Adjunctive and alternative treatments

Adjunctive and alternative treatments for bipolar disorder may be administered along with, or instead of, standard treatment options.

Adenosine modulators

What are adenosine modulators? 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. June 2020


What are anti-inflammatory medications? 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…


What are antidiabetic medications? 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 biopolar 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…


What are benzodiazepines? 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…

Calcium channel blockers

How are calcium channel blockers relevant to bipolar disorder? 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…


We have not found any systematic reviews on this topic that meet the inclusion criteria. Pending enough primary studies, we invite reviews on this topic to be conducted. Alternatively, we will endeavour to conduct our own review to fill this gap in the Library. June 2020

Cholinesterase inhibitors

What are cholinesterase inhibitors? Cholinesterase inhibitors, or anti-cholinesterase, have been proposed as an additional therapy to standard treatments in an attempt to improve functional outcomes and treat symptoms that are not addressed by the other medications. Cholinesterase receptors are known to be involved in cognition, and the use of cholinesterase inhibitors has previously shown some efficacy for improving cognition in Alzheimer’s disease. Aspects of cognition have also been shown to be impaired in bipolar disorder. What is the evidence for cholinesterase inhibitors? There is only low quality evidence currently available from small trials that show no consistent improvements in symptoms…

Dopaminergic modulators

What are dopaminergic modulators? There is increasing interest in dopamine dysfunction being a putative mechanism underlying the pathogenesis of bipolar disorder. Dopaminergic modulators include stimulants (methylphenidate, amphetamine, and lisdexamphetamine), stimulant-like agents (modafinil and armodafinil), and dopamine agonists (pramipexole). These agents increase dopaminergic neurotransmission and are thought to be useful in the treatment of depressive episodes in bipolar disorder, but not in the context of other psychiatric conditions, and they are also being tested for mania symptoms. What is the evidence for dopaminergic modulators? For depression, moderate to high quality evidence suggests a small effect of greater clinical response with lisdexamphetamine,…

Essential fatty acids

What are essential fatty acids? A supplementary, or adjunctive, treatment is administered in conjunction with a patient’s ongoing antipsychotic therapy, in an attempt to treat symptoms or improve functions that are not addressed by the antipsychotic alone. One important group of compounds that have been suggested as an adjunctive therapy are essential fatty acids (EFAs). 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. What is the evidence for essential fatty acids? High quality evidence suggests adjunctive…

Estrogen modulators

What is tamoxifen? Tamoxifen is a selective estrogen-receptor modulator that is used to treat breast cancer. Studies on the pathophysiology of bipolar disorder have demonstrated abnormalities in protein kinase C (PKC) signaling in manic states. Inhibition of PKC can result in antimanic effects. Currently, tamoxifen is the only relatively specific PKC inhibitor that is available for human use and that is capable of crossing the blood-brain barrier. What is the evidence for tamoxifen? Moderate quality evidence suggests large effects of greater improvement in acute mania symptoms with tamoxefin than with placebo, risperidone, haloperidol, olanzapine, caripraxine, lithium, carbamazepine, paliperidone, aripiprazole, asenapine,…

Glutamatergic modulators

What are glutamatergic modulators? Glutamate receptor modulators, such as ketamine and memantine, have been suggested as potential treatments for bipolar disorder when there are sub-optimal responses to other pharmaceuticals. Currently approved treatments for bipolar depression (i.e. several mood stabilisers, antidepressants and antipsychotics) are thought to involve a number of different neurotransmitters such as serotonin, dopamine, and norepinephrine. There is emerging evidence that glutamatergic system dysfunction may also play an important role in the pathophysiology of bipolar depression, and that drugs targeting the NMDA (N-methyl-D-aspartate) glutamate receptor may have antidepressant effects. What is the evidence for glutamatergic modulators? Moderate to high…

Herbal and nutrients

How are herbal treatments relevant to bipolar disorder? Herbal treatments have been suggested as possible adjunctive therapies for people with bipolar disorder who have inadequate response to their usual medications. Herbal treatments include traditional Chinese medicines, gingko biloba, folate and inositol. What is the evidence for herbal treatments? Moderate to low quality evidence suggests potential benefit of adjunctive micronutrients (EMPowerplus) for overall clinical improvement, with no benefit of adjunctive inositol for depression. June 2020


How is melatonin relevant to bipolar disorder? Melatonin is a hormone primarily synthesised by the pineal gland. Secretion of melatonin by the pineal gland shows a circadian rhythm synchronised to the light-dark cycle. Melatonin has been reported to be involved in various important biological functions in the body: sleep regulation, circadian rhythm, immune modulation, reproduction, anti-inflammation, antioxidant, and energy metabolism. Various studies have reported the beneficial effects of melatonin for improving metabolic problems; problems often observed in people taking antipsychotic medications. This topic assesses the potential benefits of adjunctive melatonin for reducing metabolic side effects among people with bipolar disorder…

Norepinephrine inhibitors

What is atomoxetine? Atomoxetine is a norepinephrine (noradrenaline) reuptake inhibitor used to treat Attention Deficit Hyperactivity Disorder (ADHD). Studies on people with bipolar disorder show rates of comorbid ADHD range from 12.8% to 16%, which is higher than observed in the general population. Having both ADHD and bipolar disorder is associated with more severe symptoms and worse outcomes of both conditions, including earlier onset of bipolar disorder, more mood episodes, shorter inter-episodic phases, and generally, greater functional impairment. What is the evidence for atomoxetine? Low quality evidence is unable to properly determine any benefits of atomoxetine for people with comorbid…

Thyroid hormones

How are thyroid hormones related to bipolar disorder? There is a well-established relationship between alterations of various hormonal systems and psychiatric disorders, including depression. This has led to clinical and research studies examining the efficacy of the different hormones, including thyroid hormones, for treatment of depression in people with bipolar disorder. What is the evidence for thyroid hormones? Low quality evidence is unable to determine any benefits of triiodothyronine for bipolar disorder. June 2020

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