Treatment and management for difficult-to-treat depression are challenging, especially in a subset of patients who are at high risk for relapse and recurrence. The conditions that represent this subset are recurrent depressive disorder (RDD) and bipolar disorder (BD). In this context, we aimed to examine the effectiveness of maintenance transcranial magnetic stimulation (TMS) on a real-world clinical basis by retrospectively extracting data from the TMS registry data in Tokyo, Japan.

Data on patients diagnosed with treatment-resistant RDD and BD who received maintenance intermittent theta burst stimulation (iTBS) weekly after successful treatment with acute iTBS between March 2020 and October 2023 were extracted from the registry.

All patients (21 cases: 10 cases with RDD and 11 cases with BD) could sustain response, and 19 of them further maintained remission. In this study, maintenance iTBS did not exacerbate depressive symptoms in any of the cases, but may rather have the effect of stabilizing the mental condition and preventing recurrence.

This case series is of great clinical significance because it is the first study to report on the effectiveness of maintenance iTBS for RDD and BD, with a follow-up of more than 2 years. Further validation with a randomized controlled trial design with a larger sample size is warranted.

Identification of the predominant polarity, i.e. hypomanic/manic (mPP) or depressive predominant polarity (dPP), might help clinicians to improve personalised management of bipolar disorder.

We performed a systematic review and meta-analysis to estimate prevalence and correlates of mPP and dPP in bipolar disorder.

The protocol was registered in the Open Science Framework Registries (https://doi.org/10.17605/OSF.IO/8S2HU). We searched main electronic databases up to December 2023 and performed random-effects meta-analyses of weighted prevalence of mPP and dPP. Odds ratios and weighted mean differences (WMDs) were used for relevant correlates.

We included 28 studies, providing information on rates and/or correlates of mPP and dPP. We estimated similar rates of mPP (weighted prevalence = 30.0%, 95% CI: 23.1 to 37.4%) and dPP (weighted prevalence = 28.5%, 95% CI: 23.7 to 33.7%) in bipolar disorder. Younger age (WMD = −3.19, 95% CI: −5.30 to −1.08 years), male gender (odds ratio = 1.39, 95% CI: 1.10 to 1.76), bipolar-I disorder (odds ratio = 4.82, 95% CI: 2.27 to 10.24), psychotic features (odds ratio = 1.56, 95% CI: 1.01 to 2.41), earlier onset (WMD = −1.57, 95% CI: −2.88 to −0.26 years) and manic onset (odds ratio = 13.54, 95% CI: 5.83 to 31.46) were associated with mPP (P < 0.05). Depressive onset (odds ratio = 12.09, 95% CI: 6.38 to 22.90), number of mood episodes (WMD = 0.99, 95% CI: 0.28 to 1.70 episodes), history of suicide attempts (odds ratio = 2.09, 95% CI: 1.49 to 2.93) and being in a relationship (odds ratio = 1.98, 95% CI: 1.22 to 3.22) were associated with dPP (P < 0.05). No differences were estimated for other variables.

Despite some limitations, our findings support the hypothesis that predominant polarity might be a useful specifier of bipolar disorder. Evidence quality was mixed, considering effects magnitude, consistency, precision and publication bias. Different predominant polarities may identify subgroups of patients with specific clinical characteristics.

Affective symptoms are a common feature of schizophrenia and define bipolar disorder. Alterations in dopamine neurotransmission and activity at D3-D2 receptors is associated with depressive symptoms providing the rationale for targeting D3-D2 receptors with partial agonists.

The aim of the analysis herein is to examine and compare the efficacy of cariprazine in treating affective symptoms in both schizophrenia and bipolar depression.

Data from 3 schizophrenia [NCT00694707, NCT01104766, NCT01104779] and 3 bipolar I depression studies [NCT013896447, NCT02670538, NCT0267055] were pooled for the analyses. To investigate efficacy across individual affective symptoms, the Marder anxiety/depression and negative symptom items of the Positive and Negative Syndrome Scale (PANSS) and single items of the Montgomery-Asberg Depression Rating Scale (MADRS) were analysed. Improvement across affective symptoms was examined primarily evaluating least square mean differences (LSMDs) in comparison to placebo in mean change from baseline.

The pooled ITT population was comprised of persons with schizophrenia (placebo=442, cariprazine=1024) and bipolar disorder (placebo=460, cariprazine=923). Cariprazine resulted in a significantly greater reduction when compared to placebo in three out of the four Marder anxiety/depression items; anxiety (p<0.01), tension (p<0.001) and depression (p<0.05). Similarly, cariprazine was significantly better than placebo in 9 out of the 10 MADRS individual items; apparent sadness (p<0.001), reported sadness (p<0.001), reduced sleep (p<0.05), reduced appetite (p<0.001), concentration difficulties (p<0.001), lassitude (p<0.001), inability to feel (p<0.001), pessimistic thoughts (p<0.01) and suicidal thoughts (p<0.05).

The results herein indicate that cariprazine treatment is significantly effective at treating affective symptoms in persons with both schizophrenia and bipolar I depression.

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Electro-convulsive Therapy (ECT) has been considered a useful for the treatment of depression and other affective disorders, however it is considered as a last resort given the risks and possible adverse effects.

The objective of this review is to assess the use of ECT (in terms of efficacy and tolerability) for patients diagnosed with bipolar disorder and how it can be compared with other treatments more commonly used to treat this disorder.

A search was carried out in Medline and in the Virtual Health Library as well as in the Trripdatabase with the search terms “Bipolar disorder”, “Bipolar Depression”, “ECT”, “ECT treatment” and “Mania” in English and narrowing the search to the last 5 years. 8 articles were included for the review after applying inclusion and exclusion criteria.

A favorable and well tolerated response was observed when applied ECT on patients with Bipolar disorder, especially the elderly populations. It was observed that the administration of unilateral and bilateral ECT are both equally effective. A better response was detected to ECT compared to newer treatments like ketamine, as well as lower suicide rate when ECT was used compared to other treatments.

ECT is considered an effective and safe treatment for Bipolar Disorder and should be taken into account not only as a last resort. Even so, given the limitations observed, it is necessary to carry out further investigation on the matter.

No significant relationships.

Pramipexole is a dopaminergic agonist used in the treatment of Parkinson’s disease and restless leg syndrome. Although there is a lack of pharmacological options to treat drug-induced parkinsonism, not many studies have been made on the use of pramipexole in its management. There is also evidence on pramipexole effectiveness on major depressive episodes, particularly for bipolar and treatment-resistant depression.

To describe a case of drug-induced parkinsonism treated with pramipexole in a complex patient with bipolar disorder type I and obsessive-compulsive disorder, long-term treated with antipsychotics and valproate.

We present the case of a 51-year-old woman admitted in our psychiatric inpatient unit mainly to treat a bipolar depression. She also presented a parkinsonian syndrome, and a neurological study was conducted. As a negative DaTSCAN concluded its cause to be pharmacological, we decided to stop lurasidone and initiated pramipexole.

Guidelines suggest that drug-induced parkinsonism should be managed by discontinuing causative drugs or switching to another agent. However, we decided to use pramipexole with the aim of not only treating the parkinsonian syndrome but helping manage the depressive episode. We observed a remission of the depressive symptoms and an improvement in the parkinsonian symptoms.

Although the best way to treat drug-induced parkinsonism is to avoid its causative agents, in clinical practice it is not always possible as some patients have resistant and complex psychiatric syndromes. We suggest considering pramipexole in its management, especially when dealing with a patient with a comorbid unipolar or bipolar depression. Further research is necessary to clarify its utility.

No significant relationships.

Depressive episodes are associated with higher morbidity, mortality (mostly suicidality. Despite the high prevalence and the devastating impact of this condition, there is a long‐standing debate about its treatment, particularly about the use of antidepressants. International guidelines and expert consensus recommend to avoid AD for bipolar depression, or to use AD with caution and as second line treatment only if the depressive episode shows poor response to mood stabilizers (MS) and to some second generation antipsychotics (SGA) (cariprazine, lurasidone, quetiapine and olanzapine combined with fluoxetine) in monotherapy and in combination. Contrary to the advice of guidelines and experts, 50%–80% of acute bipolar depressive episodes are treated with AD in everyday clinical practice.

To evaluate the effectiveness and the safety of AD acute treatment in patients with bipolar depression

Literature review (PubMed)

Short‐term safety, switching and suicidality did not differ significantly, and no suicide attempt was observed. Concerning long‐term safety, patients with bipolar depression had a significant reduction of depressive and total recurrences during the first year.

Acute AD treatment of bipolar depression is effective in the short term and safe in the short‐ and long‐term

No significant relationships.

To investigate the effect of cariprazine on cognitive symptom change across bipolar I disorder and schizophrenia.

Post hoc analyses of 3- to 8-week pivotal studies in bipolar I depression and mania were conducted; one schizophrenia trial including the Cognitive Drug Research System attention battery was also analyzed. Outcomes of interest: Montgomery-Åsberg Depression Rating Scale [MADRS], Functioning Assessment Short Test [FAST], Positive and Negative Syndrome Scale [PANSS]). LSMDs in change from baseline to end of study were reported in the overall intent-to-treat population and in patient subsets with specified levels of baseline cognitive symptoms or performance.

In patients with bipolar depression and at least mild cognitive symptoms, LSMDs were statistically significant for cariprazine vs placebo on MADRS item 6 (3 studies; 1.5 mg=−0.5 [P<.001]; 3 mg/d=−0.2 [P<.05]) and on the FAST Cognitive subscale (1 study; 1.5 mg/d=−1.4; P=.0039). In patients with bipolar mania and at least mild cognitive symptoms, the LSMD in PANSS Cognitive subscale score was statistically significant for cariprazine vs placebo (3 studies; −2.1; P=.001). In patients with schizophrenia and high cognitive impairment, improvement in power of attention was observed for cariprazine 3 mg/d vs placebo (P=.0080), but not for cariprazine 6 mg/d; improvement in continuity of attention was observed for cariprazine 3 mg/d (P=.0012) and 6 mg/d (P=.0073).

These post hoc analyses provide preliminary evidence of greater improvements for cariprazine vs placebo across cognitive measures in patients with bipolar I depression and mania, and schizophrenia, suggesting potential benefits for cariprazine in treating cognitive symptoms.

To identify demographic and clinical characteristics of bipolar depressed patients who require antidepressant (AD) augmentation, and to evaluate the short- and long-term effectiveness and safety of this therapeutic strategy.

One hundred twenty-two bipolar depressed patients were consecutively recruited, 71.7% of them received mood stabilizers (MS)/second-generation antipsychotics (SGA) with AD-augmentation and 28.3% did not. Patients were evaluated at baseline, and after 12 weeks and 15 months of treatment.

The AD-augmentation was significantly higher in patients with bipolar II compared with bipolar I diagnosis. Patients with MS/SGA + AD had often a seasonal pattern, depressive polarity onset, depressive index episode with anxious features, a low number of previous psychotic and (hypo)manic episodes and of switch. They had a low irritable premorbid temperament, a low risk of suicide attempts, and a low number of manic symptoms at baseline. After 12 weeks of treatment, 82% of patients receiving ADs improved, 58% responded and 51% remitted, 3.8% had suicidal thoughts or projects, 6.1% had (hypo)manic switch, and 4.1% needed hospitalization. During the following 12 months, 92% of them remitted from index episode, 25.5% did not relapse, and 11% needed hospitalization. Although at the start advantaged, patients with AD-augmentation, compared with those without AD-augmentation, did not significantly differ on any outcome as well on adverse events in the short- and long-term treatment.

Our findings indicate that ADs, combined with MS and/or SGA, are short and long term effective and safe in a specific subgroup for bipolar depressed patients.

The early diagnosis of bipolar II disorder remains difficult in clinical practice, hence the importance of psychometric tests.

To detect hypomania in patients followed for a major depressive disorder (MDD) and to determine factors which are correlated with it.

This was a cross-sectional, descriptive and analytical study. It involved 40 psychiatric outpatients, who were followed for MDD (isolated or recurrent episode) at the Hedi Chaker University Hospital in Sfax (Tunisia), from January 26 to February 10, 2020. The study was conducted using a questionnaire and the Angst Hypomania Checklist-20 (HCL-20).

The sex ratio (M/F) was 0.66 with an average age of 54.8 years. MDD started at an average age of 41.45 years. According to HCL-20, half of our sample had hypomania. The presence of hypomania was correlated with young age (p = 0.022), academic failure (p = 0.038) and smoking (p = 0.003). In addition, there was a statistically significant relationship between the presence of hypomania and the characteristics of the disease: number of depressive episodes ≥ 2 (p = 0.013), psychotic features (p = 0.038), melancholic features (p=0,025) and premature discontinuation of treatment (p = 0.003).

Our study confirmed that bipolar depression is still underdiagnosed and poorly treated. Questioning a patient about a history of hypomania would be a delicate task and would require the help of a scale, in particular the HCL -20.

Prescribing antidepressants in the treatment of bipolar depression remains highly controversial due to the inconsistency between routine clinical practice and the results of controlled trials.

To assess the validity of antidepressants use in bipolar depression from the point of view of evidence-based medicine.

Database search (Scopus and MEDLINE) followed by analysis of studies concerning the efficacy and safety of antidepressants in the bipolar depression treatment.

The search found 23 studies. There was a high degree of inconsistency in the results, apparently related to the methodology. Only two studies compared the effectiveness of antidepressants in monotherapy with placebo. No differences were found in the study with 740 participants but in the study with 70 participants with type 2 bipolar disorder antidepressants were found to be more effective than placebo. Nevertheless, both studies had significant methodological issues. In 6 studies comparing the effectiveness of the combination of antidepressants with mood stabilizers against the combination of mood stabilizers with placebo, only the effectiveness of fluoxetine in combination with olanzapine was confirmed, other antidepressants were ineffective. At the same time, studies where antidepressants were compared with each other in combination with mood stabilizers revealed a significant clinical response to therapy. Risk of the treatment emergency adverse events were relatively low for SSRI.

Despite the contradictory literature data, the use of antidepressants in bipolar depression is justified from the point of view of evidence-based medicine for certain groups of patients with taking into account risk factors.

To review the currently available data on the use of ketamine in the treatment of depression among older adults from randomized controlled studies.

Randomized controlled trials.

Variable.

60 years and older with depression.

Ketamine.

Change in Montgomery–Asberg Depression Rating Scale (MADRS) scores.

Two studies met the inclusion criteria. The first study showed a significant reduction in depression symptoms with use of repeated subcutaneous ketamine administration among older adults with depression. The second study failed to achieve significance on its primary outcome measure but did show a decrease in MADRS scores with intranasal ketamine along with a higher response and remission rates in esketamine group compared with the placebo group. The adverse effects from ketamine generally lasted only a few hours and abated spontaneously. No cognitive adverse effects were noted in either trial from the use of ketamine.

The current evidence for use of ketamine among older adults with depression indicates some benefits with one positive and one negative trial. Although one of the trials did not achieve significance on the primary outcome measure, it still showed benefit of ketamine in reducing depressive symptoms. Ketamine was well tolerated in both studies with adverse effects being mild and transient.

Depressive episodes are common in bipolar illness. Treatment of bipolar depression is often problematic because standard antidepressants carry a number of disadvantages: apparent lower efficacy than in unipolar depression; risk of inducing mania; risk of inducing rapid cycling. Anticonvulsants such as carbamazepine, valproate and lamotrigine are useful in the management of bipolar disorder and they can prevent episodes of depression. There is less evidence that they have antidepressant efficacy but lamotrigine was shown to produce antidepressant effects in a placebo-controlled trial in bipolar depressed patients. Lamotrigine has a role in acute management of bipolar depression and is probably free of a risk of inducing mania or rapid cycling.

To determine the efficacy of lamotrigine in treatment of patients with bipolar depression.

Investigation of lamotrigine efficacy with bipolar depression in 3 month-follow-up and 6 months follow-up treatment with lamotrigine.

The sample consisted of 30 patients with bipolar depression, age range between 26 and 58. All subjects received monotherapy with lamotrigine in the period of six months. Subjects were assessed prior to therapy and in 3 and 6 months follow-up using the following instruments: The Clinical Global Impressions scale (CGI), and Hamilton Depression Rating Scale (HAM-D-21).

The difference between three assessments on CGI was statistically significant. The results indicate statistically significant reduction of depression on HAMD-21 following six months treatment with lamotrigine.

Lamotrigine proved to be efficient in the treatment of patients with bipolar depression for the subjects in this study.

Mixed presentations, defined by simultaneous occurrence of depressive and manic symptoms, are difficult to treat. Antidepressants, although commonly used, have weak evidence of efficacy and may increase risk of mood destabilization. The aim of this pooled post hoc analysis was to evaluate the efficacy of cariprazine in the treatment of bipolar depression with or without concurrent manic symptoms.

Patients from 3 randomized, double-blind, placebo-controlled studies who met DSM-IV-TR or DSM-5 criteria for bipolar I disorder with a current major depressive episode were identified to have concurrent manic symptoms by baseline Young Mania Rating Scale total score ≥4. Efficacy was assessed in cariprazine 1.5 and 3 mg/day dose groups versus placebo; analyses included the least squares mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score.

Of 1383 patients randomized to treatment, 808 (58.4%) had concurrent manic symptoms. For patients with manic symptoms, mean reduction in MADRS total score from baseline to week 6 was significantly greater for both cariprazine 1.5 and 3 mg/day compared with placebo, with least squares mean differences (LSMDs) versus placebo of −2.5 (p = .0033) and −2.9 (p = .0010), respectively; for patients without manic symptoms, the LSMD was significant for 1.5 mg/day (−3.3; p = .0008), but not for 3 mg/day (−1.9; p = .0562).

The results of this post hoc analysis suggest that cariprazine may be an appropriate treatment option for patients with bipolar I depression with or without manic symptoms, with higher doses potentially more effective in patients with manic symptoms.

To meta-analytically summarize lamotrigine’s effectiveness and safety in unipolar and bipolar depression.

We conducted systematic PubMed and SCOPUS reviews (last search =10/01/2015) of randomized controlled trials comparing lamotrigine to placebo or other agents with antidepressant activity in unipolar or bipolar depression. We performed a random-effects meta-analysis of depression ratings, response, remission, and adverse effects calculating standardized mean difference (SMD) and risk ratio (RR) ±95% confidence intervals (CIs).

Eighteen studies (n=2152, duration=9.83 weeks) in patients with unipolar depression (studies=4, n=187; monotherapy vs lithium=1, augmentation of antidepressants vs placebo=3) or bipolar depression (studies=14, n=1965; monotherapy vs placebo=5, monotherapy vs lithium or olanzapine+fluoxetine=2, augmentation of antidepressants vs placebo=1, augmentation of mood stabilizers vs placebo=3, augmentation of mood stabilizers vs trancylpromine, citalopram, or inositol=3) were meta-analyzed. Lamotrigine’s efficacy for depressive symptoms did not differ significantly in monotherapy vs augmentation studies (vs. placebo: p=0.98, I2=0%; vs active agents: p=0.48, I2=0%) or in unipolar vs bipolar patients (vs placebo: p=0.60, I2=0%), allowing pooling of each placebo-controlled and active-controlled trials. Lamotrigine outperformed placebo regarding depressive symptoms (studies=11, n=713 vs n=696; SMD=–0.15, 95% CI=–0.27, –0.02, p=0.02, heterogeneity: p=0.24) and response (after removing one extreme outlier; RR=1.42, 95% CI=1.13–1.78; p=0.003, heterogeneity: p=0.08). Conversely, lamotrigine did not differ regarding efficacy on depressive symptoms, response, or remission from lithium, olanzapine+fluoxetine, citalopram, or inositol (studies=6, n=306 vs n=318, p-values=0.85–0.92). Adverse effects and all-cause/specific-cause discontinuation were similar across all comparisons.

Lamotrigine was superior to placebo in improving unipolar and bipolar depressive symptoms, without causing more frequent adverse effects/discontinuations. Lamotrigine did not differ from lithium, olanzapine+fluoxetine, citalopram, or inositol.

Ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists (NMDAR antagonists) recently demonstrated antidepressant efficacy for the treatment of refractory depression, but effect sizes, trajectories and possible class effects are unclear.

We searched PubMed/PsycINFO/Web of Science/clinicaltrials.gov until 25 August 2015. Parallel-group or cross-over randomized controlled trials (RCTs) comparing single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist v. placebo/pseudo-placebo in patients with major depressive disorder (MDD) and/or bipolar depression (BD) were included in the analyses. Hedges’ g and risk ratios and their 95% confidence intervals (CIs) were calculated using a random-effects model. The primary outcome was depressive symptom change. Secondary outcomes included response, remission, all-cause discontinuation and adverse effects.

A total of 14 RCTs (nine ketamine studies: n = 234; five non-ketamine NMDAR antagonist studies: n = 354; MDD = 554, BD = 34), lasting 10.0 ± 8.8 days, were meta-analysed. Ketamine reduced depression significantly more than placebo/pseudo-placebo beginning at 40 min, peaking at day 1 (Hedges' g = −1.00, 95% CI −1.28 to −0.73, p < 0.001), and loosing superiority by days 10–12. Non-ketamine NMDAR antagonists were superior to placebo only on days 5–8 (Hedges' g = −0.37, 95% CI −0.66 to −0.09, p = 0.01). Compared with placebo/pseudo-placebo, ketamine led to significantly greater response (40 min to day 7) and remission (80 min to days 3–5). Non-ketamine NMDAR antagonists achieved greater response at day 2 and days 3–5. All-cause discontinuation was similar between ketamine (p = 0.34) or non-ketamine NMDAR antagonists (p = 0.94) and placebo. Although some adverse effects were more common with ketamine/NMDAR antagonists than placebo, these were transient and clinically insignificant.

A single infusion of ketamine, but less so of non-ketamine NMDAR antagonists, has ultra-rapid efficacy for MDD and BD, lasting for up to 1 week. Development of easy-to-administer, repeatedly given NMDAR antagonists without risk of brain toxicity is of critical importance.

Evidence for a possible association between a low level of cholesterol and increased suicidal behaviour has accumulated in the recent 3 decades. The present study investigates whether lipid levels can make state-dependent markers of suicidal behaviour in Polish patients with mood disorder recently admitted to a psychiatric hospital owing to an acute depressive episode.

The study was conducted on 223 patients (73 male and 150 female) with unipolar (n=171) and bipolar (n=52) depression. They were interviewed to assess any occurrence of suicidal thoughts, suicidal tendencies and/or suicidal attempts during the 3 months before admission. Laboratory measurements [total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides and total lipids] were obtained within 24–72 h after hospital admission.

Suicidal thoughts, tendencies, and attempts were associated with low total cholesterol, LDL cholesterol, and total lipids in both male and female patients, in both diagnostic categories. Triglycerides were significantly lower in male and female patients with suicidal thoughts compared with their non-suicidal counterparts. No association with suicidality was found with HDL cholesterol.

The results of our study support a majority of research showing the association in depressed patients between suicidal behaviour and low levels of total and LDL cholesterol. In addition, the data suggest a similar association with low total lipids, and in some instances, with low triglycerides.