Bipolar disorder is thought to be associated with a purinergic system dysfunction, particularly in the manic phases of the disorder. Moreover, depressive temperaments have been related to both high and low levels of uric acid. Allopurinol is used for the treatment of gout and hyperuricemia; it inhibits purine degradation and subsequently increases adenosine levels.

What is the evidence for adenosine modulators?

Moderate quality evidence suggests adjunctive allopurinol may improve mania symptoms in people with bipolar disorder, but not for those in a mixed mood state.

November 2021

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Most antidepressants increase serotonin or noradrenaline, and are effective for the treatment of unipolar depression. However, as they may increase the risk of phase shifting from depression to mania in people with bipolar disorder, they are generally used only when the depressive phase is severe and shows poor response to mood stabilisers or antipsychotics.

What is the evidence on antidepressants for bipolar depression?

Moderate to high quality evidence suggests second generation antidepressants (with or without mood stabilisers), are a more effective long-term prophylactic treatment for relapse to depression than placebo (with or without mood stabilisers). Moderate to low quality evidence suggests no differences in relapse rates to depression or mania between antidepressants and mood stabilisers.

Moderate quality evidence suggests ~19% of people with bipolar depression taking antidepressants switch to mania. Switching rates are highest in people with a family history of affective disorders, previous suicide attempts, depression polarity of the index episode, lifetime psychotic features, and rapid- cycling course. Rates were lowest in people taking antidepressants with concurrent lithium.

November 2021

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Growing evidence suggests that inflammatory processes may contribute to the development of mental disorders. Pro-inflammatory cytokines interleukin (IL) 4, tumor necrosis factor alpha (TNF-a), soluble IL-2 receptor (sIL-2R), IL-1b, IL-6, soluble receptor of TNF-a type 1 (STNFR1), and C-reactive protein (CRP) have been shown to be elevated in people with bipolar disorder compared to healthy controls. This suggests a potential role for anti-inflammatory agents in the treatment of bipolar disorder. These agents primarily include non-steroidal anti-inflammatory agents (e.g., aspirin, celecoxib), but also omega-3 polyunsaturated fatty acids, N-acetylcysteine (a glutemate modulator) and pioglitazone (an antidiabetic) have some anti-inflammatory properties.

What is the evidence for anti-inflammatory medications?

Moderate to high quality evidence finds adjunctive omega-3 to be more effective than placebo for depression, but not for mania symptoms. There is good evidence of some benefit of adjunctive celecoxib over placebo for mania symptoms. Moderate quality evidence finds some benefit of adjunctive N-acetylcysteine over placebo for depression, with no differences in adverse events. The finding for depression was not consistently found across reviews due to slight differences in included studies. Moderate to low quality evidence finds no benefit of adjunctive aspirin for depression, and low quality evidence is unable to determine any benefits of pioglitazone.

November 2021

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Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists such as pioglitazone are used to treat type 2 diabetes. In the context of comorbid diabetes and depressive disorders, studies have shown that pioglitazone also has antidepressant properties. This topic assesses the evidence for antidiabetic medications for the treatment of depression in people with bipolar disorder.

What is the evidence for antidiabetic medications?

Low quality evidence is unable to determine the benefits of pioglitazone for depression in people with bipolar disorder. Note that this result was due to only one small study of people with bipolar disorder. When the analysis also included people with major depression, the results significantly favoured pioglitazone for the treatment of depression.

November 2021

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The primary treatments for bipolar disorder are pharmacological, and often involve second generation antipsychotic drugs such as aripiprazole. Aripiprazole is is a partial agonist of dopamine D2 and serotonin 5-HT1A receptors and an antagonist of 5-HT2A receptors. It has a distinct receptor-binding profile compared to other second generation antipsychotic drugs.

What is the evidence for aripiprazole as a treatment for bipolar disorder?

Mania and psychotic symptoms

Moderate quality evidence suggests a small effect of greater improvement with aripiprazole than with placebo. The effect for mania is large in pediatric patients. There were no differences in mania symptoms between aripiprazole and other medications, however, there were large effects of more switching to mania with aripiprazole than with quetiapine or ziprasidone.

Depressive symptoms

Moderate to high quality evidence suggests no significant differences between aripiprazole and placebo for depression. Moderate quality evidence suggests less improvement in depression, less response to treatment, and less likelihood of remission with aripiprazole than with lurasidone.

Overall symptoms and prevention of relapse

Moderate quality evidence suggests greater overall improvement in symptoms with aripiprazole than with haloperidol or lithium. There were medium-sized effects of fewer relapses with aripiprazole + valproate or aripiprazole + lamotrigine than with placebo. There were also fewer relapses with aripiprazole + valproate than with paliperidone or imipramine. Also see the topics on relapse prevention and polypharmacy.

Side effects

Moderate quality evidence suggests more high-density lipoprotein, sedation, extrapyramidal symptoms, constipation, nausea, vomiting, anxiety, salivation, fatigue, insomnia, and pain in the extremities with aripiprazole than with placebo. However, there was less hyperprolactinemia, less elevated fasting glucose, less increased appetite, and less total cholesterol with aripiprazole.

November 2021

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The treatment of bipolar disorder is complex due to the presence of varying configurations of symptoms in patients. The primary treatments for bipolar disorder are pharmacological, and often involve second generation antipsychotic drugs, such as asenapine. Based on its high affinity for seratonin receptors, asenapine has been proposed as a treatment for bipolar disorder.

What is the evidence for asenapine as a treatment for bipolar disorder?

Moderate to high quality evidence suggests small to medium-sized effects of greater improvement in mania and depression symptoms with asenapine monotherapy than with placebo. However, there were more extrapyramidal side effects, somnolence, dizziness, sedation, blood glucose, and weight gain with asenapine.

Moderate to high quality evidence suggests no differences between asenapine monotherapy and olanzapine monotherapy for mania symptoms. There was no analysis of depression symptoms. There was more dizziness and parkinsonism with asenapine, and more weight gain and higher prolactin levels with olanzapine.

Also see the topic on relapse prevention.

November 2021

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Benzodiazepines are minor tranquillisers that may be implemented as an adjunct to other medications in order to treat acute symptoms, such as agitation, aggression, irritability, and anxiety. They may also be used to treat side effects of antipsychotic medications such as movement disorders, including tardive dyskinesia. However, benzodiazepines 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 for benzodiazepines?

Moderate to low quality evidence suggests the benzodiazepine lorazepam is less effective than intramuscular antipsychotics olanzapine and aripiprazole for reducing agitation in people with bipolar disorder.

November 2021

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Even though antidepressants are effective for treating depression, their use in people with bipolar disorder can increase the risk of phase shifting from depression to mania. Most antidepressants increase serotonin or noradrenaline; in contrast, bupropion has unique pharmacokinetics as a norepinephrine-dopamine reuptake inhibitor. Therefore, it has been suggested that bupropion may have benefits for depression with less risk of phase shifting than other antidepressants.

What is the evidence for bupropion as treatment for bipolar disorder?

Moderate to low quality evidence suggests a large effect of greater improvement in depression scores with bupropion than with placebo. There were no differences between bupropion and other antidepressants for depression or phase-shifting.

November 2021

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Calcium signalling has long been implicated in bipolar disorder, with reports of altered levels of calcium in people with mania, and the observation that long-term lithium treatment is associated with altered calcium metabolism. These reports prompted investigations of calcium channel blockers (primarily verapamil) as potential treatments for bipolar disorder.

What is the evidence for calcium channel blockers?

Moderate to low quality evidence suggests no differences between verapamil and placebo or lithium for manic symptoms or rates of discontinuation. Low quality evidence is unable to determine side effects of any particular calcium channel blocker medications used by people with bipolar disorder.

November 2021

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Carbamazepine is an anticonvulsant used primarily in the treatment of seizure disorders such as epilepsy. Anticonvulsant medications influence the actions of neurotransmitters leading to a decrease in brain cell (neuron) excitability. Carbamazepine can also be used for the treatment of mania.

What is the evidence for carbamazepine as a treatment for bipolar disorder?

Moderate quality evidence suggests medium-sized effects of greater improvement in acute mania symptoms with carbamazepine than with placebo or topiramate. There was a large effect of greater improvement in acute mania symptoms with tamoxefin than with carbamazepine. There was more discontinuation of treatment with carbamazepine than with olanzapine.

Low quality evidence is unable to determine the benefits of carbamazepine over placebo for acute depression.

Also see the topic on relapse prevention.

November 2021

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