Recurrent Unipolar Depression Research Articles

Daily Left Prefrontal Repetitive Transcranial Magnetic Stimulation for Acute Treatment of Medication-Resistant Depression

Daily left prefrontal transcranial magnetic stimulation (TMS) over several weeks was first proposed as a treatment for depression in 1993, with double-blind study beginning in 1997. TMS for the treatment of depression was approved by the U.S. Food and Drug Administration (FDA) in October 2008 (1). More recently, a large trial sponsored by the National Institutes of Health using an innovative sham treatment technique found that a course of active treatment for 3–5 weeks was superior to sham treatment (remission rates were 15% in the active treatment group and 5% in the sham treatment group) and achieved a 30% remission rate in the open-label extension. These findings led to the implementation of the first new Current Procedural Terminology codes for psychiatry since the American Medical Association launched the system in 1966. In the vignette we describe the case of a 55-year-old woman with treatment-resistant recurrent unipolar depression who was successfully treated with repetitive TMS (rTMS) in each of two episodes 3 years apart. Numerous questions remain on the use of TMS for depression, several of which are raised by the case description. They include how to most effectively deliver rTMS—for example, the appropriate scalp location, the optimal “dose” (frequency, train, number of stimuli per day, and pattern of delivery), its use in combination with medications or talking/exposure therapy, and whether one can use maintenance rTMS to prevent relapse after a patient achieves remission. Daily left prefrontal rTMS reflects a paradigm shift in psychiatry in that it uses noninvasive and nonconvulsive circuitbased physiological processes to treat depression in patients who have not responded to medications or who cannot tolerate them.

The seasonality of bipolar affective disorder: Comparison with a primary care sample using the Seasonal Pattern Assessment Questionnaire

In contrast with recurrent unipolar depression, relatively little is known about the seasonality of depressive episodes in bipolar affective disorder (BAD). We compared responses on the Seasonal Pattern Assessment Questionnaire (SPAQ) between a cohort of 183 patients with BAD and a large sample of patients in primary care (N=4746). Comparisons were adjusted for age and gender. 27% of the BAD patients fulfilled SPAQ criteria for Seasonal Affective Disorder (SAD. This gave an adjusted odds ratio of 3.73 (95% confidence intervals 2.64 to 5.27) in comparison with the rate among the primary care samples. Global seasonality scores were significantly higher among BAD patients (adjusted mean difference 1.73, 95% CI 0.97 to 2.49, p<0.001). The SPAQ was originally designed as a screening instrument rather than as a case-finding instrument. Vigilance for seasonal symptom recurrence in BAD may be important with regard to management and relapse prevention.

The case of King Saul: did he have recurrent unipolar depression or bipolar affective disorder?

It is widely accepted that Saul, the first king of Israel, had a mental disorder. Probably it was depression, soothed when David played on his harp: ‘ And whenever the evil spirit from God came upon Saul, David took the lyre and played it in his hand, and Saul would be relieved and feel better and

P01-211 - Selective effect of paternal age on age-of-onset in bipolar i disorder

ObjectiveThe study investigated the effect of the parental age on the age-of-onset (AO) in bipolar I disorder (BPI) in connection with proband gender and family history for major psychoses in a directly interviewed sample of 530 BPI probands.MethodAll 530 probands, 73.0% of their first-degree and 22.62% of their second-degree relatives were administered the DIGS and FIGS interviews. The family history (FH) method was used for unavailable relatives. The impact of parental age on proband early/late AO was evaluted through logistic regressions. The commingling analysis (SAGEv6.1-software) was used to determine the cut-off age separating the early/late AO.ResultsWe evidenced a significant influence of the paternal age ≥ 35 years on AO in BPI disorder in the total sample (p = 0.023) and in some subgroups defined by positive/negative FH for major psychoses: the sporadic group (p = 0.035) and the group with FH of recurrent unipolar major depression (Mdd-RUP) (p = 0.041). No effect of the paternal/maternal age on disease AO was found in patients with FH of bipolar/schizoaffective disorders/schizoprenia (BP/SA/SCZ). The global significant effect of the advancing paternal age on the decreasing proband AO was generated by female patients (p = 0.022). No effect of the paternal/maternal age on disease AO was found in male patients. Paternal age was older in fathers of sporadic cases and of cases with FH of Mdd-RUP than in cases with FH of BP/SA/SCZ (p = 0.011).ConclusionWe evidenced a selective effect of the advancing paternal age on bipolar onset depending on offspring gender and type of FH for major psychoses.

Lithium Neurotoxicity at Normal Serum Levels

To the Editor: Lithium is used with great success in the treatment and prophylaxis of bipolar disorders, unipolar recurrent depression, and endogenous depression that is resistant to conventional treatment. It is also known to be neurotoxic at higher serum levels. In rare cases patients develop symptoms of intoxication even with normal lithium levels. 1

The DAOA/G30 locus and affective disorders: haplotype based association study in a polydiagnostic approach

BackgroundThe DAOA/G30 (D-amino acid oxidase activator) gene complex at chromosomal region 13q32-33 is one of the most intriguing susceptibility loci for the major psychiatric disorders, although there is no consensus about the specific risk alleles or haplotypes across studies.MethodsIn a case-control sample of German descent (affective psychosis: n = 248; controls: n = 188) we examined seven single nucleotide polymorphisms (SNPs) around DAOA/G30 (rs3916966, rs1935058, rs2391191, rs1935062, rs947267, rs3918342, and rs9558575) for genetic association in a polydiagnostic approach (ICD 10; Leonhard's classification).ResultsNo single marker showed evidence of overall association with affective disorder neither in ICD10 nor Leonhard's classification. Haplotype analysis revealed no association with recurrent unipolar depression or bipolar disorder according to ICD10, within Leonhard's classification manic-depression was associated with a 3-locus haplotype (rs2391191, rs1935062, and rs3916966; P = 0.022) and monopolar depression with a 5-locus combination at the DAOA/G30 core region (P = 0.036).ConclusionOur data revealed potential evidence for partially overlapping risk haplotypes at the DAOA/G30 locus in Leonhard's affective psychoses, but do not support a common genetic contribution of the DAOA/G30 gene complex to the pathogenesis of affective disorders.

Right Orbitofrontal Corticolimbic and Left Corticocortical White Matter Connectivity Differentiate Bipolar and Unipolar Depression

The absence of pathophysiologically relevant diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We aimed to determine whether whole brain white matter connectivity differentiated BD from UD depression. We employed a three-way analysis of covariance, covarying for age, to examine whole brain fractional anisotropy (FA), and corresponding longitudinal and radial diffusivity, in currently depressed adults: 15 with BD-type I (mean age 36.3 years, SD 12.0 years), 16 with recurrent UD (mean age 32.3 years, SD 10.0 years), and 24 healthy control adults (HC) (mean age 29.5 years, SD 9.43 years). Depressed groups did not differ in depression severity, age of illness onset, and illness duration. There was a main effect of group in left superior and inferior longitudinal fasciculi (SLF and ILF) (all F > or = 9.8; p < or = .05, corrected). Whole brain post hoc analyses (all t > or = 4.2; p < or = .05, corrected) revealed decreased FA in left SLF in BD, versus UD adults in inferior temporal cortex and, versus HC, in primary sensory cortex (associated with increased radial and decreased longitudinal diffusivity, respectively); and decreased FA in left ILF in UD adults versus HC. A main effect of group in right uncinate fasciculus (in orbitofrontal cortex) just failed to meet significance in all participants but was present in women. Post hoc analyses revealed decreased right uncinate fasciculus FA in all and in women, BD versus HC. White matter FA in left occipitotemporal and primary sensory regions supporting visuospatial and sensory processing differentiates BD from UD depression. Abnormally reduced FA in right fronto-temporal regions supporting mood regulation, might underlie predisposition to depression in BD. These measures might help differentiate pathophysiologic processes of BD versus UD depression.

Cognitive Deficits in Euthymic Patients With Recurrent Depression

Neurocognitive impairments are found in people recovered from major depression compared with never-depressed controls. A total of 20 patients in recovery from recurrent unipolar depression and 20 healthy controls were tested using a neuropsychological battery containing tasks of executive function (Wisconsin Card Sort Test), attention, visuomotor speed, and working memory. The recovered-depressed group performed poorly in comparison to healthy controls on the planning and problem solving aspects of the Wisconsin Card Sort Test, even after controlling for subclinical depressive symptoms. There was no significant difference between the 2 groups on set-shifting aspects of the task and the other tests. These specific deficits, even after controlling for subclinical depressive symptoms, were correlated with the number of previous episodes of depression. These findings support the hypothesis that impairments in executive function are present in recovery from unipolar depression, and so are not simply state markers. Further longitudinal research on samples free of history of depression is needed to determine whether these impairments are intermediate markers for recurrent unipolar depression, rather than "scars" caused by past episodes.

Correlation of Initial Wellness With Long-Term Morbidity in Recurrent Major Affective Disorder Patients as a Test of Survival Analysis

Because long-term monitoring of morbidity or wellness is often impractical, survival analysis is widely used in experimental therapeutics. In long-term applications, the method assumes that time-to-recurrence or time-to-intervention is a surrogate of long-term clinical status during sustained treatment. Because this plausible assumption has not been tested empirically, we evaluated prospectively and systematically acquired data from consenting adults with major affective disorders treated with lithium for an average of 5.4 years to compare, within-subjects, estimated long-term morbidity versus the first-wellness interval after clinical remission of a treated index episode. These measures were inversely correlated in all 450 subjects with mood disorder (rs = -0.65) and in those with bipolar I (n = 259; rs = -0.58), II (n = 150; rs = -0.65), or recurrent unipolar depression (n = 50; rs = -0.66). The wellness interval also predicted episodes per year (rs = -0.58, all P < 0.0001). These associations were sustained in multiple-regression modeling, in which a bipolar diagnosis (but not sex, age, or measures of preintake morbidity) was associated with greater long-term morbidity than in major depression. These findings provide moderate support for a basic assumption underlying the use of survival analysis for psychopharmacology research and suggest that clinical outcomes might be predictable from initial wellness intervals.

Minor physical anomalies in women with recurrent unipolar depression

According to earlier observations, minor physical anomalies (MPAs) are more prevalent in psychotic disorders, especially in schizophrenia, and represent an indicator of abnormal fetal development. Limited research has been conducted on these structural abnormalities among patients with unipolar depression, with and without psychotic features. We hypothesized that the mean total MPA score would be greater in patients with psychotic depression than depressive patients without psychosis and control subjects. An extended scale of MPAs was used to detect the presence or absence of 51 MPAs in women with recurrent unipolar depression with psychotic symptoms ( n = 50), women with recurrent unipolar depression without psychotic symptoms ( n = 50) and healthy female controls ( n = 50). Women with recurrent depression had significantly more MPAs than controls. With regard to MPAs of specific body regions, depressive patients had significantly higher rates of MPAs in the mouth area than control subjects. Higher rates of MPAs were not significantly related to psychotic features of depression. The study results are indicative of possible early neurodevelopmental disturbance in recurrent unipolar depression.

DNA sequence variants of the FKBP5 gene are associated with unipolar depression

FKBP5 is a glucocorticoid receptor-regulating co-chaperone of hsp-90 and, therefore, is suggested to play a role in the regulation of the hypothalamic-pituitary-adrenocortical system and the pathophysiology of depression. Previously, three studies identified single nucleotide polymorphisms (SNPs) in the FKBP5 gene associated with response to antidepressants, and one study found an association with diagnosis of depression. We selected five markers from the region of interest. A case-control sample comprising 268 German in-patients with recurrent unipolar depression, and 284 German controls recruited from the general population were available. Association of the selected FKBP5 sequence variants with clinical depression were analysed. In addition, we explored association with treatment response by (a) the Hamilton Depression Rating Scale and (b) the dexamethasone/corticotrophin-releasing hormone (Dex/CRH) test, as well as association with hippocampal volumes in a subpopulation of 110 patients. For three of the five investigated SNPs we were able to show association with the diagnosis of depression. In the subpopulation of 110 patients, diagnosis-related alleles were also associated with the reduction of cortisol secretion in the Dex/CRH test during a 4-wk treatment period, while psychopathological changes were not associated. Furthermore, diagnosis-related alleles were associated with reduction of the hippocampal volume. This study extends the replicated association of a promoter SNP with antidepressant response on a biological level by demonstrating normalization of the cortisol response under Dex/CRH stimulation during treatment. Furthermore, several of the investigated SNPs were associated with the disease status and the intermediate phenotype of hippocampal volume.

Recurrence Rates in Ontario Physicians Monitored for Major Depression and Bipolar Disorder

Physicians with recurrent conditions that may affect job performance are sometimes referred for monitoring to help ensure compliance with treatment, ongoing remission of illness, and patient safety. Little is known about recurrence rates among doctors monitored for mood disorders. Our primary objective was to describe recurrence rates among Ontario physicians monitored for recurrent unipolar depression and bipolar disorder (BD). Our secondary objective was to explore predictors of recurrence. We used a retrospective cohort design to describe the time to recurrence, defined as either stopping work owing to symptoms or any re-emergence of symptoms meeting a pre-established clinical threshold. Our exploratory analysis of recurrence predictors included age, sex, psychiatric diagnosis, psychiatric comorbidity, medical comorbidity, number of past episodes, past hospitalizations, and family history of psychiatric disorder. During a median observation of 24 months, 36% (18 of 50) of physicians stopped work owing to recurrence of symptoms, with the median time to stopping work being 11 months. As well, 52% (26 of 50) had a re-emergence of clinical symptoms, with the median time to any level of symptom re-emergence being 13 months. Physicians with psychiatric comorbidity stopped work sooner (hazard ratio [HR] 3.53; 95% CI 1.24 to 10.03, P = 0.01) and had more rapid symptom re-emergence (HR 2.96; 95% CI 1.34 to 6.52, P = 0.004) than those without comorbidity. The most common psychiatric comorbidity was a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, anxiety disorder. Recurrence rates are high among Ontario physicians referred for formal monitoring of recurrent unipolar depression and BD, and are markedly hastened by the presence of psychiatric comorbidity.

Proton-MR-spectroscopy (1H-MRS) of the left hippocampus and anterior cingulate cortex in recurrent unipolar depression: results from 176 subjects

Proton-MR-spectroscopy (1H-MRS) of the left hippocampus and anterior cingulate cortex in recurrent unipolar depression: results from 176 subjects

Circadian polymorphisms associated with affective disorders.

BackgroundClinical symptoms of affective disorders, their response to light treatment, and sensitivity to other circadian interventions indicate that the circadian system has a role in mood disorders. Possibly the mechanisms involve circadian seasonal and photoperiodic mechanisms. Since genetic susceptibilities contribute a strong component to affective disorders, we explored whether circadian gene polymorphisms were associated with affective disorders in four complementary studies.MethodsFour groups of subjects were recruited from several sources: 1) bipolar proband-parent trios or sib-pair-parent nuclear families, 2) unrelated bipolar participants who had completed the BALM morningness-eveningness questionnaire, 3) sib pairs from the GenRed Project having at least one sib with early-onset recurrent unipolar depression, and 4) a sleep clinic patient group who frequently suffered from depression. Working mainly with the SNPlex assay system, from 2 to 198 polymorphisms in genes related to circadian function were genotyped in the participant groups. Associations with affective disorders were examined with TDT statistics for within-family comparisons. Quantitative trait associations were examined within the unrelated samples.ResultsIn NR1D1, rs2314339 was associated with bipolar disorder (P = 0.0005). Among the unrelated bipolar participants, 3 SNPs in PER3 and CSNK1E were associated with the BALM score. A PPARGC1B coding SNP, rs7732671, was associated with affective disorder with nominal significance in bipolar family groups and independently in unipolar sib pairs. In TEF, rs738499 was associated with unipolar depression; in a replication study, rs738499 was also associated with the QIDS-SR depression scale in the sleep clinic patient sample.ConclusionAlong with anti-manic effects of lithium and the antidepressant effects of bright light, these findings suggest that perturbations of the circadian gene network at several levels may influence mood disorders, perhaps ultimately through regulation of MAOA and its modulation of dopamine transmission. Twenty-three associations of circadian polymorphisms with affective symptoms met nominal significance criteria (P < 0.05), whereas 15 would be expected by chance, indicating that many represented false discoveries (Type II errors). Some evidence of replication has been gathered, but more studies are needed to ascertain if circadian gene polymorphisms contribute to susceptibility to affective disorders.

Variations in tryptophan hydroxylase 2 linked to decreased serotonergic activity are associated with elevated risk for metabolic syndrome in depression

Major depression and the metabolic syndrome (MetS) are interacting clinical conditions influenced by genetic susceptibility. For both disorders, impaired serotonergic neurotransmission in specific brain areas has been suggested. This led us to investigate whether variants in the gene coding for tryptophan hydroxylase 2 (TPH2), the brain-specific and rate-limiting enzyme for serotonin biosynthesis, might be predictive for an increased liability for the development of MetS in depressed patients. In a case-control study consisting of 988 patients with recurrent unipolar depression (RUD) and 1023 psychiatric healthy controls, MetS components were ascertained according to the International Diabetes Foundation criteria. A total of 41 single nucleotide polymorphisms fully covering the TPH2 gene region were genotyped in stage 1 (300 patients/300 controls), resulting in significant genetic associations of polymorphisms located in exon 7 and intron 8 of TPH2 and the occurrence of MetS in depressed patients after correction for age, gender and multiple testing (51 RUD-MetS/179 RUD-non-MetS). We were able to confirm the significant association of rs17110690 in stage 2 (688 patients/723 controls; 110 RUD-MetS/549 RUD-non-MetS) and to link risk-genotypes and risk-haplotypes for MetS to lower TPH2 mRNA expression and to lower 5-hydroxyindoleacetic acid levels in cerebrospinal fluid previously reported in functional studies. Our findings suggest that TPH2 polymorphisms characterize a subgroup of depressed patients who are especially prone to develop metabolic disorders induced by a genotype-dependent impairment of serotonergic neurotransmission. Identifying depressed patients at high risk for MetS using genetic variants could have direct clinical impact on individualized disease management and prevention strategies.

The Sequential Combination of Pharmacotherapy and Psychotherapy in Mood Disorders

The aim of this review was to consider the literature concerned with a sequential use of pharmacotherapy and psychotherapy in mood disorders. Review of the clinical trials where treatment components were used in a sequential order were identified by using MEDLINE, a manual search of the literature and the Index Medicus. In unipolar recurrent depression, the sequential use of pharmacotherapy and psychotherapy was found to improve relapse rate. In bipolar disorder, the use of psychotherapeutic strategies in patients who were already assuming mood stabilizers was also found to yield clinical benefits. The sequential model has the potential for improving the logic and timing of interventions. A conceptual shift in current assessment methods (staging) is needed.

Why antidepressants are not antidepressants: STEP‐BD, STAR*D, and the return of neurotic depression

The widely held clinical view of 'antidepressants' as highly effective and specific for the treatment of all types of depressive disorders is exaggerated. This sobering conclusion is supported by recent findings from the NIMH-sponsored STEP-BD and STAR*D projects. Antidepressants have limited short-term efficacy in unipolar depressive disorders and less in acute bipolar depression; their long-term prophylactic effectiveness in recurrent unipolar major depression remains uncertain, and is doubtful in recurrent bipolar depression. These limitations may, in part, reflect the excessively broad concept of major depression as well as unrealistic expectations of universal efficacy of drugs considered 'antidepressants.' Treatment-refractory depression may reflect failure to distinguish depressive conditions, particularly bipolar disorder, that are inherently less responsive to antidepressants. Antidepressants probably should be avoided in bipolar depression, mixed manic-depressive states, and in neurotic depression. Expectations of antidepressants for specific types of patients with symptoms of depression or anxiety require critical re-evaluation. A revival of the concept of neurotic depression would make it possible to identify patients with mild-to-moderate, chronic or episodic dysthymia and anxiety who are unlikely to benefit greatly from antidepressants. Diagnostic criteria for a revival of the concept of neurotic depression are proposed.

Unipolar depression and hippocampal volume: Impact of DNA sequence variants of the glucocorticoid receptor gene

Glucocorticoid receptor (GR) plays a major role in regulation of the hypothalamic-pituitary-adrenocortical (HPA) system; HPA dysregulation represents the most consistent biological pattern of depression. Multiple functional polymorphisms are known for the GR gene, which might influence the development of unipolar depression. Previous studies reported associations to some variants in this gene but not consistently so. We investigated seven genetic polymorphisms in the GR gene (NR3C1) located in the putative promoter, exon 2 and intron 2 region. Study populations were 322 German inpatients with recurrent unipolar depression, and 298 German controls recruited from the general population. The relationships between intermediate phenotypes (hippocampal and amygdala volumes) and NR3C1 DNA sequence variants were additionally explored in a subpopulation of patients. We found association between the diagnosis of depression and DNA sequence variants in intron 2 as well as in the 5' region of the NR3C1 gene but not for the previously studied exon 2 and putative promoter variants (global test after control of multiple testing, P = 0.02). In patients, diagnosis-related alleles were also associated to hippocampal volume reduction and amygdala volume variation. Unipolar depression is associated with DNA variants of the NR3C1 gene in our population. Neurobiological underpinnings of depression as volumetric reductions of the hippocampus may also be mediated by variants in this gene.

Treating Suicidality in Depressive Illness. Part 2: Does Treatment Cure or Cause Suicidality?

Objectives:To systematically review studies of treatment efficacy for suicidality in mood disorders. To consider the evidence for whether antidepressants may induce suicidality. Method: Systematic review of the literature. Results and Conclusions: There is fairly good evidence that lithium reduces completed suicide and attempt rates in people with bipolar disorder and recurrent unipolar depression. Antidepressants and psychological treatments may reduce suicidal ideation in depressed patients. Antidepressant trials do not, however, a priori target suicidality as an outcome, and inferences made are post hoc. For practical reasons, no adequate trials to date have tested the efficacy of treatment aimed at reducing completed suicide in people with depressive disorders. Antidepressants have been implicated in suicide in one metaanalysis (the elderly) and in one case-control study (youth), signalling the need for caution. However, most metaanalyses have found no significant excess of completed suicide among ant...

Randomized Trial of Weekly, Twice-Monthly, and Monthly Interpersonal Psychotherapy as Maintenance Treatment for Women With Recurrent Depression

Objectives:The authors sought to determine whether a greater frequency of interpersonal psychotherapy (IPT) sessions during maintenance treatment has a greater prophylactic effect than a previously validated once-a-month treatment. Method: A total of 233 women 20–60 years of age with recurrent unipolar depression were treated in an outpatient research clinic. After participants had achieved remission with weekly IPT or, if required, with weekly IPT plus antidepressant pharmacotherapy, they were randomly assigned to weekly, twice-monthly, or monthly maintenance IPT monotherapy for 2 years or until a recurrence of their depression occurred. Results: Among participants who remitted with IPT alone and entered maintenance treatment (N = 99), 19 (26%) of the 74 who remained in the study throughout the 2-year maintenance phase experienced a recurrence of depression. Among participants who required the addition of a selective serotonin reuptake inhibitor to achieve remission (N = 90), 32 (36%) sustained that remi...