Journal of Affective Disorders

There is evidence that the endogenous opioid system (EOS) is involved in the modulation of mood and neuroendocrine function. Furthermore, the possible involvement of the EOS in major depression has been postulated, although a clear role has not been established. The affective and endocrine responses to naloxone administration in seven female depressives and in seven matched controls and their diurnal variations were investigated. Subjects had an i.v. bolus of either 0.2 mg/kg naloxone or saline at two time points (09:00 or 18:00 h) and for 2 days in a single-blind, cross-over design. The basal cortisol plasma levels, both in the morning and in the afternoon, showed higher values (P<0.05) in the depressives. There was a naloxone-induced increase in the adrenocorticotrophic hormone (ACTH), cortisol, and luteinizing hormone (LH) plasma levels, plus a subjective dysphoric effect in both groups. The depressives showed a greater dysphoric effect both in the morning and afternoon (P<0.05), and a blunted cortisol response in the afternoon (P<0.05). There were no differences between groups or time of day in the ACTH or LH responses. The sample size was small, but by studying each patient as their own control, plus a matched control for every patient, softens this effect. Finding patients with a major depressive episode free of medication is difficult, and this aspect contributes to the size of the sample. These results suggest that opioid mechanisms may be involved in the HPA axis changes and possibly in mood changes found in depression. The discrepancy between increased sensitivity in depression to mood changes and decreased change in cortisol may indicate a ceiling effect for the latter.

Electroconvulsive therapy (ECT) is a highly effective treatment for depression but its use is limited by the risk of cognitive side effects. This study explored the potential of a novel approach, ultrabrief pulsewidth (0.3 ms) right unilateral (RUL-UB) ECT, to minimise cognitive effects while preserving efficacy. Mood and neuropsychological functioning were objectively rated in 30 patients over a course of RUL-UB ECT at 6 times seizure threshold. Results (mood outcomes, ECT treatment parameters) were compared with a retrospectively assessed group of 30 age and gender matched patients who received RUL ECT (1.0 ms pulsewidth, 3.5 times seizure threshold) at the same hospital. Six treatments of RUL-UB ECT resulted in relatively few cognitive side effects, compared to reports of previous studies. The number of responders did not differ between groups but significantly more treatments were required in the RUL-UB group, suggesting a slower speed of response. Patients were not randomised to the two forms of ECT and data was obtained retrospectively in the RUL ECT comparison group. This study suggests that RUL-UB ECT can be effective in treating depression while incurring lesser cognitive side effects than a commonly used form of RUL ECT, but a greater number of treatments may be required for response.

Chronic fatigue syndrome (CFS) is associated with hypocortisolism, but it is not yet clear the extent to which enhanced negative feedback may underlie this finding. We undertook a low-dose dexamethasone (0.5 mg) suppression test in 18 CFS patients and 20 matched, healthy controls. We measured salivary cortisol levels at 0800 h, 1200 h, 1600 h and 2000 h before and after the administration of 0.5 mg of dexamethasone. Basal cortisol output was raised in this group of CFS patients compared to controls. Overall, the percentage suppression following dexamethasone administration was no different between CFS (mean+/-sem: 80.4+/-4.4%) and controls (76.2+/-4.9 %). However, the sub-group of patients with CFS and comorbid depression (n=9) showed a significant hypersuppression of salivary cortisol in response to dexamethasone (89.0+/-1.9%; p<0.05 v controls). The sub-group analysis was on small numbers and should be considered preliminary. Dexamethasone probes only glucocorticoid medicated negative feedback but does not probe mineralocorticoid feedback, the other main physiological feedback mechanism. We found partial support for the hypothesis of enhanced negative feedback in CFS but only in patients with comorbid depression and also in the context of a sample of patients with elevated basal cortisol levels, which is an atypical finding in the literature.

INN 00835 (4-fluoro-L-phenylalanyl-trans-4-hydroxy-L-prolyl-L-arginyl-glycyl-trypt ophanamide ditrifluoroacetate) is a synthetic pentapeptide antidepressant with a potential for rapid onset of action. We were interested to see if such action could be correlated with serotonin uptake by platelets. In a phase II clinical trial, unipolar depressed patients were administered active drug, INN 00835 or placebo, subcutaneously, at 0.2 mg/kg, once daily for 5 consecutive days. Efficacy of treatment was evaluated by psychometric tests (HAMD, MADS, CSRS, CGI and total VAS). Changes in platelet uptake rates of serotonin (3H-5HT) were measured in plasma from the patients participating in the phase II clinical trial, prior to and immediately after treatment with INN 00835 (19 patients) or placebo (16 patients), to evaluate the effect of treatment with INN 00835 on the rate of platelet 5-HT uptake. The data evaluated by using the psychometric tests indicated a significant response to treatment with INN 00835 after 5 days of dosing. The rates of platelet 5-HT uptake were lower prior to treatment (baseline), and increased after the 5-day treatment period. The change in the uptake rate (deltaVmax) following treatment was significantly larger in the active group than in the placebo group (P < 0.05). The difference between the placebo group and the patients who responded to treatment was even larger. Small number of subjects. The data tend to substantiate the use of platelet serotonin uptake as a biochemical marker of effective treatment of depression.

INN 00835 is a synthetic pentapeptide with a potential for rapid onset of action as an antidepressant. Its efficacy was investigated in a pilot study in patients diagnosed with major depression. Fifty two patients received either active drug - INN 00835 (26 patients) - or placebo (26 patients), subcutaneously at 0.2 mg/kg for 5 consecutive days. The patients were evaluated for an additional 4 weeks after treatment. Efficacy was evaluated by the following psychiatric rating scales: HAMD, MADRS, CSRS, CGI, and VAS. The effect of treatment was also evaluated by using a biochemical marker: changes in blood platelet serotonin (5HT) uptake rates in drug-treated patients compared to those in the placebo group. Plasma concentrations of INN 00835 were measured by LC/MS. Statistical analysis indicated a strong pharmacodynamic correlation between plasma drug concentrations at 1 h after dosing and the reduction in the severity of depression as measured by the psychiatric rating scales. A minimum effective plasma concentration (MEC) of INN 00835 was 5 ng/ml. Statistically significant differences in response to treatment (P<0.05) were found between patients with plasma concentrations above MEC and those in the placebo group, as well as between subjects with plasma concentrations above and below the MEC. The peak effect was observed after the 5-day treatment and the response to treatment persisted during the 4-week follow-up period. The change of 5HT uptake rates after treatment was significantly larger in the drug-treated group than in the placebo group. Limitations: This was a pilot study conducted in a relatively small population (52 patients) and the limited number of blood sampling times did not allow a comprehensive pharmacokinetic analysis. There was a relatively large placebo response. The results have to be confirmed in future, large scale studies. INN 00835 appears to be a promising drug for the treatment of major depression.

To investigate the association of early improvement and treatment emergent suicidal ideation in a large sample (N=705) of naturalistically treated inpatients with major depressive disorder. In line with previous reports early improvement was defined as a 20% HAMD improvement within the first two weeks of antidepressant treatment. Treatment emergent suicidal ideation was defined by a sudden increase from 0 or 1 to at least 3 on HAMD item 3 and from 0.1 to at least 4 on MADR item 10 for suicidal ideation. Early improvers were compared with non-early improvers with respect to the occurrence of treatment emergent suicidality during treatment. Early improvers were 3 (MADRS) to 3.4 (HAMD) times less likely to experience new emergence of suicidal ideation during the treatment course than non-improvers. In addition, early improvement was associated with significantly less pessimistic thoughts. The analysis is based on secondary analysis of prospectively collected data. No controlled study design. Early improvement is associated with significantly less treatment emergent suicidal ideation for it may provide rapid symptom relief and reduce hopelessness.

Human leukocyte antigen (HLA) genotypes in lamotrigine -induced (LTG-induced) cutaneous adverse drug reactions (cADRs) have been described in several reports but controversy remains even for a given ethnic group. We attempted to clarify a possible association between LTG-induced cADRs and HLA alleles in Japanese patients. Sixteen subjects, including eight patients with LTG-induced cADRs and eight LTG-tolerant controls were included in this study. All eight patients with LTG-induced cADRs gave positive results in a drug-induced lymphocyte stimulation test (DLST) with LTG. We performed HLA-typing for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1, using PCR with sequence-specific oligonucleotide probes and multiple analyte profiling (xMAP) technology (Luminex System; Luminex Corporation, Austin, TX). We examined differences between allele frequencies in our two groups of subjects and the allele frequencies in the general Japanese population. The frequencies of HLA-DRB1*0405, and HLA-DQB1*0401 alleles were higher in our LTG-cADRs patients than the reference frequencies in the general Japanese population. We also detected HLA-DQA1*0303 frequently in our LTG-cADRs patients, but data for this allele in the Japanese population was not available. Our observation was presumably due to the linkage disequilibrium among the three alleles. The haplotype frequency of HLA-DRB1*0405, DQB1*0401 and DQA1*0303 in our LTG-cADRs subjects was also different from the corresponding haplotype frequency in the database for the Japanese population and the difference was statistically significant. One patient with the HLA-DRB1*0405, -DQB1*0401 and DQA1*0303 haplotype was safely re-treated with LTG after results of a DLST with LTG ceased to be positive about 4 months after discontinuation of LTG. Our analysis included only 16 patients. Associations between LTG-induced cADRs and specific HLA loci will have to be confirmed in larger studies. LTG-induced cADRs are associated with HLA-DRB1*0405, -DQB1*0401 and -DQA1*0303. Copyright © 2015. Published by Elsevier B.V.

This study investigated the effect of past depression, past and current eating disorders (ED) on perinatal anxiety and depression in a large general population cohort of pregnant women, the Avon Longitudinal Study of Parents and Children (ALSPAC). Anxiety and depression were measured during and after pregnancy in 10,887 women using the Crown-Crisp Experiential Inventory and Edinburgh Postnatal Depression Scale. Women were grouped according to depression and ED history: past ED with (n = 123) and without past depression (n = 50), pregnancy ED symptoms with (n = 77) and without past depression (n = 159), past depression only (n = 818) and controls (n = 9,660). We compared the course of depression and anxiety with linear mixed-effect regression models; and probable depressive and anxiety disorders using logistic regression. Women with both past depression and past/current ED had high anxiety and depression across time perinatally; this was most marked in the group with pregnancy ED symptoms and past depression (b coefficient:5.1 (95% CI: 4.1-6.1), p < 0.0001), especially at 8 months post-partum. At 18 weeks in pregnancy all women (apart from those with past ED only) had a higher risk for a probable depressive and anxiety disorder compared to controls. At 8 months post-partum pregnancy ED symptoms and/or past depression conferred the highest risk for a probable depressive and anxiety disorder. Data were based on self-report. There was some selective attrition. Pregnancy ED symptoms and past depression have an additive effect in increasing the risk for depression and anxiety perinatally. Screening at risk women for anxiety and depression in the perinatal period might be beneficial.

Pharmacological studies of bipolar disorder suggest that dysfunction of calcium mobilization via phosphatidylinositol-mediated transduction may be involved in its pathogenesis. The present study tests the hypothesis that dysfunction of calcium mobilization in bipolar disorder is due to the mutation of the nucleotide sequence in the FKBP12 binding site on the inositol 1,4,5-trisphosphate type-1 receptor (IP(3)R1). Nucleotide sequence analysis of the FKBP12 binding site on IP(3)R1 was performed using reverse transcription-polymerase chain reaction and DNA sequencing. The nucleotide sequence in this region was preserved in all subjects. This finding suggests that IP(3)R1 dysfunction through the FKBP12 binding site is not involved in the pathogenesis of bipolar disorder.

OBJECTIVE: Depression cost studies have mainly taken a primary care perspective and should be completed with cost estimates from psychiatric care. The objectives of this study were to estimate the societal per-patient cost of depression in specialized psychiatric care in Sweden, and to relate costs to disease severity, depressive episodes, hospitalization, and patient functioning. METHODS: Retrospective resource use data in inpatient and outpatient care for 2006-2008, as well as ICD-10 diagnoses and Global Assessment of Functioning (GAF), were obtained from the Northern Stockholm psychiatric clinic (covering half of Stockholm's population aged 18 years and above). As a complement, data from national registers on pharmaceuticals and sick leave were used in order to estimate the societal cost of depression. RESULTS: Based on 10,430 patients (63% women), the mean annual per-patient cost was €17, 279 in 2008. The largest cost item was indirect costs due to productivity losses (88%), followed by outpatient care (6%). Patients with mild and severe depression had average costs of €14,200 and €21,500, respectively. Total costs were substantially higher during depressive episodes, among patients with co-morbid psychosis or anxiety, for hospitalized patients, and for patients with poor functioning. LIMITATIONS: Primary care costs and costs for reduced productivity at work were not included. CONCLUSIONS: The main cost item among depression patients in psychiatric care was indirect costs. Costs were higher than previously reported for primary care, and strongly related to hospitalization, depressive episodes, and low functioning. This suggests that effective treatment that avoids depressive episodes and hospitalization may reduce society's costs for depression.

We report on the assessment and outcome of the first 1000 patients referred to a tertiary referral depression clinic established to assess the utility of diagnostic sub-typing on clinical course of illness. Diagnostic, treatment recommendations, prognostic judgments and 12-week outcome data were examined. Nearly 40% of those with a primary mood disorder were diagnosed with bipolar disorder, of whom three-quarters received such a diagnosis for the first time. Alternative diagnoses or formulations were provided for 68% of the total sample, with the therapeutic paradigm altered for the majority (86%) of patients. Improvement rates were indicative of a higher level of improvement in those diagnosed with bipolar disorder (some 70%) compared to those with unipolar disorders (some 60%). Overall, however, rates of 'full remission' were low, being 2% and up to 12% for bipolar and unipolar patients respectively and perhaps reflecting the tertiary nature of the assessing clinical facility. Baseline clinician predictions were in the order of 60% accuracy in predicting outcome, irrespective of diagnostic grouping. Anticipation factors (e.g. attending a specialist tertiary referral service) may have contributed non-specifically to outcome. Use of clinician-derived diagnoses rather than strict DSM-IV criteria limits comparisons to other studies. The high rates of a first-time bipolar diagnosis suggest that detection and diagnosis of this condition continues to be problematic. Low remission rates underline the chronic nature of many mood disorders, and the need for ongoing management given the high risk of relapse. Our findings offer support for the importance of identifying bipolar disorder and distinguishing depressive sub-types in order to shape more targeted treatments, a task that might be advanced by the establishment of more tertiary referral services.

This study was undertaken to examine whether brain 5-HT(1A) receptor binding is reduced in euthymic bipolar patients. Eight medicated euthymic bipolar patients and 8 healthy volunteers underwent positron emission tomography scanning using the selective 5-HT(1A) receptor radioligand [carbonyl-(11)C]WAY-100635. No significant difference in global postsynaptic parametric binding potential (BP(ND)) was found between euthymic bipolar patients (mean + or - SD, 4.24 + or - 0.76) and healthy volunteers (mean + or - SD, 4.34 + or - 0.86). Ninety five percent Confidence Intervals for the difference in group mean global postsynaptic BP(ND) were -0.77 to 0.97. Analysis of regional BP(ND) did not reveal regional differences between patients and healthy controls. The number of subjects studied was limited and all subjects were on medication. In contrast to previous findings of reduced 5-HT(1A) receptor binding in untreated unipolar and bipolar depressed patients [Sargent, P.A., Kjaer, K.H., Bench, C.J., Rabiner, E.A., Messa, C., Meyer, J., Gunn, R.N., Grasby, P.M., Cowen, P.J., 2000. Brain serotonin1A receptor binding measured by positron emission tomography with [(11)C]WAY-100635: effects of depression and antidepressant treatment. Arch. Gen. Psychiatry 57, 174-180]; [Drevets, W.C., Frank, E., Price, J.C., Kupfer, D.J., Holt, D., Greer, P.J., Huang, Y., Gautier, C., Mathis, C., 1999. PET imaging of serotonin1A receptor binding in depression. Biol. Psychiatry 46, 1375-1387] and in recovered unipolar depressed patients [Bhagwagar, Z., Rabiner, E.A., Sargent, P.A., Grasby, P.M., Cowen, P.J., 2004. Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [(11)C]WAY-100635. Mol. Psychiatry 9, 386-92], this study found no difference in 5-HT(1A) receptor BP(ND) between medicated euthymic bipolar patients and healthy controls. Normal 5-HT(1A) receptor BP(ND) in these patients may be a result of drug treatment or could indicate that reduced 5-HT(1A) receptor binding is specific to the depressed state in bipolar patients.

Recent evidence suggests that neurodegeneration may be involved in the pathophysiology of major depression. The astroglial peptide S-100B was shown to be increased in many diseases causing neuronal cell damage or degeneration. S-100B plasma levels were determined in 28 patients with major depression and 28 matched healthy controls using an immunofluorometric sandwich assay. Patients suffering from melancholic depression showed significantly increased S-100B levels compared to healthy controls while non-melancholic patients demonstrated normal levels. Medication of patients varied. The differentiation between melancholic and non-melancholic patients was performed clinically without using a standardized instrument. Neurodegeneration or axonal remodeling may be involved in the pathogenesis of melancholic depression.

The aim of the present trial was to investigate the efficacy and safety of kava special extract WS 1490 in patients with sleep disturbances associated with anxiety, tension and restlessness states of non-psychotic origin. In a multicenter, randomized, double-blind clinical study, 61 patients received daily doses of 200 mg WS 1490 or placebo over a period of 4 weeks. Efficacy was measured by the sleep questionnaire SF-B, the Hamilton Anxiety Scale (HAMA), the Bf-S self-rating scale of well-being and the Clinical Global Impressions (CGI) scale. The confirmatory analysis of the two primary efficacy variables, the differences of sleep questionnaire SF-B sub-scores 'Quality of sleep' and 'Recuperative effect after sleep' after 4 weeks of double-blind treatment compared to baseline, demonstrated statistically significant group differences in favor of kava extract WS 1490 (P=0.007 and P=0.018, respectively). Superior effects of kava extract were also present in the HAMA psychic anxiety sub-score (P=0.002). More pronounced effects with respect to the self-rating of well-being and the global clinical evaluation also indicated superior therapeutic efficacy of kava extract. Safety and tolerability were good, with no drug-related adverse events or changes in clinical or laboratory parameters. We conclude that sleep disturbances associated with non-psychotic anxiety disorders can be effectively and safely treated with kava extract WS 1490.

First, the objective was to test the hypothesis that prefrontal cortical regions most often reported to be maximally abnormal in studies of major depressive disorder, correspond to those regions reported maximally active when healthy subjects engage in diverse emotional tasks. Second, the objective was to determine whether such regions are reported typically to be either over or under-active. Medline and Embase were used to search for neuroimaging studies of major depressive disorder from 1990 to 2005. Forty-two original studies using voxel based techniques were included, and compared with data from our previous meta-analysis on healthy subjects which included one hundred and eighty-one original studies [Steele, J.D., Lawrie, S.M., 2004b. Segregation of cognitive and emotional function in the prefrontal cortex: a stereotactic meta-analysis. Neuroimage 21, 868-875]. The medial prefrontal cortex is the region reported maximally abnormal most often when healthy subjects experience emotion. The region is centred on Broadmans Area (BA) 32 but extends into BA 25. Two further clusters of reported loci were identified in the lateral prefrontal cortex: one in the lateral orbitofrontal region reported active when healthy subjects experience emotion (BA 47); the other centred on a dorsolateral region (BA 46 and 9) associated with cognitive tasks. No reporting bias for overactivity or underactivity was identified. This study pooled data from diverse studies deliberately. There were insufficient numbers of original studies to support sub-group analyses. Despite the variability of reports in the literature, activity reported to be abnormal in depressive disorder is particularly localised to those brain regions that represent the substrate for normal emotional experience in healthy subjects.

The purpose of this study was to evaluate the reliability and psychometric properties of the Semistructured Affective Temperament Interview, and determine cut-offs for each temperament. 1010 Italian students aged between 14 and 26 were evaluated by means of the Akiskal and Mallya criteria in a Semistructured Interview for depressive, cyclothymic, hyperthymic, and irritable temperaments. This instrument has very good reliability and internal consistency. The percentage of subjects with a z-score higher than the second positive standard deviation ( + 2 SD) on the scales of depressive and cyclothymic temperaments are 3.6% and 6.3% (reaching scores of 7/7 and 9/10), respectively. Hyperthymic traits, on the other hand, are widespread in our sample: most subjects are included within the second positive standard deviation ( + 2 SD), and 8.2% of these reach a 7/7 score; therefore, the problem of defining a cut-off for this temperament is still open. By contrast, the irritable temperament is rare, conforming to a non-gaussian distribution, with 2.2% of cases above the second positive standard deviation ( + 2 SD). The data are based on subject report without collateral information and external validation. This study contributes to more accurate definition of cut-offs for individual temperament scales. The standardization of the interview thus makes it possible to compare three out of four temperamental scales, showing the dominant temperamental characteristics for each subject. Prospective studies are needed to demonstrate the stability of these traits over time.

In animals, a higher density of 5-HT1A receptors has been associated with increased behavioral despair after stress. In humans, the G variant of the C(-1019)G 5-HT1A receptor promoter gene polymorphism (rs6295) has been associated with higher expression of 5-HT1A receptors, increased depression, and lower stress preceding completed suicide. We studied the association of rs6295 with the amount of stress in early life and preceding hospitalization for a major depressive episode in course of bipolar disorder. In 74 consecutively admitted inpatients, early life and recent stressors were rated on the Social Readjustment Rating Scale and on the Risky Family Questionnaire. Homozygote carriers of the rs6295 G variant reported less stressful events before current hospitalization for bipolar depression, but not in early life. The G variant was also associated with a higher overall medication load in naturalistic settings before hospitalization. This is the first study that associated 5-HT1A receptor promoter gene variants with stressors preceding the need of hospitalization for bipolar depression. Our findings support the hypothesis that genetic factors affecting serotonergic neurotransmission might contribute to shape the individual resilience to the depressogenic effects of stress in clinical settings.

Substance dependence is common in bipolar disorder and is associated with an increase in Axis I and II comorbidity. Little research has compared the relative rates of comorbidity among bipolar patients with dependence on different substances. The Mini International Neuropsychiatric Interview (MINI) was used to assess 166 outpatients involved in one of three clinical trials of medications for bipolar disorder and substance dependence. Patients had concurrent alcohol dependence, cocaine dependence, or both conditions. Generalized anxiety disorder and current depressed mood were significantly more common in bipolar patients with alcohol dependence than bipolar patients with cocaine dependence. Those with cocaine dependence had significantly higher rates of post-traumatic stress disorder and antisocial personality disorder and were more likely to present in a mixed mood state than patients dependent on alcohol. Cocaine ENC dependent patients were more likely than alcohol dependent patients to have Bipolar I relative to Bipolar II. This is a retrospective, cross-sectional data analysis using the MINI for diagnosis. Cocaine dependence and alcohol dependence were associated with different clinical features and comorbid disorders in bipolar patients. The results may help confirm the validity of integrative models of mood, behavioral, anxiety, and personality disorders. Further studies on the causal relationship between substance dependence and concurrent and lifetime Axis I disorders for patients with bipolar disorders are indicated.

Patients with major depressive disorder (MDD) show suboptimal decision-making strategy in experimental game situations. The influence of personality traits and genetic variations on decision-making is not known. Contingency learning based on the cumulative effect of reward and punishment was assessed in 124 patients with unipolar MDD using the ABCD (reward sensitivity) and EFGH (punishment sensitivity) versions of the Iowa Gambling Test. All patients were genotyped for serotonin transporter promoter polymorphism (5-HTTLPR) and received the Temperament and Character Inventory (TCI). Patients with the ll genotype achieved higher persistence scores and used more optimal decision-making strategy on the ABCD task compared with patients with the ss genotype. Higher persistence was associated with better performance on the ABCD task, and higher harm-avoidance was associated with worse performance on the EFGH task. Healthy control volunteers were not included. Personality traits and decision-making were not assessed with multiple questionnaires and tasks. Type I errors cannot be excluded. Decision-making strategy is influenced by personality traits and genetic variations in patients with MDD. Patients carrying the ss variant of the 5-HTTLPR show less persistence and tend to be influenced by high immediate reward.

Bipolar disorder is characterized by fluctuating affect and mood, and is associated with specific neurocognitive deficits consistent with neuropathology in cerebello-striatal-prefrontal neural networks. This network is critical for emotion regulation. Relevant literature was located via PsychINFO and Medline to provide a comprehensive review of cognitive and neural mechanisms of social information processing and affect generation in bipolar disorder (BD) in the context of recent research examining the neural mechanisms of emotion regulation via conscious cognitive strategies. Emotion regulation relies on synergy within brainstem, limbic and cortical processes that promote the adaptive generation and regulation of affect, with prefrontal and cingulate regions inhibiting sub-cortical and cortical emotion processing systems in the cognitive control of emotional experience. Current evidence of structural and functional brain abnormalities in BD alongside aberrant social cognition, affect generation, and neuropsychological function are consistent with a model of emotion dysregulation to account for the symptoms of BD. A precise understanding of emotion dysregulation in BD is currently limited by a paucity of longitudinal research directly examining these issues. Aberrant emotion perception alongside increased limbic activity during emotion perception and affect generation in BD, alongside impaired executive control associated with aberrant neurophysiological abnormalities in sub-regions of the prefrontal cortex, is consistent with impaired emotion regulation. We propose a cognitive and neurophysiological framework within which the variations of mood that are characteristic of BD can be understood as specific impairments of the cognitive control of emotion.

Catechol-O-methyltransferase (COMT) inactivates catecholamines, and a G-A transition in the COMT gene (rs4680) influences the enzyme activity and the interaction between cortical and subcortical dopaminergic neurotransmission. Studies in healthy participants and in patients affected by schizophrenia suggested that rs4680 can influence the propensity to develop psychotic symptoms, with the Met low-activity allele exerting a protective role. Previous studies in bipolar patients reported non-significant trends in the same direction. We genotyped rs4680 in a sample of 467 patients affected by bipolar disorder type I with or without a previous illness episode with psychotic features (DSM-IV criteria: delusions or hallucinations). We observed a significant association between homozygosis for the rs4680 COMT low-activity variant and a reduced risk of experiencing illness episodes with psychotic features during the course of the illness. The Met/Met genotype was more common among patients without psychotic features, and while in the non-psychotic group the Val/Val genotype had a distribution similar to Met/Met, in the group of patients who experienced episodes with psychotic symptoms the proportion of Val/Val homozygotes was the double of Met/Met. We suggest that rs4680 could be an inheritable aspect of the mechanisms of dopamine regulation that could influence the individual susceptibility of patients with bipolar disorder to develop psychotic symptoms.

Catechol-O-methyltransferase (COMT) inactivates catecholamines, and a G-A transition in the COMT gene (rs4680) influences the enzyme activity and the interaction between cortical and subcortical dopaminergic neurotransmission. In patients affected by bipolar disorder rs4680 can influence antidepressant response and the propensity to develop psychotic symptoms, with the Met/Met genotype exerting a protective role. The same genotype could influence other dopamine-associated psychopathological features, such as mania. We genotyped rs4680 in a sample of 163 patients affected by bipolar disorder type I, and assessed the personal history of recurrence of the illness. We observed a significant association between homozygosis for the rs4680 COMT low-activity variant and a reduced recurrence of manic, but not depressive, episodes during the course of the illness. We suggest that rs4680 could be an inheritable aspect of the mechanisms of dopamine regulation that influence the individual susceptibility of patients with bipolar disorder to develop manic episodes of illness.

Catechol-O-methyltransferase (COMT) inactivates norepinephrine and dopamine via methyl conjugation, and a G-A transition in the COMT gene (rs4680) influences the enzyme activity. It is a current area of debate whether rs4680 can influence antidepressant response in major depressive disorder, and whether this influence extends to bipolar depression. Chronotherapeutic interventions, such as sleep deprivation and light therapy, are multi-target in nature and are effective in bipolar depression. Here we studied the effect of rs4680 on response to sleep deprivation combined with light therapy (36 h awake followed by a night of undisturbed sleep, with 10,000 lx light administered for 30 min during the night awake and upon awakening) in 87 bipolar depressed inpatients. Patients who were homozygotic for the Val/Val variant showed a significantly less efficient antidepressant effect after the night awake than those who were heterozygotic and homozygotic for the Met variant. This effect of rs4680 is similar to its observed influence on response to serotonergic and noradrenergic drug treatments in major depressive disorder. This is the first study reporting an influence of rs4680 on antidepressant response in bipolar depression. This finding supports the hypothesis of a major role for catecholamines in the mechanism of action of chronotherapeutics, and for rs4680 in modulating this effect.

Depression has been associated with decreased blood BDNF concentrations; but it is unclear if low blood BDNF levels are a state or a trait marker of depression. We investigated blood BDNF concentrations in a twin population including both subjects highly predisposed and protected against affective disorder. Whole blood assessed for BDNF concentrations and correlated to risk status, neuroticism, and number of stressful life events. Between the groups, we found no significant difference in whole blood BDNF levels. Women at high-risk for depression who had experienced three or more recent stressful events (n=26) had decreased whole blood BDNF levels compared to high-risk women with two or less recent stressful events (n=35), 21.6+/-7.0 vs. 18.5+/-4.1 ng/ml, respectively, (p<0.05). No such association was found in low-risk women or in men. In men, however, low neuroticism scores and two or less recent stressful events were associated with decreased whole blood BDNF levels (n=50, p<0.05). The cross-sectional design limits the possibility of drawing firm conclusions on causatility of the findings. The genetic risk of developing depression does not translate directly into whole blood BDNF levels. In females who are genetically disposed for depression and subjected to recent stressful life events whole blood BDNF levels are lower.

As only a few studies so far systematically reported on bipolar patients subtyped according to first-episode polarity, we took the opportunity of having at disposal a large sample of bipolar I patients to specify the characteristics of patients included in these subtypes, with a special focus on temperament and triggering events. A total of 1089 consecutive DSM-IV bipolar I manic inpatients were subtyped in manic onset (MO), depressive onset (DO) and mixed onset (MXO), and assessed for demographic, illness course, clinical, psychometric, comorbidity and temperament characteristics. The main characteristics of MO patients were a hyperthymic temperamental predisposition, a first episode triggered by substance abuse and an illness course with pure, severe and psychotic mania. In comparison, DO patients had more depressive temperaments, a first episode triggered by stress and alcohol, an illness course with more episodes, cyclicity, suicide attempts, anxious comorbidity and residual symptoms. Although sharing characteristics with either MO or DO, MXO patients had more mixed episodes and cyclothymic temperament. The following are the limitations of this study: retrospective design, bias toward preferential enrolment of MO patients, and lack of information on the number and polarity of lifetime episodes. Findings from this study tend to confirm most of the differences previously evidenced among patients subtyped according to first-episode polarity. Differences found in temperamental predisposition and illness onset triggering events are worth noting and may help target early preventive interventions as well as orientate the search for specific genetic risk factors.

This article attempts to summarize the current status of our knowledge and practice in the acute treatment and prophylaxis of bipolar depression. For prophylactic treatment, our knowledge about lithium firmly supports its usefulness against bipolar depression and its specific effectiveness for suicidal prevention. Valproic acid and carbamazepine could be effective, too, while lamotrigine which seems to be preferably effective against depression but not mania. The FDA has approved the olanzapine-fluoxetine combination and quetiapine monotherapy for the treatment of acute bipolar depression. The usefulness of antidepressants in bipolar depression is controversial both for acute and prophylactic treatment; guidelines suggest their cautious use and always in combination with an antimanic and mood stabilizer agent, because in some patients they may induce switching to mania or hypomania, mixed episodes and rapid cycling. Data on psychosocial intervention are restricted to the maintenance phase. Electroconvulsive therapy and transcranial magnetic stimulation are additional options for refractory patients. Bipolar depression seems to be a more difficult condition to treat than mania. Most patients need complex combination treatment although the published evidence on this type of treatment is limited.

Recognition by the DSM-IV of rapid cyclicity as a course specifier has raised the question of the stability and long-term outcome of rapid-cycling (RC) patients. Data on this topic is sparse and often inconsistent. To our knowledge, these are the first personally followed patients over the long term, dealing directly with the issue of the duration of the RC course. We examined the evolution of the course of 109 RC patients (68 women and 41 men) followed for a minimum of 2 years and up to 36 years, beginning with the index episode when the RC course was diagnosed by the authors (A.K., G.P.M., P.G., L.P., D.R.). Patients were included in the study if they met criteria for RC as defined by>or=4 affective episodes per year (Dunner and Fieve, 1974). The follow-up period varied from 2-5 years for 25 patients, 6-10 years for 24 patients, 11-15 years for 24 patients, 16-20 years for 19 patients, 21-25 years for 13 patients, 30-36 years for four patients. In 13 patients (12%), RC emerged spontaneously and in 96 patients (88%), it was associated with antidepressant and other treatments. In 19 women (28% of all women) RC course started in perimenopausal age (45-54 years). The mean duration of RC during the follow-up period was 7.86 years (range 1-32) and its total duration (including RC course prior to the follow-up period) was 11 years (range 1-40). The total duration of the affective disorder, from the first episode to the end of the follow-up, was 21.78 years (range 1-70). At the end of the follow-up, 36 patients (33%) had complete remission for at least the past year, 44 (40%) stayed rapid cycling with severe episodes (six of this group committed suicide), while 15 (14%) were rapid cycling but with attenuated episodes. The other 14 patients (13%) became long cyclers, eight with severe episodes and six with milder ones. The main distinguishing features between those who remitted from and those who persisted in the RC course were: (1). the initial cycle pattern: patients with Depression-Hypomania(mania)-Free interval cycles (53 patients) had a worse outcome: 26.4% remitted and 52.8% persisted in the RC course through to the end of the follow up period. The Mania/Hypomania-Depression-Free interval cycles (22 patients) had a significantly better outcome, with 50% remitted and 27.2% persisting RC; and (2). the occurrence of the switch process from depression to hypomania/mania and the occurrence of agitated depressions made the prognosis worse. Continuous treatment was more effective against mania/hypomania than against depression, yet in all persisting RC cases the mania/hypomania remitted only partially. These data derive from clinics known for their expertise in mood disorders, and they may have attracted and retained patients with a more severe course. Treatment was uncontrolled and consisted more of lithium than divalproex, lamotrigene and olanzapine, recently shown to be beneficial in subgroups of patients with rapid-cycling. Our findings suggest that rapid cyclicity, spontaneous or induced, once established, becomes for many years a stable rhythm in a substantial proportion of patients, linked to endogenous and environmental factors. The suggestion is made to consider as rapid-cyclers, at least for research purposes, those patients who have had a rapid cycling course for at least 2 years, borrowing the duration criterion currently employed for other chronic disorders such as Dysthymia and Cyclothymia. That our patients had poorer prognosis than some other cohorts in the literature is probably due to the shorter duration of "rapid-cycling" at entry in the latter cohorts. A true understanding of the nature of rapid-cycling will require a rigorous definition of not only duration, but also pole-switching and course patterns at entry into study.

Several studies indicate a specific relationship between bipolar disorder and stimulant use and abuse. It has generally been assumed that cocaine use represents self-enhancement or attempts to optimize one's level of hypomania, cyclothymia or hyperthymia. This topic required further examination among heroin abusers because cocaine abuse is commonly comorbid with heroin abuse. Cocaine abuse by bipolar subjects was investigated in a group of 1090 treatment-seeking heroin addicts enrolled between 1994 and 2005. We collected data with 1) the Drug Addiction History Rating Scale; and 2) the Semi-structured Interview for Depression, which inquires systematically among others, about hypomania, cyclothymia, hyperthymia and depressive temperament. Subjects were aged 29+/-6 years, and predominantly male (76.2%). Univariate and multivariate analyses provided correlations in favour of a link between current cocaine abuse and double diagnosis, with special relevance to the bipolar spectrum, as well as psychotic disorders (p<0.0001). The modality of access to cocaine in different communities and the difficulty to distinguish cocaine use from abuse by the rating scale administered may have limited the interpretation of results. If cocaine abuse precedes that of heroin or is concomitant, heroin may hypothetically serve as a "mood balancer" which transiently dampens subthreshold excitatory states and mood swings. Our data further suggest the need for a more complex model linking cocaine and bipolarity: subthreshold bipolarity, including hyperthymic and cyclothymic temperaments, seems to predispose to heroin addiction, but craving for the suppressed hypomania in turn could lead to cocaine abuse, which eventually unmasks a frank bipolar disorder - in some cases leading to mixed state, severe mania, as well as psychosis beyond mania. Prospective observations would shed further insight on this complex interface of major clinical and public health importance.

Background: Despite extensive research recently focused on mixed mania, it is uncertain as how best to define it clinically, psychometrically (which has major bearing on its prevalence), and the methodology needed for future research. This topic is also of historical interest, because Magnan (1890) [Magnan, V., 1890. La Folie Intermittente. G Masson, Paris.] suggested that "combined [mixed] states" linked Falret's "circular insanity" with Baillarger's "dual insanity" (both described in 1854). This work eventually led to the Kraepelinian synthesis of all manic, mixed, and depressive states into the unitary rubric of "manic-depressive insanity (1899/1921). Method: EPIMAN-II Thousand" (EPIMAN-II MILLE) is a French national collaborative study, which involved training 317 psychiatrists working in different sites representative of psychiatric practice in France. We recruited 1090 patients hospitalized for acute DSM-IV mania. assessed at index admission by the following measures: the Mania Rating Scale (MRS), the Beigel-Murphy Scale (MSRS), a newly derived checklist of depressive symptoms least contaminated by mania, MADRS for severity of depression, and the SAPS for psychotic features. Results: The rate of mixed mania, as defined by at least 2 depressive symptoms, was 30%. Even with this broad definition, we found significantly higher female representation. This clinical sub-type of mania was characterized by high frequency of past diagnostic errors, particularly those of anxiety and personality disorders. Refined definition of co-exiting depression was obtained from an abbreviated version of the MADRS (6 items), with distinct "emotional-cognitive" symptoms, and "psychomotor inhibition" factors, both of which were separable from an "irritable" factor linked to lability and poor judgment. Mixed mania was psychometrically best identified by a MADRS score of 6 (80% sensitivity, 94% specificity) and validated by a mixed polarity of first episodes, a higher rate of recurrence, psychotic features, and suicide attempts. Limitation: Cross-sectional study. Conclusions: The data deriving from EPIMAN, the largest and only national study ever conducted on mania, provide definitive characterization of the clinical and psychotic structure of mixed mania, which accounts for 1 out of 3 patients who present with mania. This figure is more accurate than higher rates reported in the literature because, in describing "mixity", we eliminated depressive features that could be contaminated by mania. Despite the prominent affective features described herein, the bipolar nature of mixed mania is often missed, with the result that these patients are diagnosed as having anxiety and/or personality disorders. It is of great public health significance for psychiatrists to recognize the bipolar nature of this condition that has been known as a major phase of manic-depressive illness since at least Magnan, a disciple of Falret and Baillarger.

Although included in successive editions of the DSM since its introduction in the IIIrd, the subtyping of manic episode into 'with mood-congruent (MCP) versus mood-incongruent (MIP) psychotic features' is yet to be fully validated. One thousand and ninety consecutive manic patients were recruited at 19 medical centers in France from December 2000 to April 2002. Patients were systematically assessed for sociodemographic characteristics, illness course, phenomenology and had to fill out biphasic mood charts during the first study week. Five hundred forty-four manic patients were psychotic, 364 (33.4%) being MCP, 180 (16.5%) MIP. Although both groups scored high on the Mania Rating Scale, MIP patients had significantly more often been diagnosed as schizophrenic, or anxiety disorders, with long delays to first diagnosis as bipolar disorder. MIP were also significantly different in a variety of domains: 2:1 female/male ratio; shorter free intervals between episodes; more auditory hallucinations, reference, persecutory and somatic delusions; more stressors; more anger; higher depression scores and diurnal variation of mood, as well as anxious symptoms and hyperemotionality upon improvement. MCP and MIP manias occurred in nearly half of this largest sample of manic patients ever reported. As postulated 150 years ago by Falret and Baillarger in France, free intervals, characterize both forms of circular insanity. Both are prevalent and severe remitting forms of mania, but the latter differs from the former by much shorter free intervals, greater instability of mood and mixed anxious-depressive features. This is compatible with the Vienna School hypothesis that dysphoric instability of the patient may induce emotional reactions in significant others, which, in turn, might lead to extremely paranoid and psychotic symptom formation of the MIP type in manic patients. From a phenomenologic perspective--arising understandably from emotional processes-these considerations would place MIP mania more in the circular affective rather than in the schizophrenic domain.

Some see current views of mental illness, such as depression, as merely contemporary social constructions, with madness seen as a modernist break from medieval and ancient concepts. In contrast to these assumptions, here we describe one of the earliest texts on melancholia and mania, by Ibn Imran, an Arab physician of the 10th century.

While considerable research exists on the role of physical illness in initiating depressive reactions, the role of depression in the onset of physical illness is much less studied. Moreover, whereas almost all previous research on depression and incident physical illness has involved specific physical illnesses, the present study examines the link between depression and incident physical illness more generally. The study followed 388 clinically depressed patients who were entering treatment for unipolar depressive disorders and 404 matched community controls across 10 years. In self-report surveys, sociodemographic and health behavior data were indexed at baseline and physician-diagnosed medical conditions were indexed at baseline and at 1, 4, and 10 years during the follow-up period. After accounting for prior physical illness and key demographic and health behavior factors, membership in the depressed group was significantly linked to physical illness during the follow-up period. In these prospective analyses, depressed patients showed an almost two-thirds higher likelihood of experiencing physical illness during the follow-up period compared to community controls. The prospective association between depression and subsequent physical illness was evident for both less serious and more serious physical illness. Although participants were asked to report only physician-diagnosed conditions, the association between depression and physical illness may have been due to depressed individuals perceiving themselves as more ill than they were. The World Health Organization has included the co-morbidity between depression and chronic physical illness among its ten concerns in global public health. The current findings broaden the growing awareness of the co-morbidity between depression and physical illness to encompass a vulnerability of depressed individuals to physical illness more generally.

Reduced dopaminergic function may occur in depressive disorders. In this paper the results of two pilot studies examining different aspects of the dopamine system in depression are presented. First, the binding of [(11)C]FLB 457 to extrastriatal D(2) receptors was measured in a group of depressed patients. Second, the hypothesis that selective serotonin reuptake inhibiting (SSRI) antidepressants affect the striatal binding of [(11)C]raclopride was tested. In the first study the binding of [(11)C]FLB 457 was compared between 7 people with depression and 7 healthy controls. In the second study the binding of [(11)C]raclopride to striatal D(2/3) receptors was compared between 8 people taking SSRI antidepressant medication and 8 healthy controls. There was no difference in the binding of [(11)C]FLB 457 between the two groups. [(11)C]raclopride binding was reduced in the dorsal striatum of people taking antidepressants suggesting either that D(2/3) expression was reduced, or that dopamine release was increased, compared to untreated controls. The depressed patients were not severely depressed and were not matched for gender with controls. In the raclopride group the patients and controls were not matched by gender and were taking different SSRI antidepressants. We found no support for the hypothesis that dopamine D(2) receptor expression is altered in extrastriatal brain regions in depression. SSRI antidepressants were associated with reduced [(11)C]raclopride binding in the dorsal striatum supporting the hypothesis that therapeutic effects of such drugs may, in part, be due to changes in the dopamine system.

The relationship between bipolar disorder and chromosome 11 markers remains uncertain. Whilst re-analysis of the Amish pedigree weakened previous evidence for close linkage (but could not exclude the possibility of genetic heterogeneity), a recent French study has found a significant association between this condition and tyrosine hydroxylase polymorphisms. We aimed to determine if bipolar disorder in two large Australian pedigrees (of Irish and English extraction respectively) was linked to these markers. Of the 84 family members available for testing, nine were diagnosed as bipolar I, one as bipolar II and six had recurrent unipolar depression. Linkage of bipolar disorder and recurrent depression to the chromosome 11p15 markers c-Harvey ras, insulin and tyrosine hydroxylase was tested using a series of genetic models with varying penetrance levels. Additionally, linkage was examined using a series of levels of definitions of affective status (ranging from bipolar I alone to all affective illnesses). Close linkage to these markers was strongly excluded using each model and definition. The findings also persisted when a wide range of rates of 'sporadic' (non-genetic) presentations of illness were incorporated in the analysis. These results are consistent with other recent studies indicating that bipolar disorder is not linked to chromosomal region 11p15.

The aim of the present study was to obtain comprehensive information on steroid metabolism in depressed patients. 24-h urinary steroids were measured by gas chromatography in patients with unipolar recurrent major depression (URMD) compared to controls, and an index of relative activity of the 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzyme was calculated. The levels of etiocholanolone (E) (p < 0.05), beta-cortolone (beta-CL) (p < 0.01) were significantly decreased, while levels of allo-tetrahydrocorticosterone (aTHB) (p < 0.05) and cortisol (F) (p < 0.01) were elevated in depressed women. The levels of dehydroepiandrosterone (DHEA) (p < 0.01), tetrahydrocorticosterone (THB) (p < 0.01), beta-CL (p < 0.01), and aTHB (p < 0.05) were found significantly decreased in depressed men. The index of 11beta-HSD activity (p < 0.01) was significantly decreased in patients in both sexes. The sample is limited to only urine samples of patient with URMD; the correlation between the severity of depression and F and DHEA was not analyzed. Our investigations confirmed that URMD associated with altered steroid metabolism, which shows gender differences, pointing to the different stress sensibility of women. These differences may be the cause as well as the consequence of the major depression (MD).

Recently, it was hypothesized that acute or cumulative suppression of non-REM sleep intensity might be related to the therapeutic effects of antidepressants. This intensity has been proposed to be expressed in the EEG power density in non-REM sleep. In the present study, the relationship was examined between the changes of EEG power density in non-REM sleep and the changes in clinical state in 8 depressed patients during treatment with trazodone. A 1-week wash-out period was followed by 1 week of placebo administration, a medication period of 5 weeks and a 1-week placebo period. To minimize systematic influences of sleep duration and non-REM-REM sleep alterations, EEG power was measured over the longest common amount of non-REM sleep stages 2-4 (168.5 min), accumulated from sleep onset onwards. During trazodone treatment, the 13- and 14-Hz bins showed a significant reduction in EEG power. No clear-cut change, however, was observed in the EEG power of the delta frequency range (1-4 Hz) which is considered to be the principle manifestation of non-REM sleep intensity. Furthermore, no overall significant relationship between EEG power suppression and clinical improvement could be demonstrated.

Late-life depression is associated with white matter hyperintense lesions (WMLs) occurring in specific fiber tracts. In this study, we sought to determine if greater WML severity in the cingulum bundle or uncinate fasciculus was associated with poor short-term antidepressant response. Eleven depressed elders completed a baseline cranial 3T MRI and received antidepressant treatment following a medication algorithm. MRIs were analyzed to measure the fraction of each fiber tract׳s volume occupied by WMLs. Statistical analyses examined the effect of dichotomized fiber tract WML severity on three- and six-month depression severity after controlling for age and baseline depression severity. Greater WML severity in the left hemispheric cingulum bundle adjacent to the hippocampus was associated with greater post-treatment depression severity at three- (F1,7=6.42, p=0.0390) and six-month assessments (F1,5=9.62, p=0.0268). Other fiber tract WML measures were not significantly associated with outcomes. The study had a small sample size and analyses were limited to only a priori fiber tracts. This pilot study supports the hypothesis that focal damage to the cingulum bundle may contribute to poor short-term antidepressant response. These findings warrant further investigation with a larger, more definitive study.

Mixed affective episode is a prevalent mood disorder characterized by the coexistence or rapid alternation of manic and depressive symptoms, which is associated with significant suffering and high risk of suicide. Unfortunately, the current diagnostic classification of mixed affective episodes in the ICD-10 lacks a detailed definition with relevant subtypes. This inconsistency has significant negative implications for both research into the disorders in the bipolar spectrum and for clinical practice. For this reason there is a need for special attention on this diagnosis in the revisions of the diagnostic manuals. In this manuscript we suggest a set of clear diagnostic criteria and exhaustive subtypes for the mixed affective episodes aimed at the upcoming ICD-11. The defined syndrome and its subtypes are in close congruence with the suggested DSM-5 "mixed episode specifier", which is an advantage for common understanding and for research across the ICD/DSM border.

While several studies have suggested that bipolar disorder may elevate risk of cardiovascular disease, few studies have examined the relationship between mania or hypomania and cardiovascular disease. The purpose of this study is to examine history of manic and hypomanic episodes as an independent risk factor for cardiovascular disease (CVD) during an 11.5 year follow-up of the Baltimore Epidemiologic Catchment Area Follow-up Study. All participants were psychiatrically assessed face-to-face based on Diagnostic Interview Schedule in 1981 and 1982 and were categorized as having either history of manic or hypomanic episode (MHE; n=58), major depressive episode only (MDE; n=71) or no mood episode (NME; n=1339). Incident cardiovascular disease (CVD; n=67) was determined by self-report of either myocardial infarction (MI) or congestive heart failure (CHF) in 1993-6. Compared with NME subjects, the odds ratio for incident CVD among MHE subjects was 2.97 (95% confidence interval: 1.40, 6.34) after adjusting for putative risk factors. These data suggest that a history of MHE increase the risk of incident CVD among community residents. Recognition of manic symptoms and addressing related CVD risk factors could have long term preventative implications in the development of cardiovascular disease in the community.

Serotonin function has been implicated in both major depressive disorder and neuroticism. In the current investigation, we examined the hypothesis that any change in depression severity is mediated through the reduction of neuroticism, but only for those compounds which target serotonin receptors. Ninety-three outpatients in the midst of a major depressive episode received one of three antidepressant medications, classified into two broad types: selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs (i.e. reversible monoamine oxidase inhibitors [RIMAs] and noradrenergic and dopaminergic reuptake blockers [NDMs]). Patients completed the Hamilton Rating Scale for Depression, Beck Depression Inventory II and Revised NEO Personality Inventory prior to and following approximately 16 weeks of treatment. Structural equation modeling was used to test two models: a mediation model, in which neuroticism change is the mechanism by which SSRIs exert a therapeutic effect upon depressive symptoms, and a complication model, in which neuroticism change is a mere epiphenomenon of depression reduction in response to SSRIs. The mediation model provided a good fit to the data; the complication model did not. Patients treated with SSRIs demonstrated greater neuroticism change than those treated with non-SSRIs, and greater neuroticism change was associated with greater depressive symptom change. These effects held for both self-reported and clinician-rated depressive symptom severity. Replication within a randomized control trial with multiple assessment periods is required. Neuroticism mediates changes in depression in response to treatment with SSRIs, such that any treatment effect of SSRIs occurs through neuroticism reduction.

A lower thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in depressed women has been associated with violent suicide attempts, suicidal intent, higher lethality and suicide risk. The cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) levels are related to suicidal behaviour. We studied the HPT axis function in twelve male suicide attempters and eight healthy volunteers submitted to lumbar puncture and to TRH test. Suicidal behaviour and depression severity were assessed. There was no association between deltamaxTSH and violent suicidality or subsequent suicide. The deltamaxTSH correlated with CSF HVA in suicide attempters. The plasma T3 showed a negative correlation with the Beck Suicide Intent Scale and the Montgomery Asberg Depression rating scale. Dopaminergic regulatory mechanisms on the thyroid hormone activity may be altered in male suicide attempters.

This paper reviews evidence from both human and non-human primate studies concerning the role of early adverse experiences in the onset and course of adult depressive disorders. Despite accumulating evidence that stressful life events can play a major role in precipitating the onset of depressive episodes in humans, the mechanisms by which early experiences mediate and moderate the risk for later affective illnesses are not fully understood. Experimental paradigms in primates have documented the important role of undeveloped (social deprivation) or disrupted attachment systems (social separation). Effects of early social deprivation can be seen in many domains. Behavioral effects include repetitive idiosyncratic behaviors, increased self-directed behaviors, inappropriate expression of aggressive behaviors, non-modulated patterns of consumption, and inappropriate sexual and maternal behaviors. Cognitively, such animals require longer habituation time for any task and demonstrate increased perseverance on tasks following non-reward. Physiological effects include an altered hypothalamic-pituitary-adrenal response to stress, changes in diurnal temperature regulation, and alterations in immune function. Neurochemical effects include abnormalities in noradrenergic, serotonergic, and dopaminergic systems. Even neuroanatomical changes following early social deprivation have been reported. Studies with primates have also confirmed that early maternal and peer separations are major behavioral and neurobiological events with both short- and long-term consequences that parallel human depression. Future utilization of experimental paradigms in non-human primates may assist in better understanding the role of early experiences in predisposing to the development of affective illnesses in humans. This review concludes by presenting a model for understanding a developmentally based vulnerability to adult depressions.

Unipolar major depressive disorder (MDD) is characterized by aberrant amygdala responses to sad stimuli and poor cognitive control, but the interactive effects of these impairments are poorly understood. To evaluate brain activation in MDD in response to cognitive control stimuli embedded within sad and neutral contexts. Fourteen adults with MDD and fifteen matched controls participated in a mixed block/event-related functional magnetic resonance imaging (fMRI) task that presented oddball target stimuli embedded within blocks of sad or neutral images. Target events activated similar prefrontal brain regions in both groups. However, responses to target events embedded within blocks of emotional images revealed a clear group dissociation. During neutral blocks, the control group demonstrated greater activation to targets in the midfrontal gyrus and anterior cingulate relative to the MDD group, replicating previous findings of prefrontal hypo-activation in MDD samples to cognitive control stimuli. However, during sad blocks, the MDD group demonstrated greater activation in a number of prefrontal regions, including the mid-, inferior, and orbito-frontal gyri and the anterior cingulate, suggesting that relatively more prefrontal brain activation was required to disengage from the sad images to respond to the target events. A larger sample size would have provided greater statistical power, and more standardized stimuli would have increased external validity. This double dissociation of prefrontal responses to target events embedded within neutral and sad context suggests that MDD impacts not only responses to affective events, but extends to other cognitive processes carried out in the context of affective engagement. This implies that emotional reactivity to sad events in MDD may impact functioning more broadly than previously understood.

A double blind comparative study of amitriptyline and a new reversible MAO A inhibitor R011-1163 was conducted in 25 depressed inpatients over 4 weeks. Response to treatment was assessed with the Hamilton depression rating scale, the Carroll depression self rating scale and the Visual analogue scale. Both drugs produced significant changes in depressive symptomatology (P less than 0.01, MANOVA) and there were no statistically significant differences between drugs (P greater than 0.05 MANOVA). Side effects were of mild to moderate severity with dry mouth the most commonly reported side effect of amitriptyline and vague, generalised headache in patients, treated with R011-1163.

Background In 2001, the Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments (CANMAT) partnered to produce evidence-based clinical guidelines for the treatment of depressive disorders. A revision of these guidelines was undertaken by CANMAT in 2008–2009 to reflect advances in the field. There is widespread interest in complementary and alternative medicine (CAM) therapies in the treatment of major depressive disorder (MDD).

While there is evidence to suggest that major depressive disorder (MDD) is associated with structural brain abnormalities, the precise nature of these abnormalities remains unclear. To review recent structural magnetic resonance imaging (MRI) research findings in MDD while considering the potential influence of key clinical and demographic variables. A selective review of all T1-weighted structural MRI studies published between 2000 and 2007 in adult samples of MDD patients. Volumetric reductions of the hippocampus, basal ganglia and OFC and SGPFC are consistently found in MDD patients, with more persistent forms of MDD (e.g., multiple episodes or repeated relapses, longer illness duration) being associated with greater impact on regional brain volumes. Gender, medication, stage of illness, and family history all affect the nature of the findings in a regionally specific manner. Overall, differences between the samples in factors such as illness severity, medication, gender and family history of mental illness makes difficult to identify their confounding effects on the observed neuroanatomical changes. Also, the tracing protocols used for particular brain regions were different amongst the reviewed studies, making difficult to compare their findings. The data support the notion that MDD involves pathological alterations of limbic and cortical structures, and that they are generally more apparent in patients with more severe or persistent forms of the illness.

Several studies have demonstrated that repetitive transcranial magnetic stimulation (rTMS) elicits moderate antidepressant effects. Several previous studies suggested that the dopaminergic system might be related to this therapeutic action of rTMS. We attempted to determine the effects of chronic rTMS on central dopaminergic function in depression using positron emission tomography (PET) with [11C]raclopride. Nine patients with depression were treated with 10 daily sessions of rTMS (10 Hz, 5 s train, 20 trains at 100% motor threshold per session) over the left dorsolateral prefrontal cortex (DLPFC). Each patient underwent two [11C]raclopride PET scans and neuropsychological tests - before rTMS and 1 day after rTMS. In five patients, the Hamilton Rating Scale for Depression (HRSD) significantly decreased. Patients showed significant improvement in verbal memory following rTMS. There were no changes in [11C]raclopride binding in the caudate nucleus and putamen after rTMS treatment. Our sample size was limited, and our study was an open trial lacking sham-treated controls. This study suggests that rTMS may be effective for the treatment of depression and also may improve verbal memory function. We observed no changes in [11C]raclopride binding, suggesting that there was no measurable increase in the release of dopamine at the second PET scan. Several animal studies and healthy human studies have indicated that dopamine can be released soon after acute rTMS. Our results suggest that release of striatal dopamine induced by rTMS may be only transient, or that dopamine release may be attenuated following chronic rTMS.

Alterations in the brain serotonin (5-HT) system have been found in patients with depression. We used the selective 5-HT transporter site ligand [11C](+)McN5652 and positron emission tomography (PET) to examine the hypothesis that alterations in 5-HT transporter levels may be present in selected regions of the brain in depressed patients. Four drug free depressed patients and four healthy control subjects were studied using [11C](+)McN5652 and PET. The distribution volume (DV) ratio of the PET ligand in selected regions of interest (ROIs) compared to cerebellum were calculated for the ROIs. Patients showed significantly larger DV ratios in the left frontal cortex (P=0.013) and right cingulate cortex (P=0.043) compared to control subjects. The sample size was modest with gender differences between the subject groups. The PET agent, [11C](+)McN5652, may have a lower binding affinity for the 5-HT transporter in the cortical regions compared to other brain regions. These findings suggest that 5-HT transporter sites may be increased in the frontal and cingulate cortices of depressed patients. These alterations in 5-HT transporter sites may be of pathophysiologic significance in the etiology of depression and its treatment.

Prolonged Grief Disorder (PGD) is a new diagnosis proposed for inclusion in the DSM-V. Although some studies have shown the distinctiveness of PGD and posttraumatic stress disorder (PTSD), this relationship has yet to be tested within a context of sudden, violent loss. We conducted an exploratory factor analysis (EFA) using self-report data collected from a sample of 587 bereaved adults who lost friends and relatives in the attacks of September 11th. Participants completed a 9-item PGD screening measure and the 17-item PTSD Checklist. A five factor solution representing two distinct constructs emerged from our analysis. Although two PGD items loaded onto factors containing PTSD symptoms, these items assessed non-specific symptomatology (i.e., generalized negative affect). Thus, overall, our results support the distinctiveness of PGD and PTSD within a context of sudden, violent loss. Data were collected using self-report. The representativeness of our sample is uncertain. These findings provide a stringent test of construct validity and suggest that PGD warrants inclusion in the diagnostic nosology. Adding PGD to the DSM-V will help clinicians better assess and treat psychopathology resulting from grief.

Previous follow-up studies indicate that increased visual cortical, ventral cingulate and subcortical responses of depressed individuals to sad facial stimuli, but not happy stimuli could represent reversible markers of disease severity. We hypothesized that greater responses in these areas to sad stimuli, but not happy stimuli, would predict better subsequent clinical outcome. We also explored areas that would predict a poor outcome. Twelve melancholically depressed individuals in the early stages of antidepressant treatment in a secondary care setting participated in two experiments comparing responses to varying intensities of sad and happy facial stimuli, respectively, using event related functional MRI. They repeated the experiments after a mean delay of 12 weeks of treatment. There was a variation in response to treatment. Greater right visual cortex and right subgenual cingulate (R-BA25) responses to sad stimuli, but not happy stimuli, in the early stages of treatment were associated with a good clinical outcome. Greater ventrolateral prefrontal cortex responses to either stimulus type were associated with a relatively poor outcome. The sample size was modest and patients were taking a variety of antidepressants. Right subgenual cingulate and right visual cortical responses to sad stimuli predict good clinical outcome in the context of antidepressant treatment for severe depression in a naturalistic setting. Ventrolateral prefrontal cortex activity may indicate poor prognosis due to its relationship with negative rumination.