Important clinical features of atypical antipsychotics in acute bipolar depression that inform routine clinical care: a review of pivotal studies with number needed to treat

English-language literature cited in MEDLINE from January,1980 to October 30,2014 was searched by using terms of antipsychotic,generic and brand names of atypical antipsychotics, "bipolar depression/bipolar disorder", "placebo",and "trial".The parameters of response(≥50%improvement on MADRS,Montgomery-Asberg Depression Rating Scale total score),remission(either ≤12 or 8 on MADRS total score at endpoint),discontinuation due to adverse events(DAEs),somnolence,≥7%weight gain,overall extrapyramidal side-effects(EPSs),and akathisia,were extracted from originally published primary outcome papers.The number needed to treat to benefit(NNT) for response and remission or harm(NNH) for DAEs or other side effects relative to placebo were estimated and presented with the estimate and 95%confidence interval.Olanzapine monotherapy,olanzapine-fluoxetine combination(OFC),quetiapine-IR monotherapy,quetiapine-XR monotherapy,lurasidone monotherapy,and lurasidone adjunctive therapy were superior to placebo with NNTs for responses of 11-12,4,7-8,4,4-5,and 7,and NNTs for remission of 11-12,4,5-11,7,6-7,and 6,respectively.There was no significant difference between OFC and lamotrigine,and between aripiprazole or ziprasidone and placebo in response and remission.Olanzapine monotherapy,quetiapine-IR,quetiapine-XR,aripiprazole,and ziprasidone 120-160 mg/day had significantly increased risk for DAEs with NNHs of 24,8-14,9,12,and 10,respectively.For somnolence,quetiapine-XR had the smallest NNH of 4.For ≥7%weight gain,olanzapine monotherapy and OFC had the smallest NNHs with both of 5.For akathisia,aripiprazole had the smallest NNH of 5.These findings suggest that among the FDA-approved agents including OFC,quetiapine-IR and-XR,lurasidone monotherapy and adjunctive therapy to a mood stabilizer,the differences in the NNTs for response and remission are small,but the differences in NNHs for DAEs and common side-effects are large.Therefore,the selection of an FDA-approved atypical antipsychotic for bipolar depression should be based upon safety and tolerability.     

Dimethyltryptamine(DMT):a biochemical Swiss Army knife in neuroinflammation and neuroprotection?

正The inflammatory theory of many neuropsychiatric illnesses has become an emerging trend in modern medicine.Various immune mechanisms–mainly via the activity of microglia–may contribute to the etiology and symptomatology of diseases,such as schizophrenia,bipolar disorder,depression,or Alzheimer’s disease(Deleidi et al.,2015;Khandaker et al.,     

双相抑郁障碍的临床特征研究进展(上)

双相障碍发病率高,双相谱系障碍的终生患病率大约3.7%～11.5%,仅双相Ⅰ型和双相Ⅱ型障碍就达约1.3%,而双相抑郁障碍(bipolar depressive disorder,BDD)表现突出,     

The multifaceted question of the prescription of antidepressants during pregnancy

Pregnancy has long been considered a period of bliss, free of psychiatric disorder. It was even supposed that if such conditions preexisted, they would momentarily be miraculously suspended. Numerous studies have now shown that not only do pre-existing psychiatric disorders such as bipolar disease and schizophrenia persist during pregnancy, but when adequate medication is discontinued relapse is likely to occur,r21 Systematic reviews suggest that up to 18.4% of pregnant women are depressed during their pregnancy and 12.7% develop major depression.I3,41 Thus, depression is common during pregnancy and, as reported by Zhang and Wang,tSl the use of antidepressants during pregnancy is equally common.     

抑郁症对海马及背外侧前额叶皮质神经元变与1HMRS表现及明尼苏达多项个性测量的相关性

Background and Purpose The present study was undertaken to elucidate neuro-structural and neuro-chemical characteristics of hippocampi and dorsolateral prefrontal cortex in patients with depressive disorder by using 1H-MRS and to study the association between 1H-MRS and Minnesota Mutiphasic Personality Inventory-2 in relation to the severity of the depression.. Methods Magnetic resonance imaging and 1H-MRS were performed on 33 patients with depressive disorder and age-18 and gender-matched healthy controls. Minnesota Mutiphasic Personality Inventory-2 test was performed on all depressive subjects and control subjects. Results Magnetic resonance imaging and 1H-MRS examinations showed widened sulcus and cisterns as well as the absence of abnormal signal in depressive patients. In addition, the N-acetyl aspartate/total creatine ratios in the bilateral hippocampi and dorsolateral prefrontal cortex were significantly lower in depressive patients than in the control subjects (P<0.01). In contrast, the choline-containing compounds/total creatine ratios in dorsolateral prefrontal cortex were remarkably higher in depressive patients than in the control subjects (Left: P<0.01, Right: P<0.01), the ratios of which were also significantly positively correlated with the depression scores of the patients assessed by Minnesota Mutiphasic Personality Inventory-2 scale (Right: r = 0.8787, Left: r = 0.9347). Conclusions 1H-MRS can be used to reveal reduced neuronal viability or function in the hippocampus and dorsolateral prefrontal cortex and altered membrane phospholipid metabolism in the dorsolateral prefrontal cortex in patients with depressive disorder. The 1H-MRS findings partially reflect the severity of the depressive disorder.     

Efficacy of Lycium barbarum polysaccharide in adolescents with subthreshold depression: interim analysis of a randomized controlled study

Subthreshold depression is a highly prevalent condition in adolescents who are at high risk for developing major depressive disorder.In preclinical models of neurological and psychiatric diseases,Lycium barbarum polysaccharide(LBP)extracted from Goji berries had antidepressant effects including but not limited to anti-oxidative and anti-inflammatory properties.However,the effect of LBP on subthreshold depression is unclear.To investigate the clinical efficacy and safety of LBP for treating subthreshold depression in adolescents,we conducted a randomized,double-blind,placebo-controlled trial(RCT)with 29 adolescents with subthreshold depression recruited at The Fifth Affiliated Hospital of Guangzhou Medical University.The participants were randomly assigned to groups where they received either 300 mg LBP(LBP group,n=15,3 boys and 12 girls aged 15.13±2.17 years)or a placebo(placebo group,n=14,2 boys and 12 girls aged 15±1.71 years)for 6 successive weeks.Interim analyses revealed that the LBP group exhibited a greater change in Hamilton Depression Scale(HAMD-24)scores relative to the baseline and a higher remission rate(HAMD-24 total score≤7)at 6 weeks compared with the placebo group.Scores on the Beck Depression Inventory-II(BDI-II),Pittsburgh Sleep Quality Index(PSQI),Kessler Psychological Distress Scale(Kessler),and Screen for Child Anxiety-Related Emotional Disorders(SCARED)were similar between the LBP and placebo groups.No side effects related to the intervention were reported in either group.These results indicate that LBP administration reduced depressive symptoms in adolescents with subthreshold depression.Furthermore,LBP was well tolerated with no treatment-limiting adverse events.Clinical trials involving a larger sample size are needed to further confirm the anti-depressive effects of LBP in adolescents with subthreshold depression.This study was approved by the Medical Ethics Committee of the Fifth Affiliated Hospital of Guangzhou Medical University(Guangzhou,China;approval No.L2019-08)on April 4,2019 and was registered on ClinicalTrials.gov(identifier:NCT04032795)on July 25,2019.     

心境障碍患者的关联性负变

Studies on brain-evoked potential and contingent negative variation (CNV) in mood disorder remain controversial.To date,no CNV difference between unipolar and bipolar depression has been reported.Brain-evoked potentials were measured in the present study to analyze CNV in three subtypes of mood disorder (mania,unipolar depression,and bipolar depression),and these results were compared with normal controls.In the mania group,CNV amplitude B was greater than in controls,and the depression group exhibited lower CNV amplitude B and smaller A-S’2 area,and prolonged post-imperative negative variation latency.The CNV comparison between unipolar and bipolar depression found that the prolonged post-imperative negative variation latency was only in unipolar depression.These results suggest that prolonged post-imperative negative variation latency is a characteristic of unipolar depression,and CNV amplitude change is a state characteristic of mood disorder patients.     

Grey matter volume abnormalities in patients with bipolar I depressive disorder and unipolar depressive disorder:a voxelbased morphometry study

Bipolar disorder and unipolar depressive disorder(UD) may be different in brain structure. In the present study,we performed voxel-based morphometry(VBM) to quantify the grey matter volumes in 23 patients with bipolar I depressive disorder(BP1) and 23 patients with UD,and 23 age-,gender-,and educationmatched healthy controls(HCs) using magnetic resonance imaging. We found that compared with the HC and UD groups,the BP1 group showed reduced grey matter volumes in the right inferior frontal gyrus and middle cingulate gyrus,while the UD group showed reduced volume in the right inferior frontal gyrus compared to HCs. In addition,correlation analyses revealed that the grey matter volumes of these regions were negatively correlated with the Hamilton depression rating scores. Taken together,the results of our study suggest that decreased grey matter volume of the right inferior frontal gyrus is a common abnormality in BP1 and UD,and decreasedgrey matter volume in the right middle cingulate gyrus may be specifi c to BP1.     

Bipolar spectrum: Relevant psychological and biological factors

The bipolar spectrum is a concept which bridges bipolar Ⅰ disorder and unipolar depression. As Kraepelin described, there may be continuity across mood disorders. If this is the case, why should we discriminate for drug choice? For example, it is generally accepted that mood stabilizers should be used for the bipolar spectrum, whereas antidepressants are for unipolar depression. If these disorders are diagnostically continuous, it is possible that the same drug could be effective in treating both bipolar Ⅰ disorder/spectrum and unipolar depression. To resolve this question, I would like to propose my hypothesis that there is an inflexion point which constitutes the boundary between the bipolar spectrum and unipolar depression. It is likely that this inflexion point consists of temperaments as, reportedly, there are many significant differences in the presence of various temperaments between the bipolar spectrum(bipolar Ⅱ, Ⅱ1/2 and Ⅳ) and unipolar depression. These findings suggest that temperaments could draw a boundary between the bipolar spectrum and unipolar depression. Moreover, it has been shown that certain temperaments may be associated with several biological factors and may be associated with drug response. As such, whilst the concept of the bipolar spectrum emphasizes continuity, it is the proposed inflexion point that discriminates drug responses between the bipolar spectrum and unipolar depression. At the moment, although hypothetical, I consider this idea worthy of further research.     

Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials

OBJECTIVES: The efficacy of lamotrigine as maintenance treatment for bipolar disorder (BD), particularly for delaying depressive episodes, is well established, but its efficacy in the acute treatment of bipolar depression is less clear. This paper reports the results of five randomized, double-blind, placebo-controlled trials of lamotrigine monotherapy for the acute treatment of bipolar depression. METHODS: Adult subjects with bipolar I or II disorder experiencing a depressive episode were randomized to placebo or lamotrigine monotherapy (after titration, at a fixed dose of 50 mg or 200 mg daily in Study 1; a flexible dose of 100-400 mg daily in Study 2; or a fixed dose of 200 mg daily in Studies 3, 4 and 5) for 7-10 weeks. RESULTS: Lamotrigine did not differ significantly from placebo on primary efficacy endpoints [17-item Hamilton Depression Rating Scale in Studies 1 and 2; Montgomery-Asberg Depression Rating Scale (MADRS) in Studies 3, 4 and 5]. In Study 1, lamotrigine significantly separated from placebo on some secondary measures of efficacy, including the MADRS, the Clinical Global Impressions-Severity (CGI-S) and the CGI-Improvement (CGI-I), but seldom differed on secondary efficacy endpoints for the other studies. CONCLUSIONS: Lamotrigine monotherapy did not demonstrate efficacy in the acute treatment of bipolar depression in four out of five placebo-controlled clinical studies. Lamotrigine was well tolerated in the acute treatment of bipolar depression.     

A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group

BACKGROUND: More treatment options for bipolar depression are needed. Currently available antidepressants may increase the risk of mania and rapid cycling, and mood stabilizers appear to be less effective in treating depression than mania. Preliminary data suggest that lamotrigine, an established antiepileptic drug, may be effective for both the depression and mania associated with bipolar disorder. This is the first controlled multicenter study evaluating lamotrigine monotherapy in the treatment of bipolar I depression. METHODS: Outpatients with bipolar I disorder experiencing a major depressive episode (DSM-IV, N = 195) received lamotrigine (50 or 200 mg/day) or placebo as monotherapy for 7 weeks. Psychiatric evaluations, including the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), Mania Rating Scale, and the Clinical Global Impressions scale for Severity (CGI-S) and Improvement (CGI-I) were completed at each weekly visit. RESULTS: Lamotrigine 200 mg/day demonstrated significant antidepressant efficacy on the 17-item HAM-D, HAM-D Item 1, MADRS, CGI-S, and CGI-I compared with placebo. Improvements were seen as early as week 3. Lamotrigine 50 mg/day also demonstrated efficacy compared with placebo on several measures. The proportions of patients exhibiting a response on CGI-I were 51%, 41%, and 26% for lamotrigine 200 mg/day, lamotrigine 50 mg/day, and placebo groups, respectively. Adverse events and other safety results were similar across treatment groups, except for a higher rate of headache in the lamotrigine groups. CONCLUSION: Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression.     

Tobacco smoking behaviors in bipolar disorder: a comparison of the general population,schizophrenia, and major depression

Objectives: This study compared the prevalence of tobacco smoking behaviors in patients with bipolar disorder with normal and psychiatric (schizophrenia and major depression) controls. The main goal was to establish that bipolar patients smoke more than normal controls. Differences with psychiatric controls were explored. Methods: Samples of 424 patients (99 bipolar, 258 schizophrenia and 67 major depression) and 402 volunteer controls were collected in Central Kentucky. Smoking data for Kentucky’s general population were available. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used to establish the strength of associations. Logistic regression was used to adjust ORs for confounding variables. Results: Using epidemiological definitions of smoking behaviors and the general population as controls provided bipolar disorder unadjusted ORs of 5.0 (95% CI: 3.3–7.8) for current cigarette smoking, 2.6 (95% CI: 1.7–4.4) for ever cigarette smoking, and 0.13 (95% CI: 0.03–0.24) for smoking cessation. Using a clinical definition and volunteers as controls provided respective bipolar disorder adjusted ORs of 7.3 (95% CI: 4.3–12.4), 4.0 (95% CI: 2.4–6.7), and 0.15 (95% CI: 0.06–0.36). Prevalences of current daily smoking for patients with major depression, bipolar disorder, and schizophrenia were 57%, 66%, and 74%, respectively. Conclusions: Bipolar disorder was associated with significantly higher prevalences of tobacco smoking behaviors compared with the general population or volunteer controls, independently of the definition used. It is possible that smoking behaviors in bipolar disorder may have intermediate prevalences between major depression and schizophrenia, but larger samples or a combination of multiple studies (meta‐analysis) will be needed to establish whether this hypothesis is correct.     

Prevalence of bipolar disorder in the general population: a Reappraisal Study of the Netherlands Mental Health Survey and Incidence Study

OBJECTIVE: The Netherlands Mental Health Survey and Incidence Study (NEMESIS) is a Dutch population study using a fully structured interview (Composite International Diagnostic Interview, CIDI), administered by trained interviewers. Based on all three assessments of NEMESIS, 2.4% of the respondents were identified with lifetime bipolar disorder (DSM-III-R). The primary aim of the study was to estimate the prevalence of bipolar disorder in the same population based on a semistructured interview administered by clinicians. METHOD: Seventy-four persons identified with a lifetime CIDI/DSM-III-R bipolar disorder and 40 persons with a major depressive disorder (MDD) were reinterviewed with the Structured Clinical Interview for DSM (SCID). RESULTS: Based on the SCID, 30 of 74 respondents with a CIDI/DSM-III-R bipolar disorder and eight of 40 respondents with MDD met DSM-IV criteria for bipolar disorder or cyclothymia, corresponding with an adjusted lifetime prevalence in these groups of 1% (95% CI: 0.7-1.3%) and 4.2% (95% CI: 1.6-6.9%) respectively. CONCLUSION: Compared with the SCID, the CIDI on the one hand overdiagnoses bipolar disorder but on the other hand underdiagnoses bipolar disorder.     

拉莫三嗪治疗双相心境障碍对照研究

目的：探讨拉莫三嗪治疗双相情感障碍的疗效与安全性。方法：双相心境障碍患者135例，其中双相抑郁78例，躁狂57例。将患者随机分为3组，每组抑郁相26例，躁狂相19例。疗程32周。前8周为急性期治疗阶段，对照组抑郁相只服选择性5-羟色胺回收抑制剂（SSRI）类抗抑郁剂，躁狂相只服利培酮；拉莫三嗪组在对照组用药的基础上加服拉莫三嗪；碳酸锂组在对照组用药的基础上加服碳酸锂。后24周为巩固治疗阶段，所有患者随机分为两组，只服拉莫三嗪或碳酸锂。采用汉密尔顿抑郁量表（HAMD）、Young躁狂评定量表（YMRS）、治疗中出现的症状量表（TESS）评定疗效及安全性。结果：急性期治疗结束后，无论躁狂相还是抑郁相，拉莫三嗪组和碳酸锂组的临床疗效显著高于对照组（P〈0．01或〈0．05）。巩固治疗阶段两组相比，拉莫三嗪的抗抑郁作用较好，碳酸锂的抗躁狂作用较强。不良反应发生率，碳酸锂组40％，拉莫三嗪组22％。巩固治疗阶段病情复发率，拉莫三嗪组8％，碳酸锂组11％，两组差异无显著性（P〉0．05）。结论：拉莫三嗪作为心境稳定剂治疗双相情感障碍疗效可靠，不良反应小，与碳酸锂相比，抗抑郁作用更强。     

Differences in the clinical characteristics of adolescent depressive disorders

Our objective was to analyze differences in clinical characteristics and comorbidity between different types of adolescent depressive disorders. A sample of 218 consecutive adolescent (ages 13-19 years) psychiatric outpatients with depressive disorders was interviewed for DSM-IV Axis I and Axis II diagnoses. We obtained data by interviewing the adolescents themselves and collecting additional background information from the clinical records. Lifetime age of onset for depression, current episode duration, frequency of suicidal behavior, psychosocial impairment, and the number of current comorbid psychiatric disorders varied between adolescent depressive disorder categories. The type of co-occurring disorder was mainly consistent across depressive disorders. Minor depression and dysthymia (DY) presented as milder depressions, whereas bipolar depression (BPD) and double depression [DD; i.e., DY with superimposed major depressive disorder (MDD)] appeared as especially severe conditions. Only earlier lifetime onset distinguished recurrent MDD from first-episode MDD, and newly emergent MDD appeared to be as impairing as recurrent MDD. Adolescent depressive disorder categories differ in many clinically relevant aspects, with most differences reflecting a continuum of depression severity. Identification of bipolarity and the subgroup with DD seems especially warranted. First episode MDD should be considered as severe a disorder as recurring MDD.     

A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder

BACKGROUND: Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials. This double-blind, placebo-controlled study was conducted to assess the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder. METHODS: After an 8- to 16-week open-label phase during which treatment with lamotrigine was initiated and other psychotropic drug regimens were discontinued, patients were randomized to lamotrigine (100-400 mg daily), lithium (0.8-1.1 mEq/L), or placebo as double-blind maintenance treatment for as long as 18 months. RESULTS: Of 349 patients who met screening criteria and entered the open-label phase, 175 met stabilization criteria and were randomized to double-blind maintenance treatment (lamotrigine, 59 patients; lithium, 46 patients; and placebo, 70 patients). Both lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode (lamotrigine vs placebo, P =.02; lithium vs placebo, P =.006). Lamotrigine was superior to placebo at prolonging the time to a depressive episode (P =.02). Lithium was superior to placebo at prolonging the time to a manic, hypomanic, or mixed episode (P =.006). The most common adverse event reported for lamotrigine was headache. CONCLUSIONS: Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression.     

Common SNPs in CSF2RB are associated with major depression and schizophrenia in the Chinese Han population

Abstract

Objectives. Colony stimulating factor 2 receptor β (CSF2RB) encodes the protein which is the common β chain of the high affinity receptor for IL-3, IL-5 and CSF. It locates in the linkage region 22q12.3 of both bipolar disorder and schizophrenia, and is expressed in most cells. Methods. We carried out a large scale case–control study to test the association between CSF2RB and three major mental disorders in the Chinese Han population. Seven single nucleotide polymorphisms were genotyped in 1140 bipolar affective disorder patients (including 645 type I bipolar affective disorder patients), 1140 schizophrenia patients, 1139 major depressive disorder patients and 1140 healthy controls. Results. Three SNPs were found to be associated with both schizophrenia and major depressive disorder. Haplotype association analysis revealed one protective haplotype (P value = 0.014 for SCZ and 0.0004 for MDD) and one risk haplotype (P value = 0.006 for SCZ and 0.001 for MDD). Additional 52 SNPs were analyzed for population stratification, which demonstrated that our positive results were not caused by population stratification. Conclusions. Our results support CSF2RB as a risk factor common to both schizophrenia and major depression in the Chinese Han population.     

A double-blind,randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes

BACKGROUND: Evidence of the antidepressant efficacy of lamotrigine is increasing, although there are no placebo-controlled trials of lamotrigine augmentation in depression. The aim of this study was to assess if augmentation with lamotrigine was superior to placebo in patients who were receiving fluoxetine for resistant major depressive episodes. METHOD: Twenty-three patients who had experienced at least 1 major depressive episode that was resistant to at least 1 prior trial of antidepressant therapy were selected. These patients were treated with fluoxetine, 20 mg/day, and concomitantly randomly assigned to receive either lamotrigine (N = 13) or placebo (N = 10) for 6 weeks. The dose of lamotrigine was titrated upward from 25 mg/day to 100 mg/day. Patients suffering from bipolar II disorder (N = 8) or from major depressive disorder (N = 15) (DSM-IV criteria) were enrolled, resulting in heterogeneity of the sample. The primary outcome measure was Hamilton Rating Scale for Depression score. Data were collected from 2000-2001. RESULTS: Lamotrigine was statistically superior to placebo on the Clinical Global Impressions scale at endpoint, both in absolute terms (mean +/- SD Clinical Global Impressions-Severity of Illness scores: lamotrigine, 2.15 +/- 1.28; placebo, 3.40 +/- 1.17; p =.0308) and using a responder analysis, with response defined as a Clinical Global Impressions-Improvement score of 2 or less (lamotrigine, 84.62% [N = 11]; placebo, 30.00% [N = 3]; p =.013). The effect of lamotrigine on Clinical Global Impressions scale scores was seen in both major depressive disorder and bipolar II disorder. Lamotrigine, however, failed to separate statistically from placebo on the Hamilton Rating Scale for Depression and Montgomery-Asberg Depression Rating Scale. This failure to differentiate on a primary outcome measure is essentially a negative study result. This result is most likely an artifact of the small sample size used and the resultant limited power of the study. CONCLUSION: The results of this trial add to the literature suggesting potential efficacy of the antidepressant profile of lamotrigine. In addition, this study points to a possible role of lamotrigine as an augmentation agent in depression.     

Ketoconazole in bipolar patients with depressive symptoms: a case series and literature review

Background: Data from several studies suggest that medications, such as ketoconazole, which lower cortisol levels, may be effective for major depressive disorder (MDD). As with MDD, the manic, depressive, and mixed phases of bipolar disorder are frequently associated with elevated cortisol levels. The literature on the use of cortisol-lowering strategies in mood disorders is reviewed, and a case series illustrating the use of ketoconazole in bipolar depression is presented. Methods: For the review, the MEDLINE and PSYCHINFO databases were searched, as were the bibliographies of pertinent articles to find papers on the use of cortisol-lowering agents in patients with mood disorders. In our open-label case series (n=6), ketoconazole (up to 800 mg/day) as an add-on therapy was given to patients with treatment-resistant or intolerant bipolar I or II disorders with current symptoms of depression. Results: Several case reports and small open studies suggest that cortisol-lowering agents may be useful for patients with depression. Two recent placebo-controlled trials of ketoconazole on patients with MDD report conflicting results. In our case series, all three patients who received a dose of at least 400 mg/day had substantial reductions in depressive symptoms. None had significant increases in mania. However, cortisol levels were not lowered in any of the subjects. Conclusions: The literature suggests that cortisol-lowering medications may be effective for a subset of depressed patients. Our preliminary findings suggest that ketoconazole may be useful in some patients with bipolar depression. Larger clinical trials are needed to confirm our observations.