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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Benzodiazepines have been proposed as an alternative therapy to standard antipsychotic treatments in an attempt to improve functional outcomes and treat symptoms that are not addressed by the antipsychotic medications. Benzodiazepine medications induce anxiolytic, sedative, muscle relaxant, and amnesic effects when used therapeutically. Benzodiazepines may be implemented as a short-term therapy in order to treat acute symptoms of psychosis, such as agitation or aggression. They have also been suggested as an ongoing treatment regime, as they may have fewer side effects than antipsychotics. However, the efficacy of benzodiazepines for reducing side effects of antipsychotics is unclear, as they may be associated with adverse effects of their own. Benzodiazepines are also associated with well-established patterns of tolerance and dependence and are prescribed with caution.

What is the evidence for benzodiazepines?

High quality evidence shows a lower risk of extrapyramidal (movement) side effects with benzodiazepines than with antipsychotics. Moderate quality evidence shows benzodiazepines were associated with a faster rate of sedation and more improvement in global state than antipsychotics. Moderate to low quality evidence suggests less excitation with antipsychotics than with benzodiazepines. No differences were found between benzodiazepines and antipsychotics in study attrition, behavioural improvement, mental state, need for additional medication or restraint, agitation, service use, hospital discharge, or relapse.

Compared to placebo, moderate to low quality evidence suggests greater clinical improvement but a significantly increased risk of side effects such as low energy levels and ataxia with benzodiazepines. No differences were found between benzodiazepines and placebo in study attrition, relapse, anxiety, or other adverse effects.

October 2020

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The plant cannabis sativa contains over 70 different constituents, including tetrahydrocannabinol (THC) and cannabidiol (CBD), which are the most concentrated substances found in cannabis extracts. Recreational cannabis use during adolescence is a well documented risk factor for schizophrenia, particularly cannabis with high THC content. While THC induces symptoms in healthy volunteers that resemble psychosis, CBD interferes with the detrimental actions of THC in terms of psychotic proneness. Therefore, there is potential for CBD to act as an antipsychotic agent.

What is the evidence for cannabidiol?

Moderate to low quality evidence is unable to determine the benefits of cannabidiol for the symptoms of schizophrenia.

October 2020

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Essential fatty acids have been proposed as a potential alternative treatment. The two main EFAs are omega-3 and omega-6. They are important compounds for brain function, as they have impact on membrane receptors, ion channels and synapse function, as well as neuronal development. However, they are not made in the body and must be sourced from the diet. People with schizophrenia have shown to have lower levels of these essential compounds and their products, including omega-3 products docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), its esther, ethyl-eicosapentaenoic acid (E-EPA), omega-6 product arachidonic acid (AA), and their metabolites including prostaglandins.

What is the evidence for fatty acids?

Overall, low quality evidence is unclear of any benefit of omega-3 as an alternative to neuroleptic medication for people with schizophrenia. There could be some benefit of omega-3 fatty acids compared to placebo for preventing transition to psychosis for up to one-year post-treatment in those at ultra-high risk of psychosis.

October 2020

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Antipsychotic medications predominantly target the dopamine neurotransmitter system, with some efficacy for alleviating the positive symptoms of schizophrenia. However, the persistence of negative and cognitive symptoms suggests that other mechanisms are also likely to be involved. Reduction of glutamatergic N-methyl-D-aspartate (NMDA) receptor function may represent a primary neuropathology in schizophrenia. Therefore, glutamate receptor modulators have been suggested as an adjunctive therapy to standard antipsychotic treatments, when individuals have sub-optimal responses to treatment. The glutamate receptor modulators that have been trialed in schizophrenia are predominantly amino acids, and act on several different aspects of the glutamatergic neurotransmission system. Agents include glycine, D-serine, D-cycloserine, D-alanine, CX516, sarcosine, N-acetyl cysteine, and memantine. These agents have been studied for efficacy in improving symptom severity and cognitive function.

What is the evidence for glutamate modulators?

Low quality evidence is unable to determine any benefit of D-cycloserine or sarcosine as an alternative treatment to antipsychotics for mental state or cognition (very small samples).

October 2020

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Herbal medicines have been suggested as a potential alternative treatment to antipsychotics. Herbal therapies can include traditional Chinese medicines and Indian ayurvedic therapy, as well as more common medicines such as Gingko Biloba.

What is the evidence for alternative herbal medicines?

Moderate to low quality evidence suggests the antipsychotic chlorpromazine may be more effective than Dang gui cheng qi tang for global symptoms.

Moderate to low quality evidence suggests wendon decoction may improve global symptoms more than no treatment, but when compared to antipsychotics, there were no differences in symptoms. However, there were fewer extrapyramidal and insomnia side effects with wendon decoction.

Low quality evidence is unable to determine any benefit of ayurvedic herbal therapies over placebo or the antipsychotic chlorpromazine.

October 2020

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Mood stabilisers, including lithium and anticonvulsants such as carbamazepine have been proposed as an alternative therapy to standard antipsychotic treatments when individuals have sub-optimal responses to treatment. Mood stabilisers 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. Mood stabiliser medications assessed in this topic include lithium as well as anticonvulsant medications.

What is the evidence for mood stabilisers?

Moderate to high quality evidence suggests a large effect of greater improvement in overall symptoms with antipsychotics than with lithium. Moderate quality evidence suggests a medium-sized increased risk of leaving the study early for any reason or due to inefficacy of treatment with lithium than with antipsychotics. Lithium may result in less sleepiness, but more toxic confusion than antipsychotics.

Moderate to low quality evidence suggests a large effect of less need for additional anticholinergic drugs with carbamazepine than with antipsychotics.

October 2020

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Serotonin is a neurotransmitter. Atypical antipsychotics are thought to have some affinity for serotonin 5-HT receptors, for example clozapine, quetiapine, and olanzapine, among others. This suggests a potential for the use of serotonin-specific medications in the treatment of schizophrenia.

What is the evidence for serotonin modulators?

Low quality evidence is unable to determine any benefit of Ondansetron as an alternative to antipsychotics.

October 2020

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