Mood stabilisers are the main treatment for bipolar disorder. However, it is uncertain which drugs have the best outcomes.

To investigate whether rates of suicide, self-harm and psychiatric hospital admission in individuals with bipolar disorder differ between mood stabilisers.

A cohort design was applied to people aged ≥15 years who were diagnosed with bipolar disorder and living in Denmark during 1995–2016. Treatment with lithium, valproate, other mood stabilisers and antipsychotics were compared in between- and within-individual analyses, and adjusted for sociodemographic characteristics and previous self-harm.

A total of 33 337 individuals with bipolar disorder were included (266 900 person-years). When compared with individuals not receiving treatment, those receiving lithium had a lower rate of suicide (hazard ratio 0.40, 95% CI 0.31–0.51). When comparing treatment and non-treatment periods in the same individuals, lower rates of self-harm were found for lithium (hazard ratio 0.74, 95% CI 0.61–0.91). Lower rates of psychiatric hospital admission were found for all drug categories compared with non-treatment periods in within-individual analyses (P<0.001). The low rates of self-harm and hospital admission for lithium in within-individual analyses were supported by results of between-individual analyses.

Lithium was associated with lower rates of suicide, self-harm and psychiatric hospital readmission in all analyses. With respect to suicide, lithium was superior to no treatment. Although confounding by indication cannot be excluded, lithium seems to have better outcomes in the treatment of bipolar disorder than other mood stabilisers.

Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.

To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.

This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.

The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.

Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.

Despite the widespread use of psychotropic medications in people with autism spectrum disorder (ASD), there is limited evidence to suggest that psychotropic medications including mood stabilisers are effective in individuals with ASD.

To carry out a systematic review and meta-analysis of randomised controlled trials (RCTs) that assessed the effectiveness of mood stabilisers in people with ASD.

We searched the following databases: Cochrane Library, MEDLINE, Embase, CINAHL, PsycINFO, ERIC, DARE, and ClinicalTrials.gov. In addition, we hand-searched 12 relevant journals. We used the Cochrane Risk of Bias and Jadad scores to assess the quality of included RCTs. We carried out a meta-analysis using a random-effects model.

We included eight RCTs (four on valproate, two on levetiracetam, and one each on lamotrigine and topiramate) that included a total of 310 people with ASD, primarily children. Outcomes were based on core and associated ASD symptoms including irritability and aggression but not bipolar disorder. Only two small studies (25%) from the same group showed definite superiority over placebo and one over psychoeducation alone. Meta-analysis of pooled data on the Aberrant Behaviour Checklist-irritability, Clinical Global Impression Scale-improvement, and Overt Aggression Scale (OAS)/OAS-modified did not show any significant inter-group difference. The rates of adverse effects did not show any significant inter-group difference.

Given the methodological flaws in the included studies and the contradictory findings, it is difficult to draw any definitive conclusion about the effectiveness of mood stabilisers to treat either ASD core symptoms or associated behaviours. Robust large-scale RCTs are needed in the future to address this issue.

PROSPERO registration: CRD42021255467 on 18 May 2021.

J.C. conducted clinical trials of antipsychotics sponsored by Janssen Pharmaceuticals between 1978 and 1998 and met Dr Paul Janssen.

Research on the risk of stroke following the use of mood stabilisers specific to patients with bipolar disorder is limited.

In this study, we investigated the risk of stroke following the exposure to mood stabilisers in patients with bipolar disorder.

Data for this nationwide population-based study were derived from the Taiwan National Health Insurance Research Database. Among a retrospective cohort of patients with bipolar disorder (n = 19 433), 609 new-onset cases of stroke were identified from 1999 to 2012. A case–crossover study design utilising 14-day windows was applied to assess the acute exposure effect of individual mood stabilisers on the risk of ischaemic, haemorrhagic and other types of stroke in patients with bipolar disorder.

Mood stabilisers as a group were significantly associated with the increased risk of stroke in patients with bipolar disorder (adjusted risk ratio, 1.26; P = 0.041). Among individual mood stabilisers, acute exposure to carbamazepine had the highest risk of stroke (adjusted risk ratio, 1.68; P = 0.018), particularly the ischaemic type (adjusted risk ratio, 1.81; P = 0.037). In addition, acute exposure to valproic acid elevated the risk of haemorrhagic stroke (adjusted risk ratio, 1.76; P = 0.022). In contrast, acute exposure to lithium and lamotrigine did not significantly increase the risk of any type of stroke.

Use of carbamazepine and valproic acid, but not lithium and lamotrigine, is associated with increased risk of stroke in patients with bipolar disorder.

None.

M.J.T. reports personal fees from Sunovion, Otsuka, Lundbeck, outside the submitted work.

The Treatment Algorithm Group (TAG) was supported logistically by Servier who provided financial assistance with travel and accommodation for those TAG members travelling interstate or overseas to attend the meeting in Sydney (held on 18 November 2017). None of the committee were paid to participate in this project and Servier have not had any input into the content, format or outputs from this project.

Lack of good animal models for affective disorders, including major depression and bipolar disorder, is noted as a major bottleneck in attempts to study these disorders and develop better treatments. We suggest that an important approach that can help in the development and use of better models is attention to variability between model animals.

Differences between mice strains were studied for some decades now, and sex differences get more attention than in the past. It is suggested that one factor that is mostly neglected, individual variability within groups, should get much more attention. The importance of individual differences in behavioral biology and ecology was repeatedly mentioned but its application to models of affective illness or to the study of drug response was not heavily studied. The standard approach is to overcome variability by standardization and by increasing the number of animals per group.

Possibly, the individuality of specific animals and their unique responses to a variety of stimuli and drugs, can be helpful in deciphering the underlying biology of affective behaviors as well as offer better prediction of drug responses in patients.

Immunological theories, particularly the sickness syndrome theory, may explain psychopathology in mood disorders. However, no clinical trials have investigated the association between overall immune system markers with a wide range of specific symptoms including potential gender differences.

We included two similar clinical trials, the lithium treatment moderate-dose use study and clinical and health outcomes initiatives in comparative effectiveness for bipolar disorder study, enrolling 765 participants with bipolar disorder. At study entry, white blood cell (WBC) count was measured and psychopathology assessed with the Montgomery and Aasberg depression rating scale (MADRS). We performed analysis of variance and linear regression analyses to investigate the relationship between the deviation from the median WBC, and multinomial regression analysis between different WBC levels. All analyses were performed gender-specific and adjusted for age, body mass index, smoking, race, and somatic diseases.

The overall MADRS score increased significantly for each 1.0×109/l deviation from the median WBC among 322 men (coefficient=1.10; 95% CI=0.32–1.89; p=0.006), but not among 443 women (coefficient=0.56; 95% CI=−0.19–1.31; p=0.14). Among men, WBC deviations were associated with increased severity of sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, inability to feel, and suicidal thoughts. Among women, WBC deviations were associated with increased severity of reduced appetite, concentration difficulties, lassitude, inability to feel, and pessimistic thoughts. Both higher and lower WBC levels were associated with increased severity of several specific symptoms.

Immune system alterations were associated with increased severity of specific mood symptoms, particularly among men. Our results support the sickness syndrome theory, but furthermore emphasise the relevance to study immune suppression in bipolar disorder. Due to the explorative nature and cross-sectional design, future studies need to confirm these findings.

Using data from the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) study, we aimed to present the rates and clinical correlates of suicidal thoughts/acts in patients recruited from a total of 40 centres in 10 Asian countries/areas: China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Singapore, Taiwan, and Thailand.

Data from 1122 patients with depressive disorders in the REAP-AD study were used. The ICD-10 was employed to diagnose depressive episodes and recurrent depressive disorder. The presence or absence of suicidal thoughts/acts and profile of other depressive symptoms was established using the National Institute for Health and Clinical Excellence guidelines for depression. Country/area differences in rates of suicidal thoughts/acts were evaluated with the χ2 test. In addition, depressive symptom profiles, other clinical characteristics, and patterns of psychotropic drug prescription in depressed patients with and without suicidal thoughts/acts were compared using analysis of covariance for continuous variables and logistic regression analysis for discrete variables to adjust the effects of covariates.

The rates of suicidal thoughts/acts in 10 countries/areas varied from 12.8% in Japan to 36.3% in China. Patients with suicidal thoughts/acts presented more persistent sadness (adjusted odds ratio [aOR]=2.64, p<0.001), loss of interest (aOR=2.33, p<0.001), fatigue (aOR=1.58, p<0.001), insomnia (aOR=1.74, p<0.001), poor concentration (aOR=1.88, p<0.001), low self-confidence (aOR=1.78, p<0.001), poor appetite (aOR=2.27, p<0.001), guilt/self-blame (aOR=3.03, p<0.001), and use of mood stabilisers (aOR=1.79, p<0.001) than those without suicidal thoughts/acts.

Suicidal thoughts/acts can indicate greater severity of depression, and are associated with a poorer response to antidepressants and increased burden of illness. Hence, suicidal thoughts/acts can provide a clinical index reflecting the clinical status of depressive disorders in Asians.

In bipolar disorder, treatment with antidepressants without concomitant use of mood stabilisers (antidepressant monotherapy) is associated with development of mania and rapid cycling and is therefore not recommended. The present study aimed to investigate the psychopharmacological treatment patterns in bipolar disorder over time, with a focus on antidepressant monotherapy.

Cohort study with annual cross-sectional assessment of the use of psychotropic medications between 1995 and 2012 for all Danish residents aged 10 years or older with a diagnosis of bipolar disorder registered in the Danish Psychiatric Central Research Register. Users of a given psychotropic medication were defined as individuals having filled at least one prescription for that particular medication in the year of interest.

We identified 20 618 individuals with bipolar disorder. The proportion of patients with bipolar disorder using antidepressants, atypical antipsychotics and anticonvulsants increased over the study period, while the proportion of patients using lithium, typical antipsychotics and benzodiazepines/sedatives decreased. The proportion of patients treated with antidepressant monotherapy decreased from 20.5% in 1997 to 12.1% in 2012, and among antidepressant users, the proportion in monotherapy decreased from 47.7% to 23.9%, primarily driven by a decrease in the use of tricyclic antidepressants.

The results show an increase in the proportion of patients with bipolar disorder being treated with antidepressants in the period from 1997 to 2012. However, in accordance with international treatment guidelines, the extent of antidepressant monotherapy decreased during the same period.

Objective: Although depressive symptoms are preponderant in the course of bipolar (BP) disorders, the treatment of BP depression remains a controversial issue with different clinical approaches available. This review addresses the issues of whether antidepressants (ADs) are effective in treating acute and long-term BP depression, risks linked to ADs and what alternatives to ADs are available.

Methods: We searched the MEDLINE databases using the following syntax: [bipolar depression AND unipolar depression AND (antidepressants OR anticonvulsants OR lithium OR antipsychotics OR dopamine-agonists OR psychoeducation OR psychotherapy OR electroconvulsive therapy OR transcranial magnetic stimulation)]. The search included studies published up to 31 May 2009 and conducted on adults.

Results: In the acute treatment of BP depression ADs are effective with no differences among drug classes. However, neither the switch into (hypo)mania induction rate nor the suicide risk linked to AD use are definitely established. The effectiveness of long-term AD use is limited to highly selected samples of patients with positive acute response. The risk of long-term ADs causing cycle acceleration and rapid cycling induction concerns a subpopulation of patients. Valid alternatives to ADs in treating acute BP depression are quetiapine, an olanzapine–fluoxetine combination, and electroconvulsive therapy for more severe patients. Lamotrigine is effective and safe in preventing depressive relapses. Psychotherapy and psychoeducation represent effective adjunctive treatments.

Conclusion: In the treatment of BP depression there is not a specific effective treatment for all the patients. Interventions should therefore be personalised and the scientific evidence should be adapted to each patient's clinical features.