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This topic includes both first and second generation antipsychotics.

Antipsychotics are effective for the symptoms of schizophrenia. Positive symptoms include the experiences of perceptual abnormalities (hallucinations) and fixed, false, irrational beliefs (delusions). Negative symptoms include a lack of ordinary mental activities such as emotional expression, social engagement, and motivation. Antipsychotics can also cause side effects. These include extrapyramidal symptoms such as dyskinesias (repetitive, involuntary, and purposeless body or facial movements), Parkinsonism (cogwheel muscle rigidity, pill-rolling tremor and reduced or slowed movements), akathisia (motor restlessness, especially in the legs, and resembling agitation), and dystonias (muscle contractions causing unusual twisting of parts of the body, most often in the neck). These effects are caused by the dopamine receptor antagonist action of antipsychotics. Other side effects may include weight, hormonal and metabolic changes, increased sedation, and ventricular anomalies (QTc prolongation).

What is the evidence for any antipsychotic efficacy compared to placebo?

Overall, moderate to high quality evidence finds a medium-sized effect of greater total symptom improvement with antipsychotics than with placebo. There was less variability in the response to antipsychotics than in the response to placebo, with older studies, those with younger patients, higher dose treatments, and greater mean difference in symptom change being associated with the least variability in response.

For particular antipsychotics, there were symptom improvements with (in descending order of efficacy compared to placebo): clozapine, amisulpride, thiotixene, zotepine, olanzapine, perphenazine, risperidone, thioridazine, zuclopenthixol, paliperidone, sulpiride, haloperidol, loxapine, chlorpromazine, flupentixol, clopenthixol, molindone, quetiapine, aripiprazole, ziprasidone, sertindole, asenapine, lurasidone, cariprazine, iloperidone, and brexpiprazole. There were no significant differences in symptoms between placebo and penfluridol, pimozide, perazine, fluphenazine, trifluoperazine, and levomepromazine.

For social functioning, there were improvements with (in descending order of efficacy compared to placebo) thioridazine, olanzapine, paliperidone, quetiapine, lurasidone, and brexpiprazole. There were no improvements in social functioning between placebo and aripiprazole, sertindole, amisulpride, ziprasidone, flupentixol, or risperidone.

For all-cause discontinuation (in descending order of effects, first being best), there was less discontinuation with clopenthixol, amisulpride, olanzapine, paliperidone, thiotixene, thioridazine, clozapine, loxapine, iloperidone, perphenazine, aripiprazole, risperidone, zuclopenthixol, zotepine, asenapine, quetiapine, lurasidone, brexpiprazole, haloperidol, and ziprasidone. There were no differences between placebo and perazine, levomepromazine, flupentixol, molindone, fluphenazine, chlorpromazine, cariprazine, sulpiride, sertindole, penfluridol, trifluoperazine, and pimozide.

For side effects (in ascending order of harm compared to placebo), there was less use of antiparkinson drugs with clozapine than with placebo, and more use of antiparkinson drugs with paliperidone, ziprasidone, risperidone, lurasidone, zotepine, cariprazine, chlorpromazine, sulpiride, perphenazine, molindone, zuclopenthixol, trifluoperazine, flupentixol, haloperidol, loxapine, penfluridol, fluphenazine, chlorpromazine, thiotixene, and pimozide.

There was more akathisia with aripiprazole, ziprasidone, thioridazine, asenapine, amisulpride, chlorpromazine, thiotixene, risperidone, cariprazine, loxapine, haloperidol, lurasidone, trifluoperazine, sulpiride, molindone, penfluridol, pimozide, fluphenazine, flupentixol, and zuclopenthixol.

There was more weight gain with haloperidol, amisulpride, asenapine, risperidone, paliperidone, clozapine, quetiapine, iloperidone, chlorpromazine, sertindole, olanzapine, and zotepine.

There was less prolactin elevation with aripiprazole, clozapine, and zotepine, and more prolactin elevation with olanzapine, asenapine, lurasidone, sertindole, haloperidol, amisulpride, risperidone, and paliperidone.

There was more sedation with aripiprazole, lurasidone, haloperidol, risperidone, asenapine, loxapine, olanzapine, chlorpromazine, thioridazine, thiotixene, ziprasidone, perazine, clozapine, clopenthixol, quetiapine, sulpiride, zotepine, and zuclopenthixol.

There was more QTc prolongation with quetiapine, olanzapine, risperidone, iloperidone, ziprasidone, amisulpride, and sertindole.

There was more anticholinergic side-effects haloperidol, olanzapine, clozapine, chlorpromazine, zotepine, iloperidone, thioridazine, and quetiapine.

October 2020

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Second generation antipsychotics (sometimes referred to as ‘atypical’ antipsychotics) such as amisulpride are a newer class of antipsychotic medication than first generation ‘typical’ antipsychotics. Second generation antipsychotics are effective for the positive symptoms of schizophrenia. It is sometimes claimed that they are more effective than first generation antipsychotics in treating the negative symptoms of schizophrenia. Negative symptoms include a lack of ordinary mental activities such as emotional expression, social engagement, thinking and motivation, whereas positive symptoms include the experiences of perceptual abnormalities (hallucinations) and fixed, false, irrational beliefs (delusions).

Second generation antipsychotics may also cause less extra-pyramidal side effects. These include dyskinesias such as repetitive, involuntary, and purposeless body or facial movements, Parkinsonism (cogwheel muscle rigidity, pill-rolling tremor and reduced or slowed movements), akathisia (motor restlessness, especially in the legs, and resembling agitation) and dystonias such as muscle contractions causing unusual twisting of parts of the body, most often in the neck. These effects are caused by the dopamine receptor antagonist action of these drugs.

What is the evidence for amisulpride?

High quality evidence suggests amisulpride may retain more patients in treatment, and be more effective for global state and negative symptoms than placebo. Moderate quality evidence suggests amisulpride may cause more extrapyramidal symptoms than placebo.

High quality evidence suggests amisulpride may retain more patients in treatment, and be more effective for global state, mental state and negative symptoms, but not positive symptoms, than first generation antipsychotics. Amisulpride may be less likely to cause at least one adverse event or extrapyramidal symptom when compared to first generation antipsychotics.

Moderate quality evidence suggests no differences in any outcome compared to other second generation antipsychotics in general. Moderate to low quality evidence suggests fewer people leaving the study early due to inefficacy with amisulpride compared to ziprasidone. Moderate to high quality evidence suggests amisulpride is associated with less weight gain than risperidone or olanzapine. Moderate quality evidence suggests agitation may be reported more often by patients receiving amisulpride than other second generation antipsychotics, with no difference in cardiac effects or extrapyramidal symptoms between amisulpride and risperidone, olanzapine or ziprasidone.

October 2020

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Amphetamines are potent stimulants that are used to treat attention deficit hyperactivity disorder, narcolepsy, and obesity. Amphetamines may also be related to an increased risk, or worsening, of psychoic symptoms. Amphetamines are not suggested as an adjuctive treatment, but rather as an investigation into their effects on symptoms.

What is the evidence for amphetamines?

Moderate quality evidence suggests single-dose dexamfetamine or methylphenidate increases severity or frequency of positive symptoms, particularly in patients who are not in remission. Compared to placebo, moderate to low quality evidence finds no benefit for cognition.

September 2020

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A supplementary, or adjunctive, treatment is administered in conjunction with a patient’s ongoing antipsychotic therapy. Analeptics, such as modafinil, have been suggested as potential adjunctive treatments for schizophrenia. Modafinal is a wake-promoting drug (mechanisms of action unknown) which is thought to help with the sedation side-effects of antipsychotics.

What is the evidence on adjunctive analeptics?

Moderate to high quality evidence suggests adjunctive modafinil can improve negative symptoms, but not positive symptoms or cognition, with no more adverse effects than placebo. Lower quality evidence also finds no differences in global state, quality of life, hospitalisation rates, or study retention.

October 2020

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Growing evidence suggests that inflammatory processes may contribute to the development of schizophrenia. This suggests a potential role for anti-inflammatory medications, such as non-steroidal agents (e.g., aspirin) which may be potentially useful therapeutic strategies, particularly in combination with ongoing antipsychotic medication.

What is the evidence for anti-inflammatory medications?

Compared to placebo, moderate to high quality evidence finds a large benefit of adjunctive N-acetylcysteine, and medium-sized benefits of adjunctive oestrogen and minocycline for improving overall symptoms. There was also a small benefit of adjunctive aspirin for symptom improvement.

Moderate quality evidence finds medium to large benefits of adjunctive melatonin, withania somnifera extract, pioglitazone, piracetam, and pregnenolone for symptom improvement. There was also a medium-sized benefit of adjunctive celecoxib for improving symptoms in first-episode patients but not in chronic patients.

There was improved executive functioning with adjunctive minocycline, and improved working memory with adjunctive N-acetylcysteine.

There were no significant benefits over placebo of adjunctive fatty acids, statins, davunetide, bexarotene, dextromethorphan, or varenicline.

September 2020

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Anticholinergics block the action of the neurotransmitter acetylcholine. Anticholinergic medications may have some utility for the treatment of side effects of antipsychotic medications, including movement disorders like akathisia (a type of restlessness, a common side effect of many neuroleptics), as well as excessive salivation. Adjunct medications prescribed to treat such side effects may contribute to increasing adherence to antipsychotic medications, and reduce the risk of psychotic relapse.

What is the evidence for anticholinergic medications?

Moderate quality evidence suggests small to medium-sized effects of greater improvement in hypersalivation with astemizole or propantheline over placebo, and no differences in adverse effects. There is moderate to low quality evidence for greater improvement in hypersalivation with propantheline over astemizole, with no differences in adverse effects.

Moderate to low quality evidence finds a significant benefit of isocarboxazid (MAO inhibitor) over the anticholinergic procyclidine for tardive dyskinesia.

September 2020

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Anticonvulsant medications influence the actions of neurotransmitters including glutamate and GABA, leading to a decrease in brain cell (neuron) excitability. They may be prescribed as an immediate adjunct to antipsychotic medication in order to treat acute symptoms of psychosis, such as aggressive behaviour. They may also be used as part of an ongoing treatment regime in order to supplement antipsychotic effects or combat side effects like movement disorders. Anticonvulsant medications assessed in this topic primarily include valproate, carbamazepine, and lamotrigine.

What is the evidence for adjunctive anticonvulsants?

Moderate to low quality evidence suggests a medium-sized effect of  improved mental health with adjunctive lamotrigine as measured on some but not all assessment scales, and with adjunctive valproate, particularly in the short-term (< 4 weeks). Lamotrigine is associated with an increased risk of any adverse effect compared to placebo.

There may be some benefit of adjunctive valproate for reducing aggressive behaviour in the short term (1 week), but not in the longer term (4 weeks). There is a lower risk of constipation and tardive dyskinesia with valproate, but an increased risk of sedation compared to placebo.

Moderate to low quality evidence suggests no improvements in symptoms after augmenting clozapine with lamotrigine or topiramate in treatment-resistant patients.

September 2020

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Anticonvulsant medications influence the actions of neurotransmitters including glutamate and GABA, leading to a decrease in brain cell (neuron) excitability. Anticonvulsants may be implemented as an immediate therapy for acute symptoms of psychosis, but they may also be used as part of an ongoing treatment regime. Anticonvulsant medication assessed in this topic primarily includes carbamazepine.

What is the evidence for anticonvulsants?

Moderate to low quality evidence finds better response to treatment with antipsychotics than with phenobarbital, a barbituate used as an anticonvulsant, although there were more side effects with antipsychotics. There were also reduced rates of parkinsonism and use of anticholinergic drugs in people receiving carbamazepine compared to antipsychotics alone.

October 2020

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Anticraving medications includes naltrexone (an opioid receptor antagonist), which aims to reduce craving for and use of substances.

What is the evidence for anticraving medications?

Low quality evidence is unclear as to the benefit of anticraving agents such as naltrexone for improving substance dependence in people with schizophrenia.

September 2020

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