Exploring peripheral biomarkers in psychostimulant use: A systematic review on neurotrophins, stress-related hormones, oxidative stress molecules and genetic factors.

BACKGROUND: This systematic review aims to comprehensively explore the impact of psychostimulant substances on neurotrophic and inflammatory pathways, including brain-derived neurotrophic factor (BDNF), pro-BDNF, cortisol, dehydroepiandrosterone sulfate (DHEAS), thiobarbituric acid reactive substances (TBARS), interleukins, and the role of genetic factors. The study seeks to address existing gaps in the literature by providing a thorough evaluation of neurotrophic and inflammatory system alterations associated with different stages of psychostimulant dependence for a more nuanced understanding of substance use disorder (SUD) neurobiology. METHODS: A systematic review was conducted in PubMed, Scopus, and Web of Science databases following the PRISMA guidelines. The research encompasses 50 studies with a participant pool totaling 6792 individuals using psychostimulant substances. RESULTS: Key findings include diverse impacts of cocaine on BDNF levels, mainly consisting of their significant increase during withdrawal. In contrast, NGF showed an opposite behavior, reducing during withdrawal. Cortisol and DHEAS levels exhibited relevant increases after psychostimulant use, while TBARS showed conflicting results. Genetic investigations predominantly focused on the Val66Met polymorphism of the BDNF gene, revealing associations with susceptibility to stimulant addiction. CONCLUSIONS: Neurotrophins and inflammatory molecules play a significant role in the pathophysiological mechanisms following psychostimulant use. A better understanding of their complex interplay could aid clinicians in identifying biomarkers of different disease stages. Moreover, clinical interventions designed to interfere with neurotrophic and inflammatory pathways could possibly lead to craving-modulatory strategies and reduce pathological neuronal and systemic consequences of psychostimulant use.

Linking Striatal Dopaminergic Asymmetry with Personality Traits: Insights from Gambling Disorder.

The role of dopamine in the pathophysiology of gambling disorder (GD) remains incompletely understood, with disparate research findings concerning presynaptic and postsynaptic structures and dopaminergic synthesis. The aim of this study was to investigate potential correlations between striatal dopamine transporter (DAT) lateralization and asymmetry index, as assessed by 123I-FP-CIT SPECT, and temperamental traits, as measured by Cloninger's Temperament and Character Inventory (TCI), in GD subjects. Significant associations were found between DAT binding asymmetries in the caudate and putamen and the temperamental dimensions of harm avoidance and novelty seeking. Specifically, high novelty seeking scores correlated with increased DAT binding in the left caudate relative to the right, whereas higher harm avoidance scores corresponded to increased DAT binding in the right putamen relative to the left. These observations potentially imply that the asymmetry in DAT expression in the basal ganglia could be an outcome of hemispheric asymmetry in emotional processing and behavioural guidance. In summary, our study provides evidence supporting the relationship between DAT asymmetries, temperamental dimensions and GD. Future investigations could be directed towards examining postsynaptic receptors to gain a more comprehensive understanding of dopamine's influence within the basal ganglia circuit in disordered gambling. If confirmed in larger cohorts, these findings could have substantial implications for the tailoring of individualized neuromodulation therapies in the treatment of behavioural addictions.

Is Antipsychotic Drug Use During Pregnancy Associated with Increased Malformation Rates and Worsening of Maternal and Infant Outcomes? A Systematic Review.

There is much debate about continuing antipsychotic medication in patients who need it when they become pregnant because benefits must be weighed against potential teratogenic and malformation effects related to antipsychotics themselves. To address this, we conducted a systematic review on the PubMed, PsycINFO and CINHAL databases and the ClinicalTrials.gov register using the following strategy: (toxicity OR teratogenicity OR malformation* OR "birth defect*" OR "congenital abnormality" OR "congenital abnormalities" OR "brain changes" OR "behavioral abnormalities" OR "behavioral abnormalities") AND antipsychotic* AND (pregnancy OR pregnant OR lactation OR delivery OR prenatal OR perinatal OR post-natal OR puerperium) on September 27, 2023. We found 38 studies to be eligible. The oldest was published in 1976, while most articles were recent. Most studies concluded that the antipsychotics, especially the second-generation antipsychotics, were devoid of teratogenic potential, while few studies were inconclusive and recommended replication. Most authoritative articles were from the Boston area, where large databases were implemented to study the malformation potential of psychiatric drugs. Other reliable databases are from Northern European registers. Overall conclusions are that antipsychotics are no more related to malformations than the disorders themselves; most studies recommend that there are no reasons to discontinue antipsychotic medications in pregnancy.

Dopaminergic dysfunction in the left putamen of patients with major depressive disorder.

INTRODUCTION: Dopaminergic transmission impairment has been identified as one of the main neurobiological correlates of both depression and clinical symptoms commonly associated with its spectrum such as anhedonia and psychomotor retardation. OBJECTIVES: We examined the relationship between dopaminergic deficit in the striatum, as measured by 123I-FP-CIT SPECT imaging, and specific psychopathological dimensions in patients with major depressive disorder. METHODS: To our knowledge this is the first study with a sample of >120 subjects. After check for inclusion and exclusion criteria, 121 (67 females, 54 males) patients were chosen retrospectively from an extensive 1106 patients database of 123I-FP-CIT SPECT scans obtained at the Nuclear Medicine Unit of Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome. These individuals had undergone striatal dopamine transporter (DAT) assessments based on the recommendation of their referring clinicians, who were either neurologists or psychiatrists. At the time of SPECT imaging, each participant underwent psychiatric and psychometric evaluations. We used the following psychometric scales: Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Snaith Hamilton Pleasure Scale, and Depression Retardation Rating Scale. RESULTS: We found a negative correlation between levels of depression (p = 0.007), anxiety (p = 0.035), anhedonia (p = 0.028) and psychomotor retardation (p = 0.014) and DAT availability in the left putamen. We further stratified the sample and found that DAT availability in the left putamen was lower in seriously depressed patients (p = 0.027) and in patients with significant psychomotor retardation (p = 0.048). CONCLUSION: To our knowledge this is the first study to have such a high number of sample. Our study reveals a pivotal role of dopaminergic dysfunction in patients with major depressive disorder. Elevated levels of depression, anxiety, anhedonia, and psychomotor retardation appear to be associated with reduced DAT availability specifically in the left putamen.

Low Dose Pregabalin Improves Gastrointestinal Symptoms of Crohn's Disease.

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are lifelong conditions with no definite cure. Several studies demonstrated that patients with IBD more frequently experience symptoms of common mental disorders, such as anxiety and depression, because of bidirectional communication through the gut-brain axis and the chronicity of symptoms, as well as because of impaired quality of life and reduced social functioning. However, psychological conditions of affected patients are often underestimated and not fully considered. Herein, we present the case of a 37-year-old woman with Crohn's disease and a mild depressive condition, characterized by anxious distress, tachycardia, tachypnea, tremors, sweating, avoidant behaviors, and intestinal somatizations (diarrhea), who was treated with Pregabalin upon indication of the referring psychiatrist. Following the beginning of the treatment, the patient rapidly reported an improvement in the overall clinical symptoms as well as a better management of psychic and physical anxiety with a marked reduction in diarrheal discharges under stress at work. After 6 months of Pregabalin therapy, we additionally observed an improvement in Crohn's disease activity, both clinically, in the laboratory, and endoscopically. Our case showed that patients with Crohn's disease and anxiety problems may benefit from low-dose Pregabalin medication to improve both their mental and physical condition.

The Patient's Perspective on the Effects of Intranasal Esketamine in Treatment-Resistant Depression.

The effectiveness of the esketamine nasal spray (ESK-NS) for treatment-resistant depression (TRD) has been confirmed by real-world studies. Available evidence derived from clinician-rated assessments might differ from patients' perceptions about the helpfulness of treatments. We aimed to verify the effect of ESK-NS from patients' view in 25 TRD patients (56% males, 55.1 ± 10.9 years) treated with ESK-NS (mean dose: 78.4 ± 11.43 mg) for three months and evaluated at different time-points through clinician-rated and self-administered scales, assessing changes in depression, anhedonia, sleep, cognition, suicidality, and anxiety. We observed an overall early improvement that lasted over time (endpoint total score reduction in Montgomery-Åsberg Depression Rating Scale, p < 0.001, Beck Depression Inventory, p = 0.003). Patients reported a significant self-rated decrease in anhedonia at two months (Snaith-Hamilton Pleasure Scale, p = 0.04) and in suicide ideation at endpoint (BDI subitem 9, p = 0.039) vs. earlier improvements detected by clinicians (one-month reduction in MADRS subitem 8, p = 0.005, and subitem 10, p = 0.007). These findings confirm the effectiveness of a three-month treatment with ESK-NS in TRD patients, highlighting an overall overlapping response from patients' and clinicians' perspectives, although with some differential effects on specific symptoms at given time-points. Including patients' viewpoints in routine assessments could inform clinical practice, ensuring a better characterization of clinical phenotypes to deliver personalized interventions.

Reduction in Cognitive Symptoms Following Intranasal Esketamine Administration in Patients With Chronic Treatment-resistant Depression: A 12-Week Case Series.

BACKGROUND: Cognitive symptoms are a core feature of depressive disorders, interfere with full functional recovery and are prominent in patients with treatment-resistant depression (TRD), particularly in severe chronic cases. Intranasal (IN) esketamine was recently approved for the treatment of TRD; however, its effects on cognitive symptoms are unclear. In this article, we describe cognitive changes in 8 patients with chronic TRD who were treated with IN administration of esketamine. METHODS: Eight outpatients with chronic TRD received IN esketamine over 3 months and were assessed at baseline and after 4, 8, and 12 weeks of treatment using the Montgomery-Åsberg Depression Rating Scale (MADRS), the Digit Symbol Substitution Test (DSST), the Trail Making Test-B (TMT-B), the Patient Deficits Questionnaire for Depression 5-item (PDQ-D5), the Hamilton Anxiety Rating Scale (HARS), and the Clinical Global Impressions Scale (CGI). FINDINGS: We observed reductions in cognitive symptoms according to DSST, TMT-B, and PDQ-D5 scores within the first 2 months of treatment with IN esketamine. These improvements were observed before patients achieved clinical response (≥50% decrease in baseline MADRS scores), and they also occurred earlier than reductions in HARS scores. CONCLUSIONS: A clinical response to IN esketamine was detected in severely ill patients with chronic TRD after 3 months of treatment. Interestingly, improvements on measures of cognitive symptoms were observed before patients achieved antidepressant response. These preliminary observations suggest an additional value to the antidepressant properties of IN esketamine. Clinical studies specifically investigating cognition as a primary outcome measure of IN esketamine in TRD are warranted.

Psychological treatment of traumatic memories in COVID-19 survivors.

The COVID-19 pandemic, which has affected a significant number of individuals worldwide, is generating serious mental health issues. Recovered COVID-19 patients have experienced traumatic events related to their symptoms, isolation, possible hospitalization, bereavement, fear of infecting loved ones and the physical consequences of COVID-19. One effective psychological treatment for these patients is Eye Movement Desensitization and Reprocessing (EMDR). The aim of this paper is to describe the therapeutic intervention and effects of EMDR in a pool of COVID-19 survivors referred to an integrated psychological/psychiatric outpatient service. Twelve patients, comprising of nine males and three females, underwent EMDR psychotherapy from October 2020 to February 2022. Each patient received 8-16 weekly treatment sessions. The standard EMDR protocol of eight stages was administered to enable desensitization and reprocessing of four main targets: first positive swab, hospitalization, isolation and fear for relatives' health. Efficacy of EMDR was demonstrated by the significant improvement at clinical scale for subjective distress caused by traumatic events. For the therapists, carrying out these treatments was an intense and challenging experience. In fact, the perceived distance between therapist and patient was less defined than in other hospital settings because the pandemic affects everyone equally. However, with the widespread availability of vaccines and although the pandemic is still ongoing with the emergence of new variants, a window of improvement in the mental health landscape is starting to open up.

Trazodone Prolonged-Release Monotherapy in Cannabis Dependent Patients during Lockdown Due to COVID-19 Pandemic: A Case Series.

(1) Background: During the SARS-CoV-2 (COVID-19) pandemic, cannabis use increased relative to pre-pandemic levels, while forced home confinement frequently caused sleep/wake cycle disruptions, psychological distress, and maladaptive coping strategies with the consequent appearance of anxiety symptoms and their potential impact on substance use problems. (2) Aim: Long-acting trazodone (150 mg or 300 mg daily) has a potential benefit as monotherapy in patients with cannabis use disorder. The present work aims to investigate the effectiveness of trazodone in optimizing the condition of people with cannabis dependence under pandemic conditions. (3) Methods: All cases with cannabis use disorder were uniformly treated with long-acting trazodone 150 mg or 300 mg/day; their craving and clinical status were monitored through appropriate psychometric scales. Side effects were recorded as they were reported by patients. We described the cases of three young patients-one man and two women-who were affected by chronic cannabis use disorder and who experienced lockdown-related psychological distress and sought psychiatric help. (4) Results: The described cases highlight that the once-a-day formulation of trazodone seems to have a therapeutic role in patients with cannabis use disorder and to guarantee tolerability and efficacy over time. No significant side effects emerged. (5) Conclusions: The use of long-acting trazodone (150 mg or 300 mg daily) has a potential benefit as monotherapy in patients with cannabis use disorder. Trazodone deserves to be studied in terms of its efficacy for cannabis use disorder.

Remission of functional motor symptoms following esketamine administration in a patient with treatment-resistant depression: a single-case report.

Functional movement disorders (FMD) involve a broad range of abnormal involuntary movements not consistent with neurological diseases. These conditions often occur in combination with mood and anxiety disorders and are associated with poor clinical outcomes. We report the case of a 57-year-old woman diagnosed with treatment-resistant depression (TRD) and comorbid FMD treated with weekly intranasal administrations of esketamine over a six-month follow-up period. A comprehensive clinical and psychometric assessment was carried out at different time points. After 2 months of treatment, a complete remission of motor and axial functional disturbances (athetosis, trunk torsion and genuflections) was detectable, along with a progressive improvement in depressive symptoms during follow-up until full remission. According to novel lines of evidence, glutamatergic transmission might play a role in the pathophysiology of FMD through aberrant limbic-motor interactions. We report that treatment with esketamine, a noncompetitive N-methyl-d-aspartate glutamatergic receptor antagonist, was associated with remission of FMD symptoms in a patient with TRD. Pharmacological compounds modulating brain glutamatergic activity may be of potential benefit in the clinical management of FMD.

Hopelessness, Dissociative Symptoms, and Suicide Risk in Major Depressive Disorder: Clinical and Biological Correlates.

Background: Major depressive disorder (MDD) has different clinical presentations and is associated with neurobiological alterations. Hopelessness, anhedonia, and dissociation represent some of the most pervasive psychopathological symptoms that often lead to suicidal thoughts, attempts, and actions. To further research on the concept of depression endophenotypes, this study aimed to assess the possible relationships between hopelessness and other clinical and biological correlates (i.e., striatal dopaminergic dysfunction) in depressed patients. Methods: We recruited 51 subjects with MDD. All subjects underwent 123I-FP-CIT SPECT to assess striatal dopamine transporter (DAT) availability and a psychometric evaluation using the psychometric scale to assess depressive, anxious, dissociative, and hopelessness symptoms aside from suicidal ideation. Result: An inverse correlation between the hopelessness score and dopamine transporter availability in all basal ganglia was bilaterally found. (Right Putamen, r = -0.445, p < 0.01; Left Putamen, r = -0.454, p < 0.01; Right Caudate, r = -0.398, p < 0.01; Left Caudate, r = -0.467, p < 0.01) Moreover, a positive correlation was also found between hopelessness and dissociative symptoms. Conclusions: These results provide important evidence on the neurobiological and clinical correlates of different psychopathological symptoms of depression with potential implications in terms of devising more effective treatment programs.

Sensitivity to Climate and Weather Changes in Euthymic Bipolar Subjects: Association With Suicide Attempts.

BACKGROUND: Climate and weather are known to affect multiple areas of human life, including mental health. In bipolar disorder (BD), seasonality represents an environmental trigger for mood switches, and climatic variables may contribute to recurrences. Several studies reported seasonal and climatic-related variations in the rate of suicide attempts. Suicide risk is relevant in BD, with approximately 25% of patients attempting suicide. Therefore, this study aimed to assess sensitivity to weather and climatic variations in BD subjects and its relationship with lifetime suicide attempts. METHODS: Three hundred fifty-two euthymic BD and 352 healthy control subjects, homogeneous with respect to socio-demographic characteristics, were enrolled. All participants were administered the METEO-Questionnaire (METEO-Q) to evaluate susceptibility to weather and climatic changes. We also investigated the potential relationship between sensitivity to climate and weather and lifetime suicide attempts in BD patients. RESULTS: METEO-Q scores and the number of subjects reaching the cut-off for meteorosensitivity/meteoropathy were significantly higher in BD patients. Within the clinical group, BD subjects with lifetime suicide attempts obtained higher METEO-Q scores, with no differences between BD-I and BD-II. The number of suicide attempts directly correlated with METEO-Q scores. The presence of suicide attempts was associated with the physical and psychological symptoms related to weather variations. DISCUSSION: Our findings support the relevance of sensitivity to weather and climate variations in a large sample of BD subjects and point out the association of this feature with lifetime suicide attempts.

Dopaminergic and clinical correlates of high-frequency repetitive transcranial magnetic stimulation in gambling addiction: a SPECT case study.

Repetitive Transcranial Magnetic Stimulation (rTMS) shows the potential to modulate local brain activity, thus resulting in a modulatory action on neurocircuitries implicated in the pathophysiology of Gambling Disorder (GD). We report the case of a GD patient treated with two weeks of high frequency (15 Hz) rTMS over the dorsolateral prefrontal cortex (DLPFC). At baseline and after rTMS treatment the patient underwent a SPECT examination with (123)I-FP-CIT tracer, to test changes in dopamine transporter (DAT) availability. The patient was followed up for six months, to explore safety and clinical correlates of a weekly high frequency rTMS maintenance treatment. Over the six-month follow-up the patient reported no episodes of gambling relapse. Also, the patient did not report craving for gambling or gambling-related symptoms. After two weeks of left DLPFC-rTMS treatment, we found a decrease in DAT availability in striatal regions, that represents a putative neurobiological substrate of dopaminergic pathways modulation. This study suggests that high frequency DLPFC-rTMS deserves further investigations in larger samples, using controlled study designs, to assess its real potential as a treatment for GD.

Striatal presynaptic dopaminergic dysfunction in gambling disorder: A 123 I-FP-CIT SPECT study.

Although the involvement of dopamine in gambling disorder (GD) has long been hypothesized, its precise role remains unclear. The action of dopamine in the synapses is regulated by the dopamine transporter (DAT). We hereinafter present significant differences between a sample of 15 treatment-seeking GD subjects and 17 healthy controls in terms of striatal DAT availability, and we explore its association with reward-based decision making. We performed 123 I-FP-CIT Single-photon emission computed tomography (SPECT) and correlated DAT binding ratios in the bilateral caudate and putamen with gambling symptoms (G-SAS, PG-YBOCS) and behaviors, as well as other psychometric variables (anhedonia and impulsivity). Gambling disorder (GD) subjects were also administered a computerized version of the Iowa gambling task (IGT) to assess reward-based decision making. We found reduced DAT availability in GD subjects compared with healthy controls (-13.30% in right caudate, -11.11% in right putamen, -11.44% in left caudate, and -11.46% in the left putamen). We also found that striatal DAT availability was inversely correlated with days spent gambling and IGT performance in GD subjects. These results provide evidence for a presynaptic dopaminergic dysfunction in striatal regions of GD subjects. Functional DAT down-regulation possibly sustains the transition towards compulsive gambling addiction, characterized both by hyperdopaminergic and hypodopaminergic states in the context of a sensitized dopaminergic system.

Psychopathological Features of Bipolar Depression: Italian Validation of the Bipolar Depression Rating Scale (I-BDRS).

Background: Aim of the study was the validation of the Bipolar Disorder Rating Scale (BDRS) in an Italian population. Secondary aim was the evaluation of differences between unipolar and bipolar depression and between bipolar I and II depressed patients. Method: 125 Bipolar Disorder and 60 Major Depressive Disorder patients were administered an Italian translation of the BDRS (I-BDRS), Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS) and Temperament and Character Inventory-Revised (TCI-R). Results: I-BDRS showed considerable validity and reliability. Factor analysis found 3 subscales, two linked to depressive symptoms and one to mixed symptoms. Measures concerning depression (MADRS and HAM-D) were positively related to the I-BDRS's subscales, but mostly to the two subscales measuring depression. In mixed symptoms, the mean of the bipolar group was significantly higher than the unipolar group suggesting that the BDRS was able to distinguish between unipolar and bipolar depressed patients. Conclusion: I-BDRS is a valid scale for the measurement of depression in BD patients, with a notable internal consistency (Cronbach's α 0.82), a significant consistency between items/total (Cronbach's α from 0.80 to 0.82) and positive correlation with other scales (MADRS r = 0.67, p < 0.001; HDRS r = 0.81, p < 0.001; YMRS r = 0.46 p < 0.0001). The mixed state sub-scale shows usefulness in differentiating bipolar from unipolar patients. I-BDRS could be a sensitive tool, both in pure depression and in mixed states, and could be used in the everyday screening and treatment of Bipolar Disorder.

A Mixed Program of Psychoeducational and Psychological Rehabilitation for Patients With Bipolar Disorder in a Day Hospital Setting.

The present study describes a new mixed program of psychoeducational and psychological interventions for bipolar patients, applicable during everyday practice. Thirty-two bipolar patients recruited at a psychiatric day-hospital service have been admitted to a program consisting of 30 meetings and 2 follow-ups at 6 and 12 months. The psychoeducational support determined a general improvement of all included patients. At baseline, patients with residual depression had higher Hamilton Depression Rating Scale (HDRS) scores than euthymic patients (mean score ± SD: 21.25 ± 3.92 vs. 7.00 ± 2.95, respectively). After psychoeducation sessions, the HDRS scores of euthymic patients remained stable (mean ± SD: 7.00 ± 3.74), whereas the HDRS scores of depressed patients demonstrated a statistically significant improvement (mean ± SD: 14.00 ± 6.72, t = 2.721, p = 0.03). Results of the Connor-Davidson Resilience scale and specifically constructed questionnaire Questionario per la Valutazione della Conoscenza e dell'Apprendimento per il Disturbo Bipolare showed a statistically significant improvement in resilience and insight in all recruited patients. Psychoeducational intervention as adjunctive treatment to pharmacotherapy seems to be very effective in bipolar patients, not only for those in the euthymic phase, but this model could also be extended to patients with an ongoing mild or moderate depressive episode.

Deep Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex in Alcohol Use Disorder Patients: Effects on Dopamine Transporter Availability and Alcohol Intake.

Repetitive Transcranial Magnetic Stimulation (rTMS) of the dorsolateral prefrontal cortex may affect neuro-adaptations associated with alcohol use disorder (AUD), potentially influencing craving and alcohol intake. We investigated alcohol intake and dopamine transporter (DAT) availability by Single Photon Emission Computed Tomography (SPECT) in the striatum of AUD patients before and after deep rTMS. Fourteen patients underwent baseline clinical and SPECT assessment. Eleven out of fourteen patients were randomized into two groups for the REAL (n.5) or SHAM (n.6) treatment. Clinical and SPECT evaluations were then carried out after four weeks of rTMS sessions (T1). At baseline, AUD patients showed higher striatal DAT availability than healthy control subjects (HC). Patients receiving the REAL stimulation revealed a reduction in DAT availability at T1, whereas the SHAM-treated group did not. In addition, patients receiving the REAL stimulation had a decrease in alcohol intake. The results of this longitudinal pilot study may suggest a modulatory effect of deep rTMS on dopaminergic terminals and a potential clinical efficacy in reducing alcohol intake in AUD patients. Further investigations are required to confirm these preliminary data.

A meta-analysis of cognitive performance in melancholic versus non-melancholic unipolar depression.

BACKGROUND: Recently there is increasing recognition of cognitive dysfunction as a core feature of Major Depressive Disorder (MDD). The goal of the current meta-analysis was to review and examine in detail the specific features of cognitive dysfunction in Melancholic (MEL) versus Non-Melancholic (NMEL) MDD. METHODS: An electronic literature search was performed to find studies comparing cognitive performance in MEL versus NMEL. A meta-analysis of broad cognitive domains (processing speed, reasoning/problem solving, verbal learning, visual learning, attention/working memory) was conducted on all included studies (n=9). Sensitivity and meta-regression analyses were also conducted to detect possible effects of moderator variables (age, gender, education, symptom severity and presence of treatments). RESULTS: MEL patients were older and more severly depressed than NMEL subjects. The MEL group was characterized by a worse cognitive performance in attention/working memory (ES=-0.31), visual learning (ES=-0.35) and reasoning/problem solving (ES=-0.46). No difference was detected in drug-free patients by sensitivity analyses. No effect was found for any of our moderators on the cognitive performance in MEL vs NMEL. CONCLUSION: Our findings seem to support a moderate but specific effect of melancholic features in affecting the cognitive performance of MDD, in particular as regards visual learning and executive functions.