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

Image: ©lyricsai – stock.adobe.com

The post Adenosine modulators appeared first on NeuRA Library.

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

Image: ©Shane Maritch Photography – stock.adobe.com

The post Anti-inflammatories appeared first on NeuRA Library.

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

Image: ©ollaweila – stock.adobe.com

The post Antidiabetics appeared first on NeuRA Library.

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

Image: ©Cappi Thompson – stock.adobe.com

The post Benzodiazepines appeared first on NeuRA Library.

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

Image: ©Alon Harel – stock.adobe.com

The post Calcium channel blockers appeared first on NeuRA Library.

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 or cognition in people with bipolar disorder with cholinesterase inhibitors donepezil or galantamine.

November 2021

Image: © iconicbestiary – stock.adobe.com

The post Cholinesterase inhibitors appeared first on NeuRA Library.

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), dopamine agonists (pramipexole), and partial dopamine agonists (aripiprazole, cariprazine, and brexpiprazole). 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. They are also being tested for mania symptoms.

What is the evidence for dopaminergic modulators?

For depression, moderate to high quality evidence finds a small effect of greater clinical response with lisdexamphetamine, pramipexole, armodafinil, modafinil, dexamphetamine, or methylphenidate than with placebo. There may also be increased remission rates with adjunctive dopaminergic modulators, including in those with treatment-resistant bipolar depression. For mania, moderate quality evidence finds medium-sized effects of greater remission rates with adjunctive cariprazine and high-, but not low-dose aripiprazole.

There was an increased risk of nausea with dopaminergic agents compared to placebo, and no increased risk of switching to mania, insomnia, restlessness, suicidality, or treatment withdrawal.

November 2021

Image: ©peshkova – stock.adobe.com

The post Dopaminergic modulators appeared first on NeuRA Library.

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?

Moderate to high quality evidence suggests adjunctive omega-3 is more effective than placebo for depression but not mania symptoms.

November 2021

Image: © jasmina976 – Fotolia – stock.adobe.com

The post Essential fatty acids appeared first on NeuRA Library.

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, quetiapine, oxcarbazepine, licarbazepine, ziprasidone, valproate, verapamil, lamotrigine or topiramate. There were no differences in all-cause discontinuation of treatment.

November 2021

Image: ©Katie Little – stock.adobe.com

The post Estrogen modulators appeared first on NeuRA Library.

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 quality evidence finds a medium-sized improvement in depression symptoms with N-acetylcysteine compared to placebo. Most studies reported no differences in adverse events. The result for depression was not consistently found across reviews due to differences in the included studies.

Moderate to high quality evidence finds no benefit of adjunctive memantine for depression or mania symptoms.
Only low quality evidence was found for adjunctive ketamine, with review authors suggesting it has the potential to have a rapid and transient antidepressant effect, although the efficacy of a single intravenous dose may be limited.

November 2021

Image: ©Sergey Tarasov – stock.adobe.com

The post Glutamatergic modulators appeared first on NeuRA Library.