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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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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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A supplementary, or adjunctive, treatment is administered in conjunction with a patient’s ongoing antipsychotic therapy. Antidepressants have been proposed as an additional therapy to standard antipsychotic treatments, in an attempt to improve functional outcomes and treat symptoms that are not addressed by the antipsychotic medication alone. Antidepressant medications have been studied as treatments for the symptoms of schizophrenia, particularly negative symptoms, as well as for treating people with co-occurring schizophrenia and depression.

What is the evidence for adjunctive antidepressants?

Moderate quality evidence finds small effects of greater improvement in overall, negative, positive, and depressive symptoms with adjunctive antidepressants. The effect size was largest for negative symptoms and smallest for positive symptoms.

Moderate to high quality evidence finds a medium-sized effect of more smoking cessation with adjunctive bupropion than with placebo, which was maintained at six months follow-up.

Moderate quality evidence finds small benefits of adjunctive antidepressants for global cognition and executive functioning, but not for memory, attention, processing speed, verbal fluency or visuospatial processing.

September 2020

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Benzodiazepines may be implemented as an adjunct to antipsychotic medication in order to treat acute symptoms of psychosis such as agitation, aggression, irritability, or anxiety. They may also be used to treat side effects of antipsychotic medications such as movement disorders including tardive dyskinesia, however they are associated with their own side effects and are associated with well-established patterns of tolerance and dependence, so they are prescribed with caution.

What is the evidence on benzodiazepines?

Moderate to low quality evidence suggests no benefit of adjunctive benzodiazepines for improving agitation or excitation in the short term (up to 30 minutes); however benzodiazepines may be associated with a faster time to sedation, better global improvements (up to 60 minutes) and lower risk of movement disorders than antipsychotics alone. There were no benefits of adjunctive benzodiazepines for reducing the need for additional medication or hospitalisation, or for improving symptoms or aggression.

September 200

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Beta blockers can be prescribed in addition to standard antipsychotic regimes in order to target some side effects of these medications, including extrapyramidal symptoms such as akathisia (a type of restlessness, a common and early-onset side effect of many neuroleptics). Beta blockers are adrenergic beta receptor antagonists, inhibiting the action of neurotransmitters adrenaline/epinephrine and noradrenaline/norepinephrine on beta-receptors, ultimately influencing brain regions that control functions such as movement. Beta blockers have also been used to reduce the physical symptoms of anxiety in people with schizophrenia (for example, pounding heart, clammy hands, sweating), and have also been suggested to reduce aggression.

What is the evidence on beta blockers?

Moderate quality evidence suggests norepinephrine reuptake inhibitors atomoxetine and reboxetine may reduce depressive symptoms, but not positive or negative symptoms. Reboxetine may result in more weight loss than placebo. Lower quality evidence suggests no benefit of beta blockers in general for improving extrapyramidal symptoms such as akathisia, or for reducing aggression.

September 2020

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