threatening. |
| Postural hypotension | Dizziness, falls, syncope, reflex tachycardia | Alpha-1 adrenergic receptor blockade | More with chlorpromazine, clozapine, quetiapine and low-potency FGAs; especially important in older adults. |
| QTc prolongation / arrhythmia risk | QT prolongation, rarely torsades de pointes, syncope or sudden cardiac death | Cardiac ion-channel effects | Risk increases with high dose, electrolyte disturbances, heart disease and combinations with other QT-prolonging drugs. ECG assessment is appropriate where risk factors exist. |
| Sexual dysfunction | Reduced libido, erectile dysfunction, impaired ejaculation/orgasm | Hyperprolactinaemia, alpha-1 blockade, anticholinergic effects, sedation | Often associated with prolactin-raising agents and drugs causing hypotension. |
| Seizures / lowered seizure threshold | New seizure or worsening of epilepsy | Reduced seizure threshold | Most notable with clozapine and at higher doses; also reported with chlorpromazine and loxapine. |
| Agranulocytosis / neutropenia | Fever, sore throat, mouth ulcers or infections due to low neutrophil count | Idiosyncratic hematologic toxicity | Characteristic serious adverse effect of clozapine. Requires mandated blood-count monitoring. |
| Myocarditis / cardiomyopathy | Chest pain, dyspnoea, palpitations, fever, tachycardia, heart failure symptoms | Idiosyncratic inflammatory cardiac toxicity | Most characteristically associated with clozapine, particularly early in treatment. |
| Hypersalivation | Excess salivation, often nocturnal drooling | Complex cholinergic effects | Common with clozapine, despite its antimuscarinic actions. |
| Photosensitivity, skin pigmentation, corneal/lens deposits | Sun sensitivity; bluish-gray skin discoloration; ocular deposits with some older agents | Drug deposition / phototoxicity | Classically described with chlorpromazine and related phenothiazines. |
| Hepatic effects | Asymptomatic transaminase elevation; rarely cholestatic jaundice/hepatitis | Idiosyncratic or metabolic hepatic injury | More classically reported with phenothiazines, but possible with many agents. |
Practical comparison
| Adverse-effect pattern | Antipsychotics commonly associated with it |
|---|---|
| High EPS and prolactin risk | Haloperidol, fluphenazine, trifluoperazine; also risperidone, paliperidone, amisulpride |
| High metabolic/weight-gain risk | Clozapine, olanzapine; moderate risk with quetiapine |
| High sedation, anticholinergic effect, and hypotension risk | Chlorpromazine, clozapine, quetiapine |
| Lowest EPS risk | Clozapine, quetiapine; aripiprazole generally lower but may cause akathisia |
| Clozapine-specific serious concerns | Agranulocytosis/neutropenia, myocarditis, seizures, severe constipation/ileus, marked metabolic effects, hypersalivation |
| QTc concern | Risk varies by agent and patient factors; avoid combining QT-prolonging medicines when possible and assess ECG/electrolyte risks |
Most adverse effects are dose-related, and the selection of an antipsychotic should balance efficacy with the individual’s risks, preferences, comorbidities, and required monitoring. EPS, weight gain, sedation, postural hypotension, anticholinergic effects, QTc prolongation, and raised prolactin are the standard core categories described in The Maudsley Prescribing Guidelines in Psychiatry, 15th ed., p. 150 and Katzung’s Basic and Clinical Pharmacology, 16th ed., p. 811. A recent systematic review also reinforces that cardiometabolic effects require attention during long-term exposure (2026 systematic review, PMID 42330864).
concised version which can be pasted into powerpoint
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Side Effects of Antipsychotics
| Category | Important side effects | High-risk drugs / notes |
|---|---|---|
| EPS | Dystonia, parkinsonism, akathisia, tardive dyskinesia | High-potency FGAs, especially haloperidol |
| Endocrine | Hyperprolactinaemia: amenorrhoea, galactorrhoea, sexual dysfunction | Risperidone, paliperidone, amisulpride, FGAs |
| Metabolic | Weight gain, diabetes, dyslipidaemia, metabolic syndrome | Clozapine, olanzapine |
| Sedation | Drowsiness, impaired attention | Clozapine, quetiapine, chlorpromazine |
| Anticholinergic | Dry mouth, blurred vision, constipation, urinary retention | Clozapine, chlorpromazine, low-potency FGAs |
| Cardiovascular | Postural hypotension, tachycardia, QTc prolongation | Chlorpromazine, clozapine, quetiapine; QT risk varies |
| Neurological | Seizures, lowered seizure threshold | Clozapine, especially at high doses |
| Serious reaction | Neuroleptic malignant syndrome: fever, rigidity, autonomic instability | Any antipsychotic; emergency |
| Clozapine-specific | Agranulocytosis, myocarditis, seizures, severe constipation, hypersalivation | Requires blood-count monitoring |
FGAs: greater EPS and prolactin elevation
SGAs: greater weight gain and metabolic adverse effects
Exception: aripiprazole may cause akathisia but has relatively low metabolic and prolactin risk.
SGAs: greater weight gain and metabolic adverse effects
Exception: aripiprazole may cause akathisia but has relatively low metabolic and prolactin risk.
an overview about third generation antipsychotics. Also about FDA approved indications and off label uses of antipsychotics
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site:accessdata.fda.gov antipsychotic prescribing information aripiprazole brexpiprazole cariprazine lumateperone FDA indications
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site:accessdata.fda.gov/drugsatfda_docs/label/2025 cariprazine brexpiprazole Vraylar Rexulti indications usage
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FDA approved indications antipsychotic medications schizophrenia bipolar depression autism Tourette dementia agitation list
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Quick answer
Third-Generation Antipsychotics (TGAs)
Definition: Dopamine-serotonin partial agonists, also called dopamine stabilizers.
Unlike first- and second-generation drugs that mainly block dopamine D2 receptors, TGAs act as partial agonists at D2/D3 receptors.
Unlike first- and second-generation drugs that mainly block dopamine D2 receptors, TGAs act as partial agonists at D2/D3 receptors.
| Drug | Key receptor action | Main clinical points |
|---|---|---|
| Aripiprazole | D2/D3 and 5-HT1A partial agonist; 5-HT2A antagonist | First TGA; relatively low prolactin and metabolic risk; may cause akathisia/insomnia |
| Brexpiprazole | D2/D3 and 5-HT1A partial agonist; 5-HT2A antagonist | Lower intrinsic D2 activity than aripiprazole; less activating, but weight gain may occur |
| Cariprazine | D3-preferring D3/D2 partial agonist; 5-HT1A partial agonist | Useful in schizophrenia and bipolar depression; akathisia/EPS may occur; long half-life |
Advantages of TGAs
- Lower risk of hyperprolactinaemia
- Lower metabolic risk than clozapine/olanzapine
- Lower EPS risk than high-potency first-generation antipsychotics
- May improve negative, cognitive, and mood symptoms in some patients
Important adverse effects
- Akathisia, restlessness, insomnia
- Nausea, headache
- EPS at higher doses
- Weight gain and metabolic changes can still occur
- Impulse-control problems: gambling, binge eating, hypersexuality, compulsive shopping, especially with aripiprazole
- Class warning: increased mortality in elderly persons with dementia-related psychosis
FDA-Approved Indications of Common Antipsychotics
| Clinical indication | Examples of FDA-approved antipsychotics |
|---|---|
| Schizophrenia | Most antipsychotics, including haloperidol, risperidone, olanzapine, quetiapine, aripiprazole, brexpiprazole, cariprazine, clozapine, lumateperone |
| Treatment-resistant schizophrenia | Clozapine |
| Reduction of recurrent suicidal behavior in schizophrenia/schizoaffective disorder | Clozapine |
| Bipolar I acute mania or mixed episodes | Lithium/valproate adjunct or monotherapy with aripiprazole, olanzapine, quetiapine, risperidone, asenapine, cariprazine, haloperidol |
| Bipolar depression | Quetiapine, lurasidone, cariprazine, lumateperone; olanzapine-fluoxetine combination |
| Maintenance treatment in bipolar disorder | Aripiprazole, quetiapine, olanzapine, risperidone long-acting injectable, among others depending on formulation |
| Adjunctive treatment of major depressive disorder | Aripiprazole, brexpiprazole, cariprazine, lumateperone |
| Irritability associated with autism spectrum disorder | Risperidone and aripiprazole |
| Tourette disorder | Aripiprazole, haloperidol, pimozide |
| Acute agitation in schizophrenia or bipolar mania | IM aripiprazole, olanzapine, ziprasidone, haloperidol; inhaled loxapine in selected patients |
| Agitation associated with dementia due to Alzheimer disease | Brexpiprazole only |
| Parkinson disease psychosis | Pimavanserin |
| Nausea and vomiting / intractable hiccups | Chlorpromazine; some phenothiazines are also antiemetics |
FDA-Approved Uses of Third-Generation Antipsychotics
| Drug | FDA-approved indications |
|---|---|
| Aripiprazole | Schizophrenia; bipolar I mania/mixed episodes and maintenance; adjunct in MDD; irritability in autism; Tourette disorder; acute agitation associated with schizophrenia or bipolar mania |
| Brexpiprazole | Schizophrenia; adjunct to antidepressants in MDD; agitation associated with dementia due to Alzheimer disease |
| Cariprazine | Schizophrenia; bipolar I mania/mixed episodes; bipolar I depression; adjunct to antidepressants in MDD |
| Lumateperone (usually classified as SGA, not TGA) | Schizophrenia; bipolar depression as monotherapy or with lithium/valproate; adjunctive treatment of MDD |
Common Off-Label Uses of Antipsychotics
| Off-label use | Drugs commonly used | Key point |
|---|---|---|
| Delirium with severe agitation or distress | Haloperidol, olanzapine, quetiapine | Treat the underlying cause first; routine use does not shorten delirium |
| Behavioral and psychological symptoms of dementia | Risperidone, quetiapine, olanzapine | Use only for severe risk/distress after non-drug measures fail; increased stroke and mortality risk |
| Insomnia | Quetiapine, olanzapine | Not routinely recommended because potential harms outweigh benefit |
| Generalized anxiety disorder / severe anxiety | Quetiapine, olanzapine | Usually only after standard treatments fail |
| Obsessive-compulsive disorder augmentation | Aripiprazole, risperidone | Consider only in treatment-resistant OCD with an SSRI/clomipramine |
| Post-traumatic stress disorder augmentation | Risperidone, quetiapine, olanzapine | Evidence is inconsistent; not first-line treatment |
| Borderline personality disorder symptoms | Aripiprazole, olanzapine, quetiapine | May target short-term severe impulsivity, anger, or transient psychotic symptoms; psychotherapy remains primary treatment |
| Eating disorders / severe behavioral dysregulation | Olanzapine, aripiprazole | Specialist-directed use only |
| Huntington disease chorea / psychosis | Olanzapine, risperidone, haloperidol | May help chorea, aggression, and psychosis |
| Tics other than approved Tourette indications | Aripiprazole, risperidone | Often used when behavioral therapy is insufficient |
Key message: Off-label prescribing is legal but should be evidence-based, documented, regularly reviewed, and balanced against metabolic, neurological, cardiovascular, and mortality risks.
just name 5 indications in each category
FDA-Approved Indications
- Schizophrenia
- Bipolar I disorder - acute mania/mixed episodes
- Bipolar depression
- Adjunctive treatment in major depressive disorder
- Irritability associated with autism spectrum disorder
Common Off-Label Uses
- Delirium with severe agitation
- Behavioral symptoms of dementia
- Insomnia
- Treatment-resistant obsessive-compulsive disorder augmentation
- Severe anxiety / generalized anxiety disorder
put in a table
| FDA-Approved Indications | Common Off-Label Uses |
|---|---|
| Schizophrenia | Delirium with severe agitation |
| Bipolar I disorder - acute mania/mixed episodes | Behavioral symptoms of dementia |
| Bipolar depression | Insomnia |
| Adjunctive treatment in major depressive disorder | Treatment-resistant OCD augmentation |
| Irritability associated with autism spectrum disorder | Severe anxiety / generalized anxiety disorder |
Classification of antidepressants, their mechanism of action and examples in a tabular format
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antidepressant classes mechanisms examples SSRIs SNRIs tricyclic MAOI NIMH
| Class | Mechanism of action | Examples |
|---|---|---|
| SSRIs | Selectively inhibit serotonin (5-HT) reuptake by blocking SERT | Fluoxetine, sertraline, escitalopram, citalopram, paroxetine, fluvoxamine |
| SNRIs | Inhibit reuptake of serotonin and noradrenaline | Venlafaxine, desvenlafaxine, duloxetine, levomilnacipran |
| TCAs | Inhibit serotonin and noradrenaline reuptake; also block muscarinic, H1 and alpha-1 receptors | Amitriptyline, imipramine, clomipramine, nortriptyline, doxepin |
| MAOIs | Inhibit monoamine oxidase, reducing breakdown of serotonin, noradrenaline and dopamine | Phenelzine, tranylcypromine, isocarboxazid, selegiline |
| NDRI | Inhibits noradrenaline and dopamine reuptake | Bupropion |
| NaSSA | Blocks presynaptic alpha-2 receptors, increasing noradrenaline and serotonin release; blocks 5-HT2 and 5-HT3 receptors | Mirtazapine |
| SARI | Blocks 5-HT2A receptors and weakly inhibits serotonin reuptake | Trazodone, nefazodone |
| Serotonin modulators | Inhibit serotonin reuptake and modulate multiple serotonin receptors | Vortioxetine, vilazodone |
| Melatonergic antidepressant | MT1/MT2 receptor agonist and 5-HT2C antagonist | Agomelatine |
| NMDA receptor antagonist | Modulates glutamatergic transmission through NMDA receptor antagonism | Ketamine, esketamine |
SSRIs and SNRIs are commonly used first-line antidepressants.
Classification based on standard pharmacology references including Katzung’s Basic and Clinical Pharmacology, 16th ed., p. 811.
Classification based on standard pharmacology references including Katzung’s Basic and Clinical Pharmacology, 16th ed., p. 811.
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| Abbreviation | Full name |
|---|---|
| SSRI | Selective Serotonin Reuptake Inhibitor |
| SNRI | Serotonin-Norepinephrine Reuptake Inhibitor |
| TCA | Tricyclic Antidepressant |
| MAOI | Monoamine Oxidase Inhibitor |
| NDRI | Norepinephrine-Dopamine Reuptake Inhibitor |
| NaSSA | Noradrenergic and Specific Serotonergic Antidepressant |
| SARI | Serotonin Antagonist and Reuptake Inhibitor |
| SMS | Serotonin Modulator and Stimulator |
| MRA | Melatonergic Receptor Agonist |
| NMDA antagonist | N-Methyl-D-Aspartate Receptor Antagonist |
FDA approved and off label uses in a tabular form
Do you mean the FDA-approved and off-label uses of antidepressants or of antipsychotics?
Asking for Preferences
Which drug group should the table cover?
| System / adverse effect | Typical clinical features | Usual mechanism | Drugs with relatively higher risk / key points |
|---|---|---|---|
| Extrapyramidal symptoms (EPS) | Acute dystonia, parkinsonism, akathisia, tardive dyskinesia | Nigrostriatal D2 receptor blockade. Tardive dyskinesia is linked to dopamine-receptor supersensitivity after chronic blockade. | More likely with high-potency first-generation agents, especially haloperidol and fluphenazine; dose-related. Lower risk with clozapine and quetiapine. |
| Acute dystonia | Painful sustained muscle contractions: torticollis, jaw spasm, oculogyric crisis; rarely laryngospasm | D2 blockade in nigrostriatal pathway | Usually hours to days after starting/increasing dose; more frequent in young males and with high-potency FGAs. |
| Drug-induced parkinsonism | Tremor, rigidity, bradykinesia, masked facies, shuffling gait | D2 blockade | Often develops over days to weeks. |
| Akathisia | Subjective inner restlessness, pacing, inability to sit still; may be mistaken for agitation | D2 blockade | Can occur early. Recognize because it is distressing and may be associated with suicidal ideation. |
| Tardive dyskinesia | Late-onset, often persistent involuntary choreiform/athetoid movements: lip smacking, chewing, tongue protrusion, limb movements | Dopamine receptor supersensitivity | Risk rises with cumulative exposure, older age, and higher doses. |
| Neuroleptic malignant syndrome (NMS) | Hyperthermia, severe rigidity, altered consciousness, autonomic instability, elevated CK; medical emergency | Marked central dopamine blockade | Can occur with any antipsychotic, often after rapid dose escalation or parenteral high-potency drugs. Stop the drug and provide urgent hospital care. |
| Hyperprolactinaemia | Galactorrhoea, amenorrhoea/oligomenorrhoea, infertility, sexual dysfunction, gynecomastia; long-term bone loss risk | Tuberoinfundibular D2 blockade removes dopamine inhibition of prolactin release | Common with FGAs, risperidone, paliperidone and amisulpride. Aripiprazole, clozapine and quetiapine are relatively prolactin-sparing. |
| Weight gain and metabolic syndrome | Increased appetite, weight gain, central obesity, dyslipidaemia, insulin resistance, type 2 diabetes | Histamine H1 and serotonin 5-HT2C antagonism contribute | Particularly important with clozapine and olanzapine; monitor weight, waist circumference, glucose/HbA1c and lipids. |
| Sedation / cognitive slowing | Daytime drowsiness, reduced alertness, impaired concentration | H1 histamine receptor blockade, sometimes antimuscarinic effect | Higher with clozapine, olanzapine, quetiapine, chlorpromazine and other low-potency phenothiazines. |
| Anticholinergic effects | Dry mouth, blurred vision/loss of accommodation, constipation, urinary retention, tachycardia; confusion or delirium in susceptible patients | Muscarinic M1 blockade | More with low-potency FGAs, clozapine, olanzapine and quetiapine. Constipation with clozapine can become severe or life-threatening. |
| Postural hypotension | Dizziness, falls, syncope, reflex tachycardia | Alpha-1 adrenergic receptor blockade | More with chlorpromazine, clozapine, quetiapine and low-potency FGAs; especially important in older adults. |
| QTc prolongation / arrhythmia risk | QT prolongation, rarely torsades de pointes, syncope or sudden cardiac death | Cardiac ion-channel effects | Risk increases with high dose, electrolyte disturbances, heart disease and combinations with other QT-prolonging drugs. ECG assessment is appropriate where risk factors exist. |
| Sexual dysfunction | Reduced libido, erectile dysfunction, impaired ejaculation/orgasm | Hyperprolactinaemia, alpha-1 blockade, anticholinergic effects, sedation | Often associated with prolactin-raising agents and drugs causing hypotension. |
| Seizures / lowered seizure threshold | New seizure or worsening of epilepsy | Reduced seizure threshold | Most notable with clozapine and at higher doses; also reported with chlorpromazine and loxapine. |
| Agranulocytosis / neutropenia | Fever, sore throat, mouth ulcers or infections due to low neutrophil count | Idiosyncratic hematologic toxicity | Characteristic serious adverse effect of clozapine. Requires mandated blood-count monitoring. |
| Myocarditis / cardiomyopathy | Chest pain, dyspnoea, palpitations, fever, tachycardia, heart failure symptoms | Idiosyncratic inflammatory cardiac toxicity | Most characteristically associated with clozapine, particularly early in treatment. |
| Hypersalivation | Excess salivation, often nocturnal drooling | Complex cholinergic effects | Common with clozapine, despite its antimuscarinic actions. |
| Photosensitivity, skin pigmentation, corneal/lens deposits | Sun sensitivity; bluish-gray skin discoloration; ocular deposits with some older agents | Drug deposition / phototoxicity | Classically described with chlorpromazine and related phenothiazines. |
| Hepatic effects | Asymptomatic transaminase elevation; rarely cholestatic jaundice/hepatitis | Idiosyncratic or metabolic hepatic injury | More classically reported with phenothiazines, but possible with many agents. |
Practical comparison
| Adverse-effect pattern | Antipsychotics commonly associated with it |
|---|---|
| High EPS and prolactin risk | Haloperidol, fluphenazine, trifluoperazine; also risperidone, paliperidone, amisulpride |
| High metabolic/weight-gain risk | Clozapine, olanzapine; moderate risk with quetiapine |
| High sedation, anticholinergic effect, and hypotension risk | Chlorpromazine, clozapine, quetiapine |
| Lowest EPS risk | Clozapine, quetiapine; aripiprazole generally lower but may cause akathisia |
| Clozapine-specific serious concerns | Agranulocytosis/neutropenia, myocarditis, seizures, severe constipation/ileus, marked metabolic effects, hypersalivation |
| QTc concern | Risk varies by agent and patient factors; avoid combining QT-prolonging medicines when possible and assess ECG/electrolyte risks |
Most adverse effects are dose-related, and the selection of an antipsychotic should balance efficacy with the individual’s risks, preferences, comorbidities, and required monitoring. EPS, weight gain, sedation, postural hypotension, anticholinergic effects, QTc prolongation, and raised prolactin are the standard core categories described in The Maudsley Prescribing Guidelines in Psychiatry, 15th ed., p. 150 and Katzung’s Basic and Clinical Pharmacology, 16th ed., p. 811. A recent systematic review also reinforces that cardiometabolic effects require attention during long-term exposure (2026 systematic review, PMID 42330864).### Side Effects of Antipsychotics
| Category | Important side effects | High-risk drugs / notes |
|---|---|---|
| EPS | Dystonia, parkinsonism, akathisia, tardive dyskinesia | High-potency FGAs, especially haloperidol |
| Endocrine | Hyperprolactinaemia: amenorrhoea, galactorrhoea, sexual dysfunction | Risperidone, paliperidone, amisulpride, FGAs |
| Metabolic | Weight gain, diabetes, dyslipidaemia, metabolic syndrome | Clozapine, olanzapine |
| Sedation | Drowsiness, impaired attention | Clozapine, quetiapine, chlorpromazine |
| Anticholinergic | Dry mouth, blurred vision, constipation, urinary retention | Clozapine, chlorpromazine, low-potency FGAs |
| Cardiovascular | Postural hypotension, tachycardia, QTc prolongation | Chlorpromazine, clozapine, quetiapine; QT risk varies |
| Neurological | Seizures, lowered seizure threshold | Clozapine, especially at high doses |
| Serious reaction | Neuroleptic malignant syndrome: fever, rigidity, autonomic instability | Any antipsychotic; emergency |
| Clozapine-specific | Agranulocytosis, myocarditis, seizures, severe constipation, hypersalivation | Requires blood-count monitoring |
FGAs: greater EPS and prolactin elevation
SGAs: greater weight gain and metabolic adverse effects
Exception: aripiprazole may cause akathisia but has relatively low metabolic and prolactin risk.## Third-Generation Antipsychotics (TGAs)
SGAs: greater weight gain and metabolic adverse effects
Exception: aripiprazole may cause akathisia but has relatively low metabolic and prolactin risk.## Third-Generation Antipsychotics (TGAs)
Definition: Dopamine-serotonin partial agonists, also called dopamine stabilizers.
Unlike first- and second-generation drugs that mainly block dopamine D2 receptors, TGAs act as partial agonists at D2/D3 receptors.
Unlike first- and second-generation drugs that mainly block dopamine D2 receptors, TGAs act as partial agonists at D2/D3 receptors.
| Drug | Key receptor action | Main clinical points |
|---|---|---|
| Aripiprazole | D2/D3 and 5-HT1A partial agonist; 5-HT2A antagonist | First TGA; relatively low prolactin and metabolic risk; may cause akathisia/insomnia |
| Brexpiprazole | D2/D3 and 5-HT1A partial agonist; 5-HT2A antagonist | Lower intrinsic D2 activity than aripiprazole; less activating, but weight gain may occur |
| Cariprazine | D3-preferring D3/D2 partial agonist; 5-HT1A partial agonist | Useful in schizophrenia and bipolar depression; akathisia/EPS may occur; long half-life |
Advantages of TGAs
- Lower risk of hyperprolactinaemia
- Lower metabolic risk than clozapine/olanzapine
- Lower EPS risk than high-potency first-generation antipsychotics
- May improve negative, cognitive, and mood symptoms in some patients
Important adverse effects
- Akathisia, restlessness, insomnia
- Nausea, headache
- EPS at higher doses
- Weight gain and metabolic changes can still occur
- Impulse-control problems: gambling, binge eating, hypersexuality, compulsive shopping, especially with aripiprazole
- Class warning: increased mortality in elderly persons with dementia-related psychosis
FDA-Approved Indications of Common Antipsychotics
| Clinical indication | Examples of FDA-approved antipsychotics |
|---|---|
| Schizophrenia | Most antipsychotics, including haloperidol, risperidone, olanzapine, quetiapine, aripiprazole, brexpiprazole, cariprazine, clozapine, lumateperone |
| Treatment-resistant schizophrenia | Clozapine |
| Reduction of recurrent suicidal behavior in schizophrenia/schizoaffective disorder | Clozapine |
| Bipolar I acute mania or mixed episodes | Lithium/valproate adjunct or monotherapy with aripiprazole, olanzapine, quetiapine, risperidone, asenapine, cariprazine, haloperidol |
| Bipolar depression | Quetiapine, lurasidone, cariprazine, lumateperone; olanzapine-fluoxetine combination |
| Maintenance treatment in bipolar disorder | Aripiprazole, quetiapine, olanzapine, risperidone long-acting injectable, among others depending on formulation |
| Adjunctive treatment of major depressive disorder | Aripiprazole, brexpiprazole, cariprazine, lumateperone |
| Irritability associated with autism spectrum disorder | Risperidone and aripiprazole |
| Tourette disorder | Aripiprazole, haloperidol, pimozide |
| Acute agitation in schizophrenia or bipolar mania | IM aripiprazole, olanzapine, ziprasidone, haloperidol; inhaled loxapine in selected patients |
| Agitation associated with dementia due to Alzheimer disease | Brexpiprazole only |
| Parkinson disease psychosis | Pimavanserin |
| Nausea and vomiting / intractable hiccups | Chlorpromazine; some phenothiazines are also antiemetics |
FDA-Approved Uses of Third-Generation Antipsychotics
| Drug | FDA-approved indications |
|---|---|
| Aripiprazole | Schizophrenia; bipolar I mania/mixed episodes and maintenance; adjunct in MDD; irritability in autism; Tourette disorder; acute agitation associated with schizophrenia or bipolar mania |
| Brexpiprazole | Schizophrenia; adjunct to antidepressants in MDD; agitation associated with dementia due to Alzheimer disease |
| Cariprazine | Schizophrenia; bipolar I mania/mixed episodes; bipolar I depression; adjunct to antidepressants in MDD |
| Lumateperone (usually classified as SGA, not TGA) | Schizophrenia; bipolar depression as monotherapy or with lithium/valproate; adjunctive treatment of MDD |
Common Off-Label Uses of Antipsychotics
| Off-label use | Drugs commonly used | Key point |
|---|---|---|
| Delirium with severe agitation or distress | Haloperidol, olanzapine, quetiapine | Treat the underlying cause first; routine use does not shorten delirium |
| Behavioral and psychological symptoms of dementia | Risperidone, quetiapine, olanzapine | Use only for severe risk/distress after non-drug measures fail; increased stroke and mortality risk |
| Insomnia | Quetiapine, olanzapine | Not routinely recommended because potential harms outweigh benefit |
| Generalized anxiety disorder / severe anxiety | Quetiapine, olanzapine | Usually only after standard treatments fail |
| Obsessive-compulsive disorder augmentation | Aripiprazole, risperidone | Consider only in treatment-resistant OCD with an SSRI/clomipramine |
| Post-traumatic stress disorder augmentation | Risperidone, quetiapine, olanzapine | Evidence is inconsistent; not first-line treatment |
| Borderline personality disorder symptoms | Aripiprazole, olanzapine, quetiapine | May target short-term severe impulsivity, anger, or transient psychotic symptoms; psychotherapy remains primary treatment |
| Eating disorders / severe behavioral dysregulation | Olanzapine, aripiprazole | Specialist-directed use only |
| Huntington disease chorea / psychosis | Olanzapine, risperidone, haloperidol | May help chorea, aggression, and psychosis |
| Tics other than approved Tourette indications | Aripiprazole, risperidone | Often used when behavioral therapy is insufficient |
Key message: Off-label prescribing is legal but should be evidence-based, documented, regularly reviewed, and balanced against metabolic, neurological, cardiovascular, and mortality risks.### FDA-Approved Indications
- Schizophrenia
- Bipolar I disorder - acute mania/mixed episodes
- Bipolar depression
- Adjunctive treatment in major depressive disorder
- Irritability associated with autism spectrum disorder
Common Off-Label Uses
- Delirium with severe agitation
- Behavioral symptoms of dementia
- Insomnia
- Treatment-resistant obsessive-compulsive disorder augmentation
- Severe anxiety / generalized anxiety disorder| FDA-Approved Indications | Common Off-Label Uses | |---|---| | Schizophrenia | Delirium with severe agitation | | Bipolar I disorder - acute mania/mixed episodes | Behavioral symptoms of dementia | | Bipolar depression | Insomnia | | Adjunctive treatment in major depressive disorder | Treatment-resistant OCD augmentation | | Irritability associated with autism spectrum disorder | Severe anxiety / generalized anxiety disorder || Class | Mechanism of action | Examples | |---|---|---| | SSRIs | Selectively inhibit serotonin (5-HT) reuptake by blocking SERT | Fluoxetine, sertraline, escitalopram, citalopram, paroxetine, fluvoxamine | | SNRIs | Inhibit reuptake of serotonin and noradrenaline | Venlafaxine, desvenlafaxine, duloxetine, levomilnacipran | | TCAs | Inhibit serotonin and noradrenaline reuptake; also block muscarinic, H1 and alpha-1 receptors | Amitriptyline, imipramine, clomipramine, nortriptyline, doxepin | | MAOIs | Inhibit monoamine oxidase, reducing breakdown of serotonin, noradrenaline and dopamine | Phenelzine, tranylcypromine, isocarboxazid, selegiline | | NDRI | Inhibits noradrenaline and dopamine reuptake | Bupropion | | NaSSA | Blocks presynaptic alpha-2 receptors, increasing noradrenaline and serotonin release; blocks 5-HT2 and 5-HT3 receptors | Mirtazapine | | SARI | Blocks 5-HT2A receptors and weakly inhibits serotonin reuptake | Trazodone, nefazodone | | Serotonin modulators | Inhibit serotonin reuptake and modulate multiple serotonin receptors | Vortioxetine, vilazodone | | Melatonergic antidepressant | MT1/MT2 receptor agonist and 5-HT2C antagonist | Agomelatine | | NMDA receptor antagonist | Modulates glutamatergic transmission through NMDA receptor antagonism | Ketamine, esketamine |
SSRIs and SNRIs are commonly used first-line antidepressants.
Classification based on standard pharmacology references including Katzung’s Basic and Clinical Pharmacology, 16th ed., p. 811.| Abbreviation | Full name | |---|---| | SSRI | Selective Serotonin Reuptake Inhibitor | | SNRI | Serotonin-Norepinephrine Reuptake Inhibitor | | TCA | Tricyclic Antidepressant | | MAOI | Monoamine Oxidase Inhibitor | | NDRI | Norepinephrine-Dopamine Reuptake Inhibitor | | NaSSA | Noradrenergic and Specific Serotonergic Antidepressant | | SARI | Serotonin Antagonist and Reuptake Inhibitor | | SMS | Serotonin Modulator and Stimulator | | MRA | Melatonergic Receptor Agonist | | NMDA antagonist | N-Methyl-D-Aspartate Receptor Antagonist |Do you mean the FDA-approved and off-label uses of antidepressants or of antipsychotics?
Classification based on standard pharmacology references including Katzung’s Basic and Clinical Pharmacology, 16th ed., p. 811.| Abbreviation | Full name | |---|---| | SSRI | Selective Serotonin Reuptake Inhibitor | | SNRI | Serotonin-Norepinephrine Reuptake Inhibitor | | TCA | Tricyclic Antidepressant | | MAOI | Monoamine Oxidase Inhibitor | | NDRI | Norepinephrine-Dopamine Reuptake Inhibitor | | NaSSA | Noradrenergic and Specific Serotonergic Antidepressant | | SARI | Serotonin Antagonist and Reuptake Inhibitor | | SMS | Serotonin Modulator and Stimulator | | MRA | Melatonergic Receptor Agonist | | NMDA antagonist | N-Methyl-D-Aspartate Receptor Antagonist |Do you mean the FDA-approved and off-label uses of antidepressants or of antipsychotics?
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