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Mixed depression (MXD), defined as (hypo)manic symptoms occurring within major depressive episodes, is common in both bipolar and unipolar disorders, but its prognostic and treatment implications remain unclear. This study aimed to examine the relationship between hypomanic symptoms, treatment response and remission of suicidal thoughts. We analyzed 1243 adults with major depressive disorder (MDD), recruited for a naturalistic study on treatment-resistant depression. Data were gathered cross-sectionally and retrospectively through structured interviews and clinical rating scales including the Young Mania Rating Scale (YMRS) and Montgomery-Asberg Depression Rating Scale (MADRS); statistical analyses were performed using univariate and multivariate methods. Hypomanic symptoms were present in 651 patients (45 %), while 307 patients (25 %) responded to treatment. Both treatment responders (p < 0.0001) and those who achieved remission from suicide ideation (p = 0.0085) showed lower hypomanic (YMRS) scores. Multivariate analysis showed that hypomanic symptoms were negatively linked to treatment response (O.R. 0.71–0.87), while bipolar spectrum markers such as age at illness onset (O.R. 1.00–1.03) and MDD recurrence (O.R. 0.47–0.89) predicted remission from suicidal thoughts. Medications commonly used to treat bipolar disorder showed some benefits, with dopamine/serotonin antagonists improving suicide ideation (p < 0.0001) and mood stabilizers being associated with reduced hypomanic symptoms (p = 0.0003). The study lacked prospective clinical assessments and treatment randomization. Hypomanic symptoms are common in unipolar depression; their assessment is essential to identify challenging-to-treat cases and select the best pharmacological options. • Hypomanic symptoms are quite common in unipolar depression • Depression with hypomanic features is associated with treatment resistant depression • Depression with hypomanic features is associated with a reduced remission of suicidal thoughts • The concomitant use of mood stabilizers in depression with hypomanic features is only marginally useful [ABSTRACT FROM AUTHOR]

Introduction: Suicidal behaviour (SB) has a complex aetiology. Although suicidal ideation (SI) is considered the most important risk factor for future attempts, many people who engage in SB do not report it. Methods: We investigated neurological, metabolic, and psychopathological correlates of lifetime SB in two independent groups of patients with major depression (sample 1: n = 230; age: 18–65 years; sample 2: n = 258; age >60 years) who did not report SI during an index episode. Results: Among adults (sample 1), SB was reported by 141 subjects (58.7%) and severe SB by 33 (15%). After controlling for interactions, four risk factors for SB emerged: male gender (OR 2.55; 95% CI: 1.06–6.12), negative self-perception (OR 1.76; 95% CI: 1.08–2.87), subthreshold hypomania (OR 4.50; 95% CI: 1.57–12.85), and sexual abuse (OR 3.09; 95% CI: 1.28–7.48). The presence of at least two of these factors had the best accuracy in predicting SB: sensitivity = 57.6% (39.2–74.5); specificity = 75.1% (68.5–82.0); PPV = 27.9% (20.9–37.2); NPV = 91.4% (87.6–94.1). In older patients (sample 2), 23 subjects (9%) reported previous suicide attempts, which were characterized by earlier onset (25 years: OR 0.95: 0.92–0.98), impaired verbal performance (verbal fluency: OR 0.95: 0.89–0.99), higher HDL cholesterol levels (OR 1.04: 1.00–1.07) and more dyskinesias (OR 2.86: 1.22–6.70). Conclusion: Our findings suggest that SB is common in major depressive disorder, even when SI is not reported. In these individuals it is feasible and recommended to investigate both psychiatric and organic risk factors. The predictive power of models excluding SI is comparable to that of models including SI. Plain Language Summary: Although thinking of suicide for some period of time (suicide ideation) is traditionally viewed as necessary to attempt suicide in the future, many people who engage in suicide behaviour do not report specific suicidal thoughts during clinical interviews. We wanted to know how to predict suicide in these subjects; therefore, we investigated a number of promising characteristics in two different age groups of depressed patients (sample 1: n = 230; age: 18–65 years; sample 2: n = 258; age >60 years) who were negatively tested for the presence of suicide ideation. As expected, SB was not rare in these groups. Among younger patients, suicide attempts were a little more frequent than in the other group (15 vs. 9%); they more often involved men, those who had been victims of sexual abuse in childhood, those who had negative thoughts about themselves or were predisposed to bipolar disorder. On the other hand, in old age, suicide risk was correlated with neurological problems, foremost alterations in language and movement disorders, and cholesterol levels. Thanks to this information, to determine suicide risk is still possible even when intent to die is not reported. [ABSTRACT FROM AUTHOR]

Introduction: Irritable mood (IM) and subthreshold hypomanic symptoms are reported in half and two-fifths of major depressed subjects respectively, but their clinical and prognostic meanings remain unclear. The aim of this study was to test the clinical usefulness of 2 specifiers in DSM-IV major depressive disorder (MDD): IM occurring during an index episode (IM+) and lifetime episodes of elated mood or IM with at least 2 concurrent hypomanic symptoms (subthreshold hypomanic episodes [SHEs]). Method: We included 482 outpatients with MDD participating in the Combining Medications to Enhance Depression Outcome study (mean age 43.14 ± 12.46 years, 144 males – 30%). The main aim of the original study was to test whether 2 different medications when given in combination as the first treatment step, compared to 1 medication, would improve antidepressant response. Results: IM + subjects (N = 349; 70%) were younger and more often females, with a more severe depression, a more marked social impairment, and more psychiatric comorbidities. The IM + group was also characterized by higher levels of suicidal ideation and more cases of emotional abuse. The combination of IM+ and SHEs was associated with an even more severe clinical picture. Limitations include the post hoc method, incomplete assessment of bipolar validators (e.g., family history of bipolar illness), personality disorders and suicide attempts. Conclusions: The presence of IM and SHEs in MDD correlate with an overall more severe clinical condition. [ABSTRACT FROM AUTHOR]

Background: Initial improvement in the first weeks of antidepressant (AD) treatment is a useful early predictor of complete AD response. We performed a meta-analysis of AD studies to investigate whether a partial decrease in depressive symptoms by week 4 was associated with response and remission by weeks 6-14 in major depressive disorder (MDD). Finally, we focused on treatment-resistant depression (TRD: lack of response to prior AD) to test the impact of early improvement on a second AD treatment outcome and to compare different switching strategies.Methods: Meta-analysis was conducted on AD naturalistic studies published between 01.01.2000 and 06.30.2017. TRD was an exclusion criterion. TRD was analyzed in 407 MDD patients treated with venlafaxine for 6 weeks. The MADRS was used to define very early improvement (VEI: > 20% decrease at week 2), early improvement (EI: > 30% decrease at week 4) and remission (week 6 MADRS < 10). A theoretical model was used to simulate AD switch in TRD patients who failed to achieve remission (Algorithm A), VEI (Algorithm B) or EI (Algorithm C).Results: Our meta-analysis (9 studies; N = 6185) showed significant associations between early improvement, response (OR: 3.28 95% C.I: 2.06-5.20) and remission (OR: 2.10 95% C.I: 1.53-2.87). 24.6% of TRD sample remitted. VEI was a poor outcome predictor: sensitivity = 0.52 (0.40-0.63); specificity = 0.82 (0.76-0.86); AUC = 0.67 (0.62-0.71). EI had a moderate predictive power: sensitivity = 0.87 (0.77-0.93); specificity = 0.71 (0.66-0.77); AUC = 0.76 (0.71-0.80). The best treatment scenario was Algorithm C (switch after 4 weeks) in which remission rate was marginally increased (35.1% vs 33.7% of Algorithm A). Algorithm B (switch after 2 weeks) led to a 4.3% decrease in remission compared to Algorithm A.Limitations: Inclusion of a naturalistic sample without a control arm; simulation of treatments.Conclusion: Although literature data suggest a correlation between an initial improvement of depressive symptoms and later response and remission during AD treatment, our analysis shows that such an early improvement is not a reliable outcome predictor in TRD. The nature of TRD is complex and different biological mechanisms and treatments might be necessary for TRD patients. [ABSTRACT FROM AUTHOR]

Objective Paroxetine titration may be difficult in older individuals as they are more sensitive to side effects. The current study extends to 6 months our previously published report in which paroxetine was started at 2.5 mg/day and slowly increased by 2.5 mg on alternate days (slow titration) or rapidly titrated to target dose from 10 mg/day (standard titration) in a naturalistic setting. Methods Here, the follow-up period was extended to 26 weeks. We performed an intent-to-treat analysis of 47 subjects from the original sample (major depressive disorder and/or generalized anxiety disorder (GAD); >60 years of age). Missing evaluations were replaced by last observations carried forward. GAD was included as a stratification factor. Results Patients in whom paroxetine was slowly up-titrated were more likely to remit (84.0% vs 54.5%; p = 0.028) and had lower core depression ( p = 0.0015) and psychic anxiety levels ( p = 0.006) after 26 weeks. Dropout rate was 20% in the slow titration group compared with 77.3% in the standard titration arm ( p < 0.001). Patients with GAD accounted for all significant associations. No substantial differences were reported between slow and standard titration groups in the subsample without GAD. Conclusions Despite some limitations, these findings suggest that paroxetine treatment should be started at lower doses in older depressed patients and slowly up-titrated. This strategy would allow to increase antidepressant response and the likelihood of completing treatment cycle in patients with high anxiety levels and GAD comorbidity. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: In major depression, when a first antidepressant does not cause remission of symptoms (60%–75%), there are several options for continuing treatment in the next step. This study is a cost-utility analysis (CUA) of different second-line approaches. In a simulated trial outpatients with MDD were treated with citalopram for 13 weeks (level 1), then based on two alternative algorithms implemented from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Algorithm A: citalopram was continued until study endpoint (week 26). Algorithm B: patients who remitted during level 1 continued citalopram. Those who did not remit could opt for switching to another antidepressant (venlafaxine; sertraline) (b1) or adding bupropion to citalopram treatment (augmentation; b2). Algorithm B increased remission rate by 10.6% over Algorithm A (number needed to treat: 9.9; sensitivity range: 9.1–12.5). As a comparison, differences between active antidepressants and placebo are associated with NNT values of 6 to 8. In CUA Algorithm B was dominant with an ICER of $11,813 (sensitivity range=$1783 – $21,784), which is <1GDP per capita cost-effectiveness threshold (USA=$47,193). Among Algorithm B options, switching (b1) dominated Algorithm A with a smaller number of responders than augmentation approach (b2) (NNT 11 vs. 7.7), whereas ICER values were similar (b1: $14,738; b2: $15,458). However we cannot exclude a bias in selecting second treatment. This cost-utility analysis shows (in line with current guidelines) a benefit in modifying antidepressant treatment if response to first-line agent does not occur within 3 months, but not a clear-cut evidence in terms of NNT. [Copyright &y& Elsevier]

Objective. To evaluate the benefit of pharmacogenetics in antidepressant treatment. Methods. In a simulated trial 100,000 subjects in a current episode of major depressive disorder (MDD) received citalopram or bupropion based on the clinician's decision (algorithm A) or following indications from 5-HTTLPR genetic testing (algorithm B), which effect size of was estimated from a meta-analysis of pharmacogenetic trials. A and B were compared in a cost-utility analysis (12 weeks). Costs (international $$, 2010) were drawn from official sources. Treatment effects were expressed as quality-adjusted life weeks (QALWs). Outcome was incremental cost-effectiveness ratio (ICER). Results. Under base-case conditions, genetic test use was associated with increases in antidepressant response (0.062 QALWs) and tolerability (0.016 QALWs) but cost benefit was not acceptable (ICER == $$2,890; $$1,800-$$4,091). However, when the joint effect on antidepressant response and tolerability was analyzed in two recurrent episodes, ICER dropped to $$1,392 ($$837-$$1,982). Cost-effectiveness acceptability curve (CEAC) showed a >80% probability that ICER value fell below the commonly accepted 3 times Gross Domestic Product (GDP) threshold (World Health Organization) and therefore suggesting cost-effectiveness. Conclusion. Notwithstanding some caveats (exclusion of gene-gene and gene-environment interactions; simple 5-HTTLPR architecture), this simulation is favourable to incorporate pharmacogenetic test in antidepressant treatment. [ABSTRACT FROM AUTHOR]

Abstract: Predicting the outcome of antidepressant treatment by pre-treatment features would be of great usefulness for clinicians as up to 50% of major depressives may not have a satisfactory response in spite of adequate trials of antidepressant drugs. In the present article we compared a linear multivariate model of predictors with a few artificial neural network (ANN) models differing from one another by outcome definition and validation procedure. The sample consisted of a reanalysis of 116 inpatients with a major depressive episode included in a 6-week open-label trial with fluvoxamine. With the original outcome definition (responders/non-responders), ANN performed better than logistic regression (90% of correct classifications in the training sample vs. 77%). However only 62% of new patients were correctly predicted by ANN for their outcome class. Length of the index episode, psychotic features and suicidal behavior emerged as outcome predictors in both models, while demographic characteristics, personality disorders and concomitant somatic morbidity were pointed to only by ANN analysis. Increase of classes in the outcome field resulted in a more elevated error: 46.4% for three classes, 60.4% for four classes and 70.3% for five classes. Overall, our findings suggest that antidepressant outcome prediction based on clinical variables is poor. The ANN approach is as valid as traditional multivariate techniques for the analysis of psychopharmacology studies. The complex interactions modelled through ANN may eventually be applied at the clinical level for individualized therapy. However, the accuracy of prediction is still far from satisfactory from a clinical point of view. [Copyright &y& Elsevier]

The article discusses the pharmacogenetics of major depression in bipolar and unipolar disorder. According to the author, the theoretical understanding of depression neurobiology is rooted in the monoamine hypothesis. This theory held that the biological basis for depression was a lack in brain norepinephrine. It became clear that all monoamine systems play a role in depression neurobiology.

In bipolar depression, psychomotor agitation is relatively common and often is associated with other noneuphoric hypomanic symptoms and suicidal ideation. Our goal in this retrospective study was to ascertain the co-occurrence of agitation, bipolar features, and suicidal ideation in unipolar disorder. We retrospectively evaluated 314 inpatients with DSM-IV major depressive disorder (MDD) and no other Axis I diagnosis with the National Institutes of Mental Health (NIMH) Life Chart Method and the Operational Criteria for Psychotic Illness (OPCRIT) checklist to ascertain their symptom profiles across all episodes. Univariate and multivariate comparisons were performed between the subgroups with and without psychomotor agitation (OPCRIT item 23≥1). Agitated depression (AD, a major depressive episode with psychomotor agitation) was present in 19% of the sample. Compared to nonagitated counterparts, patients with AD were older and had lower educational levels and more dysphoria, insomnia, positive thought disorder, and psychotic manifestations. Hypomanic symptoms other than agitation were relatively uncommon (<10%) and more represented in subjects with AD. No significant differences emerged between AD and control groups with respect to most bipolar validators (gender, familiarity, recurrence). Patients with AD had higher levels of suicidal ideation than non-AD controls; however, such a difference was no longer significant after controlling for psychotic features. Excessive self-reproach, early awakening, diurnal changes, poor appetite, and hypomanic symptoms were independently associated with suicidal thoughts in nonpsychotic MDD. Incomplete information on drug treatment, exclusion of patients with Axis I comorbidity, and tertiary care setting were the most important limitations of the study. Although we failed to support the bipolar nature of MDD–AD by common validators, probably because we used a more heterogeneous definition of agitation compared to similar studies, our data confirm the association of agitation with hypomanic symptoms and suicidal thoughts in major depression, and emphasize the complex phenomenology of AD in an inpatient setting. Depression and Anxiety 23:389–397, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: To ascertain the impact of postpartum onset (PPO) on the subsequent time course of mood disorders. Methods: This retrospective study compared per year rates of excited (manic or mixed) and depressive episodes between fifty-five women with bipolar (N = 22) or major depressive (N = 33) disorders with first episode occurring postpartum (within four weeks after childbirth according to DSM-IV definition) and 218 non-postpartum onset (NPPO) controls. Such patients had a traceable illness course consisting of one or more episodes alternating with complete symptom remission and no additional diagnoses of axis I disorders, mental retardation or brain organic diseases. A number of variables reported to influence the course of mood disorders were controlled for as possible confounding factors Results: Bipolar women with postpartum onset disorder had fewer excited episodes (p = 0.005) and fewer episodes of both polarities (p = 0.005) compared to non-postpartum onset subjects. No differences emerged in the rates of depressive episodes. All patients who met criteria for rapid cycling bipolar disorder (7 out of 123) were in the NPPO group. Among major depressives, PPO patients experienced fewer episodes (p = 0.016). With respect to clinical and treatment features, PPO-MDD subjects had less personality disorder comorbidity (p = 0.023) and were less likely to be on maintenance treatment compared to NPPO comparison subjects (p = 0.002) Conclusion: Such preliminary findings suggest that PPO mood disorders may be characterized by a less recurrent time course. Future research in this field should elucidate the role of comorbid personality disorders and treatment. Moreover it should clarify whether PPO disorders are also associated with a more positive outcome in terms of social functioning and quality of life. [ABSTRACT FROM AUTHOR]

Abstract: Decrease in self-esteem (SE) is found in all mood disorders during inter-episode phases. This trait was associated with relapse and suicidality but its genetic basis is still undefined, probably because SE has multiple components. The aim of the current study was to ascertain which of those components were altered in a sample of affective patients. Three hundred and thirty-one outpatients with bipolar (N =199) and major depressive MD (N =132) disorders in remission for at least three months and one hundred controls completed the Rosenberg Self-esteem Scale (RSE; [Rosenberg, M., 1965. The measurement of self-esteem, Society and the Adolescent Self-Image. Princeton University Press, pp.16–36]). Principal component analysis was performed to identify RSE factor structure. Extracted factors were compared across case and control groups in the whole sample (N =431) and in a sub-sample (N =301) with low self-esteem (RSE &#60;20). PCA yielded a two-factor solution with self-confidence (SC) and self-deprecation (SD) that was largely consistent with the existing literature. Such factors were both associated with lower scores in affective patients than controls (SC: F =52, p &#60;0.01; SD: F =43, p &#60;0.01). However in the low RSE group only self-confidence was found to be decreased in subjects with mood disorders (SC: F =13.8, p &#60;0.01; SD: F =0.05, p =0.9). These findings suggest that self-esteem deficit in affective disorders might involve specific components. Implications for research and clinical practice are discussed. [Copyright &y& Elsevier]

Background: Classical authors such as Kraepelin, as well as the emerging literature during the past decade, indicate that manic-like signs and symptoms are present to a variable degree in all mood disorders. Current nosography does not differentiate between them and only the number of symptoms or severity is used for classification. This is particularly true for mania and hypomania. This paper will analyze the patterns of manic symptoms in bipolar I (BP-I), bipolar II (BP-II) and major depressive disorders (MDD), to test the hypothesis that mania and hypomania have different profiles, and ascertain which excitatory manic phenomena do occur in unipolar MDD. Methods: Six hundred and fifty-two inpatients (158 BP-I, 122 BP-II and 372 MDD) were assessed using the operational criteria for psychotic illness checklist (OPCRIT) [Arch. Gen. Psychiatry 48 (1991) 764] with a lifetime perspective. Manic or hypomanic symptoms were investigated and compared between BP-I, BP-II and MDD. Results: When compared with BP-II, BP-I disorder had a higher prevalence of reckless activity, distractibility, psychomotor agitation, irritable mood and increased self-esteem. These five symptoms correctly classified 82.8% of BP-I and 80.1% of BP-II patients. One or two manic symptoms were observed in more than 30% of major depressive patients; psychomotor agitation was the most frequent manifestations present in 18% of the MDD group. Limitations: We did not control for severity of symptoms, nor for neuroleptic use that could produce akathisia. Conclusions: This study suggests that mania and hypomania can be differentiated in their symptom profiles, and highlights the presence of few manic symptoms, particularly psychomotor agitation, in MDD. From the standpoint of number of manic signs and symptoms, controlling for psychomotor agitation did not substantially change the predictive power of the remaining manic symptoms. Given that excitatory manic signs and symptoms are present to a decreasing degree in BP-I, BP-II and MDD, these disorders can be proposed to lie along a dimensional model. Overall, these data are compatible with the concept of a bipolar spectrum, whereby each of the affective subtypes requires specific genetic factors. [Copyright &y& Elsevier]