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.

November 2021

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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.

November 2021

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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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Stressful Life events that occur during adulthood are defined as particularly significant experiences that result in substantial changes to personal circumstances. These changes may be positive or they may be negative changes and can occur across all aspects of life, including health, education, employment, relationships, bereavement, housing, legal, and financial issues. These can all contribute to the development of mental health problems.

What is the evidence for adult life events as risk factors for bipolar disorder?

Moderate to high quality evidence suggests no differences in the number of stressful events experienced prior to onset of bipolar disorder compared to unipolar depression or people without a mental illness.

October 2021

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Differences observed in the age at onset of bipolar disorder may be influenced by genetic and/or environmental factors. Understanding these factors could lead to better understanding of the disorder, early identification, and improved intervention strategies for patients.

What is the evidence for age at onset of bipolar disorder?

Moderate quality evidence suggests the median age at onset of bipolar disorder is around 33 years old. Moderate to high quality evidence finds a trimodal distribution, with 45% of people with bipolar disorder showing an early-onset age (~17 years), 35% showing a mid-onset age (~26 years), and 20% showing a late-onset age (~42 years).

High quality evidence shows younger age at onset is associated with increased severity of depression. Moderate to high quality evidence finds younger age at onset is associated with having a personality disorder or longer delays to treatment. Moderate quality evidence finds younger age at onset is associated with suicide attempts, anxiety disorders, and substance use disorders. There were no associations between younger age at onset and severity of mania symptoms, first polarity being mania, psychotic symptoms, rapid cycling, or mixed bipolar episodes.

March 2022

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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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Comorbid anxiety disorders are common in people with bipolar disorder. Generalised anxiety disorder is characterised by continuous and excessive worrying for six months or more. Specific phobias are characterised by anxiety provoked by a feared object or situation, resulting in avoidance. Social phobia is anxiety provoked by social or performance situations. Agoraphobia is anxiety about situations where escape may be difficult or where help might not be available. Panic disorder is characterised by a panic attack, which is a distinct episode where a person experiences sudden apprehension and fearfulness, and may experience shortness of breath, palpitations, chest pain or feeling of choking.

What is the evidence regarding anxiety disorders in people with bipolar disorder?

Moderate quality evidence found the lifetime prevalence of anxiety disorders in children, adolescents, and adults with bipolar disorder is around 45%, and the prevalence in adults in the euthymic phase is around 35%. These rates are significantly higher than in people without bipolar disorder.

The most common anxiety disorders in adults were generalised and social anxiety disorders, agoraphobia, specific phobias, and panic disorders. The most common anxiety disorders in children were generalised and separation anxiety disorders. The most common anxiety disorders in adolescents were panic disorder and social phobia.

Moderate to low quality evidence found cognitive behavioural therapy is effective for improving symptoms of anxiety in people with bipolar disorder.

Please also see the related topics on comorbid post-traumatic stress disorder and obsessive compulsive disorder, which are no longer considered anxiety disorders in the DSM-5.

October 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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