Background: Serotonin-noradrenaline reuptake inhibitors (SNRI) are widely used in medical practice. Their discontinuation has been associated with a wide range of symptoms. The aim of this paper is to identify the occurrence, frequency, and features of withdrawal symptoms after SNRI discontinuation. Methods: PRISMA guidelines were followed to conduct a systematic review. Electronic databases included PubMed, the Cochrane Library, Web of Science, and MEDLINE from the inception of each database to June 2017. Titles, abstracts, and topics were searched using a combination of the following terms: “duloxetine” OR “venlafaxine” OR “desvenlafaxine” OR “milnacipran” OR “levomilnacipran” OR “SNRI” OR “second generation antidepressant” OR “serotonin norepinephrine reuptake inhibitor” AND “discontinuation” OR “withdrawal” OR “rebound.” Only published trials in the English language were included. Results: Sixty-one reports met the criteria for inclusion. There were 22 double-blind randomized controlled trials, 6 studies where patients were treated in an open fashion and then randomized to a double-blind controlled phase, 8 open trials, 1 prospective naturalistic study, 1 retrospective study, and 23 case reports. Withdrawal symptoms occurred after discontinuation of any type of SNRI. The prevalence of withdrawal symptoms varied across reports and appeared to be higher with venlafaxine. Symptoms typically ensued within a few days from discontinuation and lasted a few weeks, also with gradual tapering. Late onset and/or a longer persistence of disturbances occurred as well. Conclusions: Clinicians need to add SNRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with other types of psychotropic drugs. The results of this study challenge the use of SNRI as first-line treatment for mood and anxiety disorders.

<b><i>Introduction</i></b>: Appraisal of prodromal symptoms of unipolar depression may complement the traditional cross-sectional approach and provide a longitudinal perspective, according to a staging model of the illness. <b><i>Objective:</i></b> To provide an updated systematic review of clinical studies concerned with prodromal symptoms of unipolar depression, according to PRISMA guidelines. <b><i>Methods:</i></b> Keyword searches were conducted in PubMed, Scopus, and Web of Science. Longitudinal studies on prodromal symptoms and signs in adult patients primarily diagnosed with unipolar depression were selected. Findings were examined separately according to study design (i.e., retrospective or prospective). <b><i>Results:</i></b> Twenty-five studies met the criteria for inclusion in this systematic review. Findings indicate that a distinct prodromal symptomatology – commonly characterized by anxiety, tension, irritability, and somatic complaints – exists before the onset of unipolar depression. The duration of the prodromal phase was highly variable across studies, ranging from less than a month to several years. Prodromal symptoms profile and duration were consistent within individuals across depressive episodes. There was a close relationship between prodromal and residual symptoms of the same depressive episode. <b><i>Conclusions:</i></b> The present systematic review addresses an important, and yet relatively neglected, clinical issue that deserves further investigation and may be of immediate practical value. The findings provide challenging insights into the pathogenesis and course of unipolar depression, which may result in more timely and effective treatment of recurrences. The definition of a prodromal phase in depression would benefit from the joint use of symptom identification, biomarkers, and neuroimaging.

<b><i>Introduction:</i></b> Patient-reported outcomes (PROs) are of increasing importance in clinical medicine. However, their evaluation by classic psychometric methods carries considerable limitations. The clinimetric approach provides a viable framework for their assessment. <b><i>Objective:</i></b> The aim of this paper was to provide a systematic review of clinimetric properties of the Symptom Questionnaire (SQ), a simple, self-rated instrument for the assessment of psychological symptoms (depression, anxiety, hostility, and somatization) and well-being (contentment, relaxation, friendliness, and physical well-being). <b><i>Methods:</i></b> The PRISMA guidelines were used. Electronic databases were searched from inception up to March 2019. Only original research articles, published in English, reporting data about the clinimetric properties of the SQ, were included. <b><i>Results:</i></b> A total of 284 studies was selected. The SQ has been used in populations of adults, adolescents, and older individuals. The scale significantly discriminated between subgroups of subjects in both clinical and nonclinical settings, and differentiated medical and psychiatric patients from healthy controls. In longitudinal studies and in controlled pharmacological and psychotherapy trials, it was highly sensitive to symptoms and well-being changes and discriminated between the effects of psychotropic drugs and placebo. <b><i>Conclusions:</i></b> The SQ is a highly sensitive clinimetric index. It may yield clinical information that similar scales would fail to provide and has a unique position among the PROs that are available. Its use in clinical trials is strongly recommended.

Background: The aim of this paper was to perform a systematic review and, when feasible, a meta-analysis of randomized controlled trials (RCT) which used benzodiazepines (BZD) as a monotherapy versus placebo, antidepressant drugs (AD), or both. Methods: Keyword searches were conducted for identifying RCT comparing BZD and AD, and/or placebo in the treatment of depression, using electronic databases from their inception up to April 2017. We selected reports of RCT in which BZD were compared to AD and/or placebo in the treatment of adult patients with a primary diagnosis of depressive disorder or anxious depression. When feasible, data were subjected to meta-analysis. Results: A total of 38 studies met the criteria for inclusion and were then included in the systematic review. Only 1 study concerned a newer AD, fluvoxamine. For the meta-analysis, we submitted data on response rate from 22 RCT, considering BZD versus placebo (8 comparisons) and BZD versus tricyclic antidepressants (TCA) (20 comparisons). There was a lack of significant differences as to response rate between BZD and placebo, as well as between BZD and TCA. Analysis of individual studies disclosed that, in more than half of the studies comparing BZD to TCA and/or placebo, BZD were significantly more effective than placebo and as effective as TCA. Conclusions: BZD are a therapeutic option in anxious depression and there are no indications that AD are preferable. There is a pressing need for RCT of adequate methodological quality and follow-up comparing BZD to second-generation AD and placebo in anxious depression.

The combination of pharmacotherapy and psychotherapy in the setting of anxiety disorders is often viewed as a potential source of augmentation of clinical effects, with little attention paid to the potential occurrence of negative events. In most of the studies, however, if benefits ensued, they were modest and likely to fade. Further, 4 high-quality and well-designed individual studies suggest that the addition of a benzodiazepine or an antidepressant to cognitive behavioral treatment of anxiety disorders could be detrimental compared to placebo at follow-up. The aim of this review was to outline a novel hypothesis, which needs to be adequately tested but may shed some new light on this interaction. Any type of psychotropic drug treatment, particularly after long-term use, may increase the risk of experiencing additional psychopathological problems that do not necessarily subside with discontinuation of the drug or of modifying responsiveness to subsequent treatments. The changes are persistent and not limited to a short phase, such as in the case of withdrawal reactions, and cannot be subsumed under the generic rubrics of adverse events or side effects. The term ‘iatrogenic comorbidity' refers to unfavorable modifications in the course, characteristics, and responsiveness of an illness that may be related to treatments that were administered previously. The likelihood of iatrogenic comorbidity needs to be considered in clinical practice: The concurrent use of pharmacotherapy and psychotherapy may yield advantages in the short term, but its costs at some later point in time may largely outweigh such benefits.