Objectives
For the first time to present a systematic review of observational studies on the efficiency of lithium monotherapy in comparison with other maintenance mood stabilizers in monotherapy and ...in combination.
Methods
As part of the International Society for Bipolar Disorders (ISBD) Task Force on Lithium Treatment, we undertook a systematic literature search of non‐randomized controlled observational studies on (i) lithium monotherapy vs treatment with another maintenance mood stabilizer in monotherapy and (ii) lithium in combination with other mood stabilizers vs monotherapy.
Results
In eight out of nine identified studies including a total of < 14 000 patients, maintenance lithium monotherapy was associated with improved outcome compared with another mood stabilizer in monotherapy, including valproate, lamotrigine, olanzapine, quetiapine, unspecified anticonvulsants, carbamazepine/lamotrigine, unspecified atypical antipsychotics and unspecified antipsychotics. Among the four identified studies including a total of > 4000 patients comparing maintenance combination therapy with maintenance monotherapy, a few combination therapies were found to be superior to monotherapy in some analyses, but many were not.
Conclusions
The results show the superiority in real life of lithium monotherapy compared with monotherapy with other maintenance mood stabilizers. The four largest register‐based studies largely addressed confounding, but, as ever, residual confounding cannot be excluded. Nevertheless, the observational findings substantially add to the findings from randomized controlled trials, whose designs often limit the validity of comparison between medicines.
Evidence is limited regarding the most effective pharmacological treatment for psychotic depression: monotherapy with an antidepressant, monotherapy with an antipsychotic, another treatment (e.g. ...mifepristone), or combination of an antidepressant plus an antipsychotic. This is an update of a review first published in 2005 and last updated in 2015.
1. To compare the clinical efficacy of pharmacological treatments for patients with an acute psychotic depression: antidepressant monotherapy, antipsychotic monotherapy, mifepristone monotherapy, and the combination of an antidepressant plus an antipsychotic versus placebo and/or each other. 2. To assess whether differences in response to treatment in the current episode are related to non-response to prior treatment.
A search of the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR); Ovid MEDLINE (1950-); Embase (1974-); and PsycINFO (1960-) was conducted on 21 February 2020. Reference lists of all included studies and related reviews were screened and key study authors contacted.
All randomised controlled trials (RCTs) that included participants with acute major depression with psychotic features, as well as RCTs consisting of participants with acute major depression with or without psychotic features, that reported separately on the subgroup of participants with psychotic features.
Two review authors independently extracted data and assessed risk of bias in the included studies, according to criteria from the Cochrane Handbook for Systematic Reviews of Interventions. Data were entered into RevMan 5.1. We used intention-to-treat data. Primary outcomes were clinical response for efficacy and overall dropout rate for harm/tolerance. Secondary outcome were remission of depression, change from baseline severity score, quality of life, and dropout rate due to adverse effects. For dichotomous efficacy outcomes (i.e. response and overall dropout), risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. Regarding the primary outcome of harm, only overall dropout rates were available for all studies. If the study did not report any of the response criteria as defined above, remission as defined here could be used as an alternative. For continuously distributed outcomes, it was not possible to extract data from the RCTs. MAIN RESULTS: The search identified 3947 abstracts, but only 12 RCTs with a total of 929 participants could be included in the review. Because of clinical heterogeneity, few meta-analyses were possible. The main outcome was reduction in severity (response) of depression, not of psychosis. For depression response, we found no evidence of a difference between antidepressant and placebo (RR 8.40, 95% CI 0.50 to 142.27; participants = 27, studies = 1; very low-certainty evidence) or between antipsychotic and placebo (RR 1.13, 95% CI 0.74 to 1.73; participants = 201, studies = 2; very low-certainty evidence). Furthermore, we found no evidence of a difference in overall dropouts with antidepressant (RR 1.24, 95% CI 0.34 to 4.51; participants = 27, studies = 1; very low-certainty evidence) or antipsychotic monotherapy (RR 0.79, 95% CI 0.57 to 1.08; participants = 201, studies = 2; very low-certainty evidence). No evidence suggests a difference in depression response (RR 2.09, 95% CI 0.64 to 6.82; participants = 36, studies = 1; very low-certainty evidence) or overall dropouts (RR 1.79, 95% CI 0.18 to 18.02; participants = 36, studies = 1; very low-certainty evidence) between antidepressant and antipsychotic. For depression response, low- to very low-certainty evidence suggests that the combination of an antidepressant plus an antipsychotic may be more effective than antipsychotic monotherapy (RR 1.83, 95% CI 1.40 to 2.38; participants = 447, studies = 4), more effective than antidepressant monotherapy (RR 1.42, 95% CI 1.11 to 1.80; participants = 245, studies = 5), and more effective than placebo (RR 1.86, 95% CI 1.23 to 2.82; participants = 148, studies = 2). Very low-certainty evidence suggests no difference in overall dropouts between the combination of an antidepressant plus an antipsychotic versus antipsychotic monotherapy (RR 0.79, 95% CI 0.63 to 1.01; participants = 447, studies = 4), antidepressant monotherapy (RR 0.91, 95% CI 0.55 to 1.50; participants = 245, studies = 5), or placebo alone (RR 0.75, 95% CI 0.48 to 1.18; participants = 148, studies = 2). No study measured change in depression severity from baseline, quality of life, or dropouts due to adverse events. We found no RCTs with mifepristone that fulfilled our inclusion criteria. Risk of bias is considerable: we noted differences between studies with regards to diagnosis, uncertainties around randomisation and allocation concealment, treatment interventions (pharmacological differences between various antidepressants and antipsychotics), and outcome criteria.
Psychotic depression is heavily under-studied, limiting confidence in the conclusions drawn. Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo. Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone. Evidence for efficacy of mifepristone is lacking.
Quetiapine, combined with lithium or divalproex, demonstrates efficacy in the maintenance treatment of bipolar I disorder. This study investigated the efficacy and safety of quetiapine monotherapy as ...maintenance treatment in bipolar I disorder compared with switching to placebo or lithium.
Patients aged ≥ 18 years with DSM-IV-diagnosed bipolar I disorder and a current or recent manic, depressive, or mixed episode received open-label quetiapine (300-800 mg/d) for 4-24 weeks. Patients achieving stabilization were randomized to continue quetiapine or to switch to placebo or lithium (0.6-1.2 mEq/L) for up to 104 weeks in a double-blind trial. Outcome measures included times to recurrence of any mood event (primary outcome measure), manic event, or depressive event. Safety assessments included adverse events and laboratory values. The study was terminated early after planned interim analysis provided positive results. The study was conducted between March 2005 and July 2007.
Of 2,438 patients starting open-label quetiapine, 1,226 (50.3%) were randomized to double-blind treatment, including 1,172 (95.6%) in the intent-to-treat population. Time to recurrence of any mood event was significantly longer for quetiapine versus placebo (hazard ratio HR = 0.29; 95% CI, 0.23-0.38; P < .0001) and for lithium versus placebo (HR = 0.46; 95% CI, 0.36-0.59; P < .0001). Quetiapine and lithium significantly increased time to recurrence of both manic events (quetiapine: HR = 0.29; 95% CI, 0.21-0.40; P < .0001; lithium: HR = 0.37; 95% CI, 0.27-0.53; P < .0001) and depressive events (quetiapine: HR = 0.30; 95% CI, 0.20-0.44; P < .0001; lithium: HR = 0.59; 95% CI, 0.42-0.84; P < .004) compared with placebo. Overall rates of adverse events were generally similar between treatment groups, and safety findings for quetiapine were consistent with its known profile.
In patients stabilized during acute quetiapine treatment, continuation of quetiapine significantly increased time to recurrence of any mood, manic, or depressive event compared with switching to placebo. Switching to lithium was also more effective than placebo for the prevention of manic and depressive events.
clinicaltrials.gov Identifier: NCT00314184.
Past episodes of depressive or anxiety disorders and subthreshold symptoms have both been reported to predict the occurrence of depressive or anxiety disorders. It is unclear to what extent the two ...factors interact or predict these disorders independently.
To examine the extent to which history, subthreshold symptoms and their combination predict the occurrence of depressive (major depressive disorder, dysthymia) or anxiety disorders (social phobia, panic disorder, agoraphobia, generalised anxiety disorder) over a 2-year period.
This was a prospective cohort study with 1167 participants: the Netherlands Study of Depression and Anxiety. Anxiety and depressive disorders were determined with the Composite International Diagnostic Interview, subthreshold symptoms were determined with the Inventory of Depressive Symptomatology-Self Report and the Beck Anxiety Inventory.
Occurrence of depressive disorder was best predicted by a combination of a history of depression and subthreshold symptoms, followed by either one alone. Occurrence of anxiety disorder was best predicted by both a combination of a history of anxiety disorder and subthreshold symptoms and a combination of a history of depression and subthreshold symptoms, followed by any subthreshold symptoms or a history of any disorder alone.
A history and subthreshold symptoms independently predicted the subsequent occurrence of depressive or anxiety disorder. Together these two characteristics provide reasonable discriminative value. Whereas anxiety predicted the occurrence of an anxiety disorder only, depression predicted the occurrence of both depressive and anxiety disorders.
We examined the influence of age at onset of illness and the delay in time to first treatment on morbidity in adulthood.
529 adult outpatients with a mean age of 42 years, who entered our research ...network from 1996 through 2001 and who were diagnosed with bipolar disorder according to DSM-IV criteria, were rated prospectively on a daily basis with the National Institute of Mental Health-Life Chart Method during naturalistic treatment for up to 4 years.
Fifty percent of patients had illness onset in childhood (<13 years of age) or adolescence (13-18 years of age). In year 1 of follow-up, these patients, compared to those with adult onset, showed significantly (P<.05) greater severity of depression and mania, greater number of episodes, more days depressed, more days of ultradian cycling, and fewer days euthymic. After 4 years, the mean severity and duration of depression remained greater and the number of days euthymic fewer in those with childhood compared to adult onset (P<.05). The delays to first treatment correlated inversely with age at onset of illness. Independently, delay to first treatment was associated with more time depressed, greater severity of depression, greater number of episodes, more days of ultradian cycling, and fewer days euthymic (all P<.05).
These data converge with other evidence that onset of bipolar disorder in childhood is common and often associated with extraordinarily long delays to first pharmacologic treatment. Both childhood onset and treatment delay were associated with a persistently more adverse course of illness rated prospectively in adults. These data should help foster efforts to ensure earlier and more effective treatment of bipolar illness in children and adolescents. It is hoped that appropriate early intervention would result in a more benign illness and a better prognosis in adulthood.
Abstract Background This systematic review evaluated all published double-blind, randomized controlled antidepressant trials (RCTs) of acute phase treatment of older depressed patients. Methods ...Meta-analyses were conducted in 51 double-blind RCTs of antidepressants in older patients. The results were also compared with 29 double-blind RCTs that did not produce extractable data to enter the meta-analysis. Results All classes of antidepressant (TCA's, SSRIs and other antidepressants) were more effective than placebo in achieving response. In achieving remission however, only pooling all 3 classes of antidepressants together showed a statistically significant difference from placebo. No differences were found in remission or response rates between classes of antidepressants. TCAs were also equally effective compared with SSRIs in achieving response in more severely depressed patients. The numbers needed to treat (NNT) were 14.4 (95% CI 8.3–50) for one additional remission to antidepressants compared with placebo and 6.7 (95% CI 4.8–10) for response. The results of the double-blind RCTs that did not produce extractable data to enter the meta-analysis were in concordance with the RCTs that were included in the meta-analysis. Limitations Only 4 RCTs were found that have not been published. Few studies have focused on severely depressed older people. Conclusions Antidepressant treatment in older depressed patients is efficacious. We could not demonstrate differences in effectiveness between different classes of antidepressants; this was also the case in more severely depressed patients.
Taking the perspective of somebody else (Theory of Mind; ToM) is an essential human ability depending on a large cerebral network comprising prefrontal and temporo-parietal regions. Recently, ToM was ...suggested to consist of two processes: (1) self-perspective inhibition and (2) belief reasoning. Moreover, it has been hypothesized that self-perspective inhibition may build upon basic motor response inhibition. This study tested both hypotheses for the first time using functional Magnetic Resonance Imaging (fMRI), through administering both a ToM and a stop-signal paradigm in the same subjects. Both self-perspective and motor response inhibition yielded bilateral inferior frontal gyrus (IFG) activation, suggesting a common inhibitory mechanism, while belief reasoning was mediated by the superior temporal gyrus (STG) and temporo-parietal junction (TPJ). Thus, we provide neurobiological evidence for a subdivision of ToM into self-perspective inhibition and belief reasoning. Furthermore, evidence for partially shared neural mechanisms for inhibition in complex social situations and basic motor response inhibition was found.
► ToM can be subdivided into self-perspective inhibition and belief reasoning. ► Self-perspective inhibition is mediated by the bilateral IFG. ► Belief reasoning is mediated by the left STG, TPJ and MTG. ► Self-inhibition and response inhibition build upon similar neural mechanisms.
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