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The purpose of this study was to investigate the occurrence of antidepressants among suicides in the era since the introduction of newer less toxic antidepressants. Comprehensive post mortem toxicological examinations were performed on 94% of certain and uncertain suicides in Mobile County, Alabama, between October 1, 1990 and September 30, 1995. Comparisons were made between current data from Mobile and data from the San Diego study in 1981-83. About twice as many suicides in Mobile were positive for antidepressants than in San Diego (15% vs. 8%). The proportions of antidepressant overdose deaths were the same (5%), however. Antidepressants were found in significantly fewer males than females and blacks than whites in Mobile. Although antidepressants were found in a greater proportion of people who committed suicide in Mobile, they were not used more frequently as a means of suicide. The authors conclude that this may represent improvement in care received by people with depression. It remains to be determined what suicide preventive effects individual antidepressants or groups of antidepressants may have.

Background: The severity of bipolar disorder can be assessed using the daily prospective National Institute of Mental Health's Life Chart Method (LCM-p). Also for scientific research the LCM-p, has been used frequently. However, processing and analyzing the LCM-p for research purposes, are challenging because of the multitude of complex measures that can be derived from the data. In the current paper we review the different LCM-p course variables (mood episodes, average severity, proportion of time ill and mood switches) and their definitions. Strengths and limitations and the impact of the use of different LCM-p course measures and definitions on the research results are described.Method: A systematic review of original papers on the LCM was conducted using 9 electronic databases for literature between January 1996 and December 2014. Papers using other prospective charting procedures were not evaluated in the current study.Results: The initial literature search led to 1352 papers of which 21 were eventually selected. A relatively wide variety of definitions of LCM-p course variables was used across the studies. Especially for the calculation of number of episodes and mood switch no univocal definition seems to exist. Across studies several different durations and severity criteria are applied to calculate these variables. We describe which variables and definitions are most suitable for detecting specific bipolar disease course characteristics and patterns.Conclusion: In the absence of a golden standard for the calculation of LCM-p course variables, researchers should report the exact method they applied to their LCM-p data, and clearly motivate why this is their method of first choice considering their research aim. (C) 2015 Elsevier B.V. All rights reserved.

Background: The severity of bipolar disorder can be assessed using the daily prospective National Institute of Mental Health's Life Chart Method (LCM-p). Also for scientific research the LCM-p, has been used frequently. However, processing and analyzing the LCM-p for research purposes, are challenging because of the multitude of complex measures that can be derived from the data. In the current paper we review the different LCM-p course variables (mood episodes, average severity, proportion of time ill and mood switches) and their definitions. Strengths and limitations and the impact of the use of different LCM-p course measures and definitions on the research results are described. Method: A systematic review of original papers on the LCM was conducted using 9 electronic databases for literature between January 1996 and December 2014. Papers using other prospective charting procedures were not evaluated in the current study. Results: The initial literature search led to 1352 papers of which 21 were eventually selected. A relatively wide variety of definitions of LCM-p course variables was used across the studies. Especially for the calculation of number of episodes and mood switch no univocal definition seems to exist. Across studies several different durations and severity criteria are applied to calculate these variables. We describe which variables and definitions are most suitable for detecting specific bipolar disease course characteristics and patterns. Conclusion: In the absence of a golden standard for the calculation of LCM-p course variables, researchers should report the exact method they applied to their LCM-p data, and clearly motivate why this is their method of first choice considering their research aim. (C) 2015 Elsevier B.V. All rights reserved.

Following a review of the clinical trials of reboxetine, a new nonadrenegic reuptake inhibitor antidepressant, this paper presents a heuristic theoretical framework to better understand selective antidepressant action. For over three decades, the dominant views of antidepressant action have seen these agents active across all constitutional types and regardless of social setting. An increasing number of studies using quality of life methods are at odds with this view. This paper summarizes several of these studies, along with two studies of the effects of reboxetine on the quality of life, which reveal differential effects of selective agents that demand alternative explanations to the conventional monoamine theories. The authors submit that any revisions in our understanding of what is happening will have to pay attention to temperamental inputs that antedate affective episodes and to the sense of wellbeing and level of residual symptoms patients have on treatment after the acute phase of their illness has remitted. Obviously much more research needs to be done in this area. This invited paper sketches out, in very general terms, some provocative possibilities of how future understanding of antidepressants, temperament and their neurobiologic substrates could lead to better matching of specific antidepressants to specific temperament types.

Background: SSRIs have been one of the major innovations in psychopharmacology in recent years. The debate over the competing claims of SSRIs and the older, cheaper TCAs has implications for clinical practice and prescribing expenditure. Several reviewers have focused on acquisition costs and stressed the higher costs associated with using SSRIs. Methods: Recently there have been several applications of economics to the issue of whether to use SSRIs or TCAs as first-line antidepressants. Most have argued that there is an economic case for using SSRIs. Several previous papers have used modelling techniques and decision analysis to generate economic evaluations from clinical trials. This paper examines some recent studies based on retrospective evaluations of real patients and real practices. Their methods and results are summarised and discussed. Results: They all suggest that in practice, where concerns are with effectiveness rather than efficacy, there are advantages to be gained from using SSRIs. Conclusions: There are important questions about how to perform such economic evaluations. Clinical practice has long viewed the RCT as a `gold standard' for evaluation. Some SSRI/TCA comparisons, incorporating economic studies, are under way and will be reported on eventually. When they appear, these studies should be examined carefully for their implications for antidepressant prescribing.

Objectives We sought to identify and consider methodological issues that may have limited or confounded investigations into links between depression and acute coronary syndrome (ACS) events. Methods We reviewed salient research studies to identify such issues. Results Against previous conclusions, we found that lifetime depression is unlikely to have any primary ACS impact, while we clarify that ‘incident depression’ (depression commencing at variable periods around the time of the ACS event) appears to confer a greater risk than non-incident depression. As the time periods of incident depressions are likely to have quite differing causes, evaluating any consolidated risk period appears unwise. It remains unclear whether it is ‘depression’ that provides the risk for ACS events or a higher order factor. Variable use of depression measures and failure to evaluate depressive sub-types have further limited clarification. The response by ACS patients to antidepressant medication appears limited, and it remains to be determined whether exposure to an antidepressant might be a contributing factor. Finally, studies may have focused on an excessively refined association, and neglected to recognise that depression is associated with a wide range of vascular events, suggesting that a broader conceptual model may be required. Limitations The authors have considered only a limited set of studies in preparing this review, with the critique relying at times on subjective interpretation. Conclusions After decades of research pursuing links between depression and ACS events explanatory links remain obscure, presumably reflecting a range of methodological issues that we have discussed in this paper .

Objective The relationship between ketamine's hallucinogenic- and dissociative-type effects and antidepressant mechanism of action is poorly understood. This paper reviewed the correlation between subjective effects defined by various psychometric scales and observed clinical outcomes in the treatment of patients with Major Depressive Disorder ( MDD ). Methods Based on PRISMA guidelines, we reviewed the dissociative and psychotomimetic mental state induced with ketamine during MDD treatment. Our selected studies correlated depression rating with validated scales collected at regular intervals throughout the study period such as the Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS), and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). We excluded studies with bipolar depression or with repeated dosing and no single-dose phase. We included 8 of 556 screened reports. Results Two of five CADSS studies found significant negative correlations between increases in CADSS scores and depression scores. One of six BPRS studies demonstrated correlations between BPRS scores and depression scores. The 5D-ASC's one study found no correlation with the MADRS. Conclusions Ketamine's dissociative and psychotomimetic effects were correlated with depression changes in 37.5% of studies, but most studies did not examine this relationship and future studies should consider this association since it appears important for MDMA and psilocybin therapies.

Background Switching antidepressant medications is recommended when an initial antidepressant is not effective, when it is unable to be tolerated or when there are significant drug interactions. The aim of this paper is to review the evidence regarding when to switch antidepressants and the optimal approach to switching. Methods Clinical and academic experts in mood disorders from Australia and New Zealand (Treatment Algorithm Group, TAG) met to discuss the key considerations regarding switching antidepressants in the treatment of depression and formulate recommendations about switching strategies. Results While switching is recommended, there is limited data to guide on how best to approach switching antidepressants (e.g. whether to switch within class or out of class), and how to define the best time to consider switching. Broadly, switching within class after non-response is recommended for mild-moderate depression and out-of-class for patients with a more severe depression or melancholia. Limitations There is a limited evidence-base to draw on to make definitive recommendations on switching approaches. Conclusions Switching antidepressants is an appropriate strategy to use if there is a minimal response to an initial antidepressant. Further research is required to determine the optimal switching approach.

Background Photobiomodulation (PBM) with red and near-infrared light (NIR) –also known as Low-Level Light Therapy–is a low risk, inexpensive treatment–based on non-retinal exposure–under study for several neuropsychiatric conditions. The aim of this paper is to discuss the proposed mechanism of action and to perform a systematic review of pre-clinical and clinical studies on PBM for major depressive disorder (MDD). Methods A search on MEDLINE and EMBASE databases was performed in July 2017. No time or language restrictions were used. Studies with a primary focus on MDD and presenting original data were included (n = 17). References on the mechanisms of action of PBM also included review articles and studies not focused on MDD. Results Red and NIR light penetrate the skull and modulate brain cortex; an indirect effect of red and NIR light, when delivered non-transcranially, is also postulated. The main proposed mechanism for PBM is the enhancement of mitochondrial metabolism after absorption of NIR energy by the cytochrome C oxidase; however, actions on other pathways relevant to MDD are also reported. Studies on animal models indicate a benefit from PBM that is comparable to antidepressant medications. Clinical studies also indicate a significant antidepressant effect and good tolerability. Limitations Clinical studies are heterogeneous for population and treatment parameters, and most lack an appropriate control. Conclusions Preliminary evidence supports the potential of non-retinal PBM as a novel treatment for MDD. Future studies should clarify the ideal stimulation parameters as well as the overall efficacy, effectiveness and safety profile of this treatment.

Background Repetitive transcranial magnetic stimulation (rTMS) is an increasingly used treatment for patients with depression. The use of rTMS in depression is supported by over 20 years of clinical trials. There has been a significant increase in knowledge around the use of rTMS in recent years. Objective The aim of this paper was to review the use of rTMS in depression to provide an update for rTMS practitioners and clinicians interested in the clinical use of this treatment. Methods A targeted review of the literature around the use of rTMS treatment of depression with a specific focus on studies published in the last 3 years. Results High-frequency rTMS applied to the left dorsolateral prefrontal cortex is an effective treatment for acute episodes of major depressive disorder. There are several additional methods of rTMS delivery that are supported by clinical trials and meta-analyses but no substantive evidence that any one approach is any more effective than any other. rTMS is effective in unipolar depression and most likely bipolar depression. rTMS courses may be repeated in the management of depressive relapse but there is less evidence for the use of rTMS in the maintenance phase. Conclusions The science around the use of rTMS is rapidly evolving and there is a considerable need for practitioners to remain abreast of the current state of this literature and its implications for clinical practice. rTMS is an effective antidepressant treatment but its optimal use should be continually informed by knowledge of the state of the art.

Background Phosphodiesterase-5 inhibitors (PDE5Is) are used to treat erectile dysfunction (ED). Recently, the antidepressant-like effect of PDE5Is was demonstrated in animal models of depression. In clinical settings, PDE5Is were studied only for ED associated depression. Hence, there are no studies evaluating the effects of PDE5Is for the treatment of major depressive disorder (MDD) without ED. In this review article, we aimed to discuss the use of PDE5Is in the context of MDD, highlighting the roles of PDE genes in the development of MDD, the potential mechanisms by which PDE5Is can be beneficial for MDD and the potentials and limitations of PDE5Is repurposing to treat MDD. Methods We used PubMed (MEDLINE) database to collect the studies cited in this review. Papers written in English language regardless the year of publication were selected. Results A few preclinical studies support the antidepressant-like activity of PDE5Is. Clinical studies in men with ED and depression suggest that PDE5Is improve depressive symptoms. No clinical studies were conducted in subjects suffering from depression without ED. Antidepressant effect of PDE5Is may be explained by multiple mechanisms including inhibition of brain inflammation and modulation of neuroplasticity. Limitations The low number of preclinical and absence of clinical studies to support the antidepressant effect of PDE5Is. Conclusions No clinical trial was conducted to date evaluating PDE5Is in depressed patients without ED. PDE5Is’ anti-inflammatory and neuroplasticity mechanisms may justify the potential antidepressant effect of these drugs. Despite this, clinical trials evaluating their efficacy in depressed patients need to be conducted.

Background Major depression is a neuropsychiatric disorder that can involve profound dysregulation of mood. While depression is associated with additional abnormalities besides reduced mood, such as cognitive dysfunction, it is not well established that sensory perception is also altered in this disorder (aside from in psychotic depression). Recent studies have shown that visual processing, in as early a stage as the retina, is impaired in depression. This paper examines the hypothesis that major depression can involve alterations in sensory perception. Methods A Pubmed literature search investigated several lines of evidence: innervation of sensory cortex by serotonin and norepinephrine; antidepressant drugs and depression itself affecting processing of facial expressions of emotion; electroencephalography (EEG) studies of depressed persons and antidepressant drugs; involvement of the serotonergic 5HT2A receptor in both depression and hallucinogenic drug action; psychotic depression involving sensory distortions; dopamine possibly playing a role in depression; and the antidepressant effect of blocking the NMDA receptor with ketamine. Results Data from each of these lines of evidence support the hypothesis that major depression can involve sensory perceptual alterations. Conclusions Loss of interest in one's daily activities and inability to experience pleasure, also known as anhedonia, in major depression may in part be mediated by sensory abnormalities, whereby normal sensory perceptions are no longer present to activate reward circuitry. Limitations The data supporting the hypothesis tend to be associative, so further confirmation of the hypothesis awaits additional controlled experiments.

St John's wort is a popular herbal remedy recommended by Traditional Chinese Medicine (TCM) practitioners and licensed and widely prescribed for depression in many European countries. However, conflicting data regarding its benefits and risks exist, and the last large meta-analysis on St John's wort use for depression was done in 2008, with no updated meta-analysis available.Using the keywords [St John's Wort OR Hypericum perforatum OR hypericin OR hyperforin OR johanniskraut OR] AND [depression OR antidepressant OR SSRI], a preliminary search (without language restriction) on the PubMed, Ovid, Clinical Trials Register of the Cochrane Collaboration Depression, Anxiety and Neurosis Group, Cochrane Field for Complementary Medicine, China National Knowledge Infrastructure and WanFang database yielded 5428 papers between 1-Jan-1960 and 1-May-2016.27 clinical trials with a total of 3808 patients were reviewed, comparing the use of St John's wort and SSRI. In patients with depression, St John's wort demonstrated comparable response (pooled RR 0.983, 95% CI 0.924-1.042, p0.001) and remission (pooled RR 1.013, 95% CI 0.892-1.134, p0.001) rate, and significantly lower discontinuation/dropout (pooled OR 0.587, 95% CI 0.478-0.697, p0.001) rate compared to standard SSRIs. The pooled SMD from baseline HAM-D scores (pooled SMD -0.068, 95% CI -0.127 to 0.021, p0.001) also support its significant clinical efficacy in ameliorating depressive symptoms.Evidence on the long-term efficacy and safety of St. John's wort is limited as the duration of all available studies ranged from 4 to 12 weeks. It is also unclear if St John's wort would be beneficial for patients with severe depression, high suicidality or suicide risk.For patients with mild-to-moderate depression, St John's wort has comparable efficacy and safety when compared to SSRIs. Follow-up studies carried out over a longer duration should be planned to ascertain its benefits.

Background Knowledge regarding the relative cost-effectiveness of different antidepressants is crucial for the planning of depression treatment. However, there have been only a small number of reviews of such evidence and synthesizing economic evidence across studies is methodologically challenging. In particular, there have been few reviews of the methods employed in database analyses (studies that use data from real-world practice). Methods Published economic evaluations based on database analyses were systematically reviewed to compare antidepressant treatments in depression. Prospective studies of cost-effectiveness were also reviewed to highlight unanswered questions through comparisons between these two different study designs. Results Forty papers met the criteria and were included. A relatively large number of industry-sponsored evaluations of escitalopram were identified and these found escitalopram to be potentially cost-effective in depression treatment. Evidence of cost-effectiveness differences between other individual SSRIs was not unequivocally established. Inconsistent findings further emerged concerning the cost-effectiveness of SSRIs versus TCAs between retrospective database analyses and prospective studies. Limitations Different outcome measures and cost perspectives make it difficult to make comparisons across studies. Conclusions Evidence regarding the cost-effectiveness of different antidepressants in depression continues to accumulate. Beyond the efficacy or tolerability data found for newer antidepressants in controlled trials, further research from real-world settings is needed to examine the relative cost-effectiveness of different antidepressant agents.

Background Randomized clinical trials [RCT] are the Gold Standard of medical evidence. However, observational comparative effectiveness research [CER] based on real-world data is receiving national attention. This paper demonstrates how observational CER can fill important gaps in clinical knowledge left behind by RCT approaches. An example of CER in bipolar disorders is presented. Methods Paid claims data from a large commercial insurer were used to identify episodes of drug therapy. Episodes were defined each time a patient initiated or restarted therapy using an antipsychotic, antidepressant or mood stabilizing medication. Episode definitions were based on calculations of continuous days of drug therapy using a 15 day gap definition. 105,440 episodes of drug therapy were included in the analysis. Results Most episodes were initiated using a mood stabilizing drug (40%) or an antidepressant (40%). Over 59% of all episodes were for augmentation therapy, followed by switching episodes (25%) and restart episodes (16%). Patient outcomes measured by either duration of uninterrupted therapy or one-year post-treatment cost varied significantly with patient treatment history, especially episode type. The comparative effectiveness of alternative therapies was sensitive to the extent to which treatment history is taken into account. Conclusions Observational research can evaluate patient outcomes across a wide range of clinical presentations with regard to the patient's treatment history. Treatment history is a major determinant of patient compliance and future treatment costs. Failure to account for treatment history can introduce bias into comparative effectiveness results. Observational CER research can also uncover important questions that require future research.

Background 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 [11C]FLB 457 to extrastriatal D2 receptors was measured in a group of depressed patients. Second, the hypothesis that selective serotonin reuptake inhibiting (SSRI) antidepressants affect the striatal binding of [11C]raclopride was tested. Methods In the first study the binding of [11C]FLB 457 was compared between 7 people with depression and 7 healthy controls. In the second study the binding of [11C]raclopride to striatal D2/3 receptors was compared between 8 people taking SSRI antidepressant medication and 8 healthy controls. Results There was no difference in the binding of [11C]FLB 457 between the two groups. [11C]raclopride binding was reduced in the dorsal striatum of people taking antidepressants suggesting either that D2/3 expression was reduced, or that dopamine release was increased, compared to untreated controls. Limitations 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. Conclusion We found no support for the hypothesis that dopamine D2 receptor expression is altered in extrastriatal brain regions in depression. SSRI antidepressants were associated with reduced [11C]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.

Several studies have analyzed prescription patterns for bipolar disorder, but few have for acute mania. Treatment strategies in this complex domain change over time and do not always follow evidence-based guidelines.Prescription data of in-patients suffering from acute mania in the time period from 2005 to 2012 were obtained from the database of the Drug Safety Program in Psychiatry (Institut für Arzneimittelsicherheit in der Psychiatrie; AMSP). Data were collected on two index dates per year. Changes over time were analyzed comparing the time periods 2005/06 and 2011/12.Among 1650 patients (mean ±SD; age: 48.9±14.91 years; 53.1% females) 54.1% received anticonvulsants, 74.5% second-generation antipsychotics (SGAs), 17.8% first-generation antipsychotics (FGAs), 29.1% lithium, 44.1% benzodiazepines and 14.5% antidepressants. Prescription of SGAs increased from 70% to 79% (p=0.005), while prescription of FGAs and anticonvulsants decreased from 19% to 13% (p0.05) and 59% to 46% (p0.001), respectively. Only 30% of patients received monotherapy with one mood stabilizer. We observed an impact of gender, age and psychotic symptoms on treatment strategy. 36.8% of the women≤40 years received valproate.Follow-up data are missing and no differentiation between acute and maintenance treatments could be made due to the cross-sectional design. Additionally, our findings do not necessarily translate to outpatients or to other countries.Combination therapies represent standard clinical practice. Though many results reflect clinical necessity, the high number of antidepressant prescriptions or valproate use in women of child-bearing age should be judged critically. Further prospective studies should focus on real-world prescription practice in acute mania to evaluate efficacy and safety of common practice. This paper is dedicated to Prof. Dr. Hanns Hippius on the occasion of his 90th birthday.

Background Treatment resistant depression is a complex disorder and an important source of morbidity and mortality. Identification of risk factors of resistance may be useful to improve early recognition as well as treatment selection and prediction of outcome in patients with depression. Methods The aim of this paper was to review the current status of knowledge regarding risk factors of treatment resistance in unipolar depression, in patients who failed to respond to at least two successive and adequate antidepressant treatments. Results Systematic literature search yielded 8 publications exploring clinical and biological factors. Specific psychiatric comorbidities, psychosocial factors, clinical characteristics of the depressive episode and biological markers emerge as possible risk factor for treatment resistant depression. Limitations Due to the lack of objective definition and diagnostic criteria for treatment resistant depression, and the paucity of reports on risk factors, our review only summarized a small number of studies. Conclusion Future investigations of risk factors should help to improve the understanding of the mechanisms underlying resistance in mood disorders and contribute to improve their therapeutic management.

Recent advances in our understanding of both short- and long-term therapeutic interventions for depressive disorders have necessitated greater precision in defining appropriate therapeutic interventions. While these remarkable changes in treatment have been based on the introduction of newer antidepressant agents, the advances have occurred because of more systematic clinical trials and a greater sophistication in defining diagnostic and treatment response criteria. This paper reviews key findings in recurrent depression with respect to long-term treatment. Particular attention is paid to the combination treatment of psychotherapy and antidepressant drugs.

Objective Treatment resistant depression is a common clinical problem and a major public health concern. The use of antidepressant combinations to overcome treatment resistance, while somewhat controversial, is a popular strategy in practice. This paper reviews published trials on combination antidepressants with a view to inform clinical practice. Method A systematic but selective review of the published literature was conducted using EMBASE, PSYCHLIT and MEDLINE with relevant search terms. Results A number of trials suggesting efficacy of combination antidepressants were found. These are incorporated into a number of treatment guidelines for the management of treatment refractory depression. Clinicians should be cautious regarding pharmacokinetic and pharmacodynamic interactions, including the serotonin syndrome, however combination strategies are an effective option. Conclusions Many antidepressants can be usefully combined especially if they engage separate mechanisms of action. Clinically, antidepressant combinations provide a useful resort in otherwise treatment resistant individuals. However, much further research is needed to determine relative efficacy and determine long term outcome.

Background. The purpose of this paper was to examine the optimal adjunctive dose of clonazepam for the treatment of prolonged depression. Methods. Sixty nine patients with prolonged depression were enrolled in an open trial over a 4 week period during which clonazepam was added to their medication. Results. A daily dose of 3.0 mg clonazepam as augmentation was significantly more effective than doses of 1.5 mg and below. Most of the improved patients showed a rapid onset of action within 2 weeks, and side effects were not severe. Conclusion. A daily dose of at least 3.0 mg clonazepam as augmentation of ongoing antidepressant treatment should be considered in prolonged depressive patients with suboptimal improvement. Limitations. The effect on clonazepam alone on prolonged depression was not established, and its effect of on severe depression is unknown. High dose treatment was not carried out in this study.

This paper reports combined antidepressant treatment with isocarboxazid /mianserin in 60 patients with endogenous depression/melancholia. The combination was used as the first drug treatment choice in 33 cases. Thirty-two patients obtained complete remission and one responded only incompletely. The depression improved after a few days' treatment, and full recovery was obtained after approximately 2 weeks. There were no serious side-effects or interactions, but weight gain was a common problem.