Antidepressant-placebo response-differences (RDs) in controlled trials have been declining, potentially confounding comparisons among older and newer drugs. For clinically employed antidepressants, ...we carried out a meta-analytic review of placebo-controlled trials in acute, unipolar, major depressive episodes reported over the past three decades to compare efficacy (drug-placebo RDs) of individual antidepressants and classes, and to consider factors associated with year-of-reporting by bivariate and multivariate regression modeling. Observed drug-placebo differences were moderate and generally similar among specific drugs, but larger among older antidepressants, notably tricyclics, than most newer agents. This outcome parallels selective increases in placebo-associated responses as trial-size has increased in recent years. Study findings generally support moderate efficacy of clinically employed antidepressants for acute major depression, but underscore limitations of meta-analyses of controlled trials for ranking drugs by efficacy. We suggest that efficiency and drug-placebo differences may be improved with fewer sites and subjects, and better quality-control of diagnostic and clinical assessments.
Suicidal behavior is strongly associated with depression in major depressive (MDD) and bipolar (BD) disorders, especially with associated behavioral activation, dysphoria, or agitation. A rare ...intervention with evidence of suicide risk-reducing as well as mood-stabilizing effects in mood disorder patients is lithium.
We reviewed available research evidence on associations of long-term treatment with lithium with risk of suicidal behavior. We meta-analyzed 12 randomized trials in 10 reports (with at least 1 suicide in either treatment arm) including both BD and MDD subjects, with particular attention to comparisons of lithium with placebo or other pharmacological treatments. We also summarized ecological studies on lithium concentration in local drinking water and reported suicide rates.
We found substantial reduction of risks of suicide and attempts with long-term lithium treatment, particularly in depressive phases of BD and in MDD. Risk of suicidal behavior was higher in mixed (agitated-dysphoric) states than in manic or hypomanic periods. Risk of suicide fatality, specifically, was lower with lithium than with placebo and probably with mood-altering anticonvulsants or antidepressants.
Long-term treatment with lithium has growing evidence of suicide- and attempt-sparing effects, probably greater than with anticonvulsants or antidepressants; antipsychotics remain to be tested adequately. However, the ethical and scientifically adequate design and conduct of trials of treatments aimed at suicide prevention remain challenging and underdeveloped.
Suicide and suicide attempts have become more prevalent in recent years, with notable increases in the US in all age groups and geographic locations. Risk of suicide is particularly high among ...patients diagnosed with bipolar disorder or severe depression, especially when associated with mixed features or agitation, or with co-occurring substance abuse. Factors contributing to such risk include relative social and geographic isolation and low access to sources of support or clinical care. In addition, unemployment, poverty, demoralisation and opioid abuse have been identified as important risk factors. Notably, overall longevity rates in the US, though rising for many decades, have recently been declining, in part owing to suicide and substance overdoses. A particular circumstance associated with strikingly high rates of suicides and attempts is the days and weeks following discharge from psychiatric hospitalisation. Although the incidence of such events is low, there is a need for more secure aftercare planning and implementation. Research on therapeutics aimed at reducing suicidal risk and all-cause mortality among psychiatric patients remains severely under-developed.
Background
Excess mortality is a critical hallmark of bipolar disorder (BD) due to co‐occurring general medical disorders and especially from suicide. It is timely to review of the status of suicide ...in BD and to consider the possibility of limiting suicidal risk.
Methods
We carried out a semi‐systematic review of recent research reports pertaining to suicide in BD.
Findings
Suicide risk in BD is greater than with most other psychiatric disorders. Suicide rates (per 100,000/year) are approximately 11 and 4 in the adult and juvenile general populations, but over 200 in adults, and 100 among juveniles diagnosed with BD. Suicide attempt rates with BD are at least 20 times higher than in the adult general population, and over 50 times higher among juveniles. Notable suicidal risk factors in BD include: previous suicidal acts, depression, mixed–agitated‐dysphoric moods, rapid mood‐shifts, impulsivity, and co‐occurring substance abuse. Suicide‐preventing therapeutics for BD remain severely underdeveloped. Evidence favoring lithium treatment is stronger than for other measures, although encouraging findings are emerging for other treatments.
Conclusions
Suicide is a leading clinical challenge for those caring for BD patients. Improved understanding of risk and protective factors combined with knowledge and close follow‐up of BD patients should limit suicidal risk. Ethically appropriate and scientifically sound studies of plausible medicinal, physical, and psychosocial treatments aimed at suicide prevention specifically for BD patients are urgently needed.
We summarize evidence supporting contemporary pharmacological treatment of phases of BD, including: mania, depression, and long-term recurrences, emphasizing findings from randomized, controlled ...trials (RCTs). Effective treatment of acute or dysphoric mania is provided by modern antipsychotics, some anticonvulsants (divalproex and carbamazepine), and lithium salts. Treatment of BD-depression remains unsatisfactory but includes some modern antipsychotics (particularly lurasidone, olanzapine + fluoxetine, and quetiapine) and the anticonvulsant lamotrigine; value and safety of antidepressants remain controversial. Long-term prophylactic treatment relies on lithium, off-label use of valproate, and growing use of modern antipsychotics. Lithium has unique evidence of antisuicide effects. Methods of evaluating treatments for BD rely heavily on meta-analysis, which is convenient but with important limitations. Underdeveloped treatment for BD-depression may reflect an assumption that effects of antidepressants are similar in BD as in unipolar major depressive disorder. Effective prophylaxis of BD is limited by the efficacy of available treatments and incomplete adherence owing to adverse effects, costs, and lack of ongoing symptoms. Long-term treatment of BD also is limited by access to, and support of expert, comprehensive clinical programs. Pursuit of improved, rationally designed pharmacological treatments for BD, as for most psychiatric disorders, is fundamentally limited by lack of coherent pathophysiology or etiology.
Bipolar depression: a major unsolved challenge Baldessarini, Ross J.; Vázquez, Gustavo H.; Tondo, Leonardo
International Journal of Bipolar Disorders,
01/2020, Letnik:
8, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Depression in bipolar disorder (BD) patients presents major clinical challenges. As the predominant psychopathology even in treated BD, depression is associated not only with excess morbidity, but ...also mortality from co-occurring general-medical disorders and high suicide risk. In BD, risks for medical disorders including diabetes or metabolic syndrome, and cardiovascular disorders, and associated mortality rates are several-times above those for the general population or with other psychiatric disorders. The SMR for suicide with BD reaches 20-times above general-population rates, and exceeds rates with other major psychiatric disorders. In BD, suicide is strongly associated with mixed (agitated-dysphoric) and depressive phases, time depressed, and hospitalization. Lithium may reduce suicide risk in BD; clozapine and ketamine require further testing. Treatment of bipolar depression is far less well investigated than unipolar depression, particularly for long-term prophylaxis. Short-term efficacy of antidepressants for bipolar depression remains controversial and they risk clinical worsening, especially in mixed states and with rapid-cycling. Evidence of efficacy of lithium and anticonvulsants for bipolar depression is very limited; lamotrigine has long-term benefit, but valproate and carbamazepine are inadequately tested and carry high teratogenic risks. Evidence is emerging of short-term efficacy of several modern antipsychotics (including cariprazine, lurasidone, olanzapine-fluoxetine, and quetiapine) for bipolar depression, including with mixed features, though they risk adverse metabolic and neurological effects.
Background:
Findings of substantial remaining morbidity in treated major depressive disorder (MDD) led us to review controlled trials of treatments aimed at preventing early relapses or later ...recurrences in adults diagnosed with MDD to summarize available data and to guide further research.
Methods:
Reports (n = 97) were identified through systematic, computerized literature searching up to February 2015. Treatment versus control outcomes were summarized by random-effects meta-analyses.
Results:
In 45 reports of 72 trials (n = 14 450 subjects) lasting 33.4 weeks, antidepressants were more effective than placebos in preventing relapses (response rates RR = 1.90, confidence interval CI: 1.73–2.08; NNT = 4.4; p < 0.0001). In 35 reports of 37 trials (n = 7253) lasting 27.0 months, antidepressants were effective in preventing recurrences (RR = 2.03, CI 1.80–2.28; NNT = 3.8; p < 0.0001), with minor differences among drug types. In 17 reports of 22 trials (n = 1 969) lasting 23.7 months, psychosocial interventions yielded inconsistent or inconclusive results.
Conclusions:
Despite evidence of the efficacy of drug treatment compared to placebos or other controls, the findings further underscore the substantial, unresolved morbidity in treated MDD patients and strongly encourage further evaluations of specific, improved individual and combination therapies (pharmacological and psychological) conducted over longer times, as well as identifying clinical predictors of positive or unfavorable responses and of intolerability of long-term treatments in MDD.
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