Antonio Tundo

Background: At least 50% of patients with treatment-resistant depression (TRD) fail to respond to antidepressant augmentation with aripiprazole (AA), currently the augmentation strategy with the best evidence of efficacy. The present observational study investigated whether pramipexole augmentation (PA) might be useful for patients who failed AA. Methods: We compared the short- and long-term effectiveness and safety of PA in 81 consecutively recruited unipolar patients with TRD, 58 (71.6%) not previously treated with AA (UAA) and 23 (28.4%) who previously failed AA (FAA). Results: The FAA and UAA groups did not differ significantly in terms of remission, response, improvement, and general functioning at 12 and 24 weeks and in terms of freedom from relapse at 12 and 24 months. The response rates at 24 weeks were 69.6% (n = 16) and 77.6% (n = 45), and the remission rates were 60.9% (n = 14) and 74.1% (n = 43), respectively. The rates of sustained response at 24 months were 72.7% (n = 8) and 84.2% (n = 16), respectively. The 2 groups did not differ significantly on safety outcomes (acceptability, tolerability, suicidality and suicide attempts) in the short and long term. Conclusions: Our study showed that the off-label use of PA may be a promising treatment for patients with unipolar TRD who had previously failed respond to AA. The present findings are preliminary and should be interpreted with caution due to study limitations, including the flexibility of the add-on schedule and the small sample size of patients followed up for 12 and 24 months, and need to be confirmed in larger studies.

Background: This study compares the short- and long-term effectiveness and safety of pramipexole augmentation (PA) and aripiprazole augmentation (AA) for unipolar treatment-resistant depression (TRD). Methods: Patients were recruited in a private out-patients clinic specializing in mood disorders. At intake and at each visit, depressive and (hypo)manic symptoms, clinical status, and level of functioning were evaluated with appropriate scales. The trend of outcomes was analyzed using mixed-effect linear regression models. Results: The study includes 81 patients with unipolar TRD treated with PA and 51 with AA. After 12 and 24 weeks of treatment with PA, the predicted response (64.1% and 76.2%) and remission rates (49.7% and 72.7%) were significantly higher than the predicted response (32.2% and 38.0%) and remission rates (18.9% and 28.1%) for AA. The improvement in psychosocial functioning was significantly greater and faster in PA than in AA. PA showed significant superiority over AA as a maintenance strategy (time spent ill and psychosocial functioning) up to 12 months. No difference in safety was found at each time point. Conclusions: PA could be an alternative option for the short- and long-term treatment of unipolar TRD, more effective than AA and similar in safety. These preliminary results need confirmation from randomized clinical trials.

Background. This study compares the short- and long-term effectiveness and safety of pramipexole augmentation (PA) and aripiprazole augmentation (AA) for unipolar treatment-resistant depression (TRD). Methods. Patients were recruited in a private out-patients clinic specialized in mood disorders. At intake and at each visit depressive and (hypo)manic symptoms, clinical status, and level of functioning were evaluated with appropriate scales. The trend of outcomes was analyzed using mixed-effect linear regression models. Results. The study includes 81 unipolar TRD patients treated with PA and 51 with AA. After 12 and 24 weeks of treatment with PA, the predicted response (64.1% and 76.2%) and remission rates (49.7% and 72.7%) were significantly higher than the predicted response (32.2% and 38.0%) and remission rates (18.9% and 28.1%) for AA. The improvement in psychosocial functioning was significantly greater and faster in PA than in AA. PA showed significant superiority over AA as a maintenance strategy (time spent ill and psychosocial functioning) up to 12 months. No difference in safety was found at each time point. Conclusions. PA could be an alternative option for short and long-term treatment of unipolar TRD, more effective and similar in safety with AA. These preliminary results need confirmation from randomized clinical trials.

Background: Diagnostic criteria are not always useful to discriminate major depression with anxious distress (ADS-D; Diagnostic and Statistical Manual for Mental Disorders, version-5 [DSM-5] criteria) from mixed depression (Koukopoulos’ criteria; KMX-D). So, clinicians need alternative tools to improve their diagnostic ability and to choose the most appropriate treatment. The aim of the present study is to identify socio-demographic and clinical features that discriminate patients with ADS-D from those with KMX-D. Methods: Two hundred and forty-one consecutive outpatients with unipolar (51%) and bipolar (49%) disorder, fulfilling DSM-5 criteria for a current major depressive episode (MDE) and with a 21-item Hamilton Depression Rating Scale score ≥ 14, were recruited and treated in a prospective observational study. Results: Ten percent of patients met criteria for KMX-D, 22% ADS-D, and 37% for both. Irritable premorbid temperament, mixed depression polarity at onset, mixed depression recurrence, and a high number of mania symptoms at intake were typical features of patients with KMX-D. Depressive polarity at onset, a low number of mania symptoms at intake, and generalized anxiety disorder comorbidity were typical features of patients with ADS-D. Multinomial logistic regression confirmed that higher rate of irritable temperament and higher Young Mania Rating Scale total score differentiated patients with KMX-D from patients with pure MDE. Conclusion: Our findings suggest some clinical features that could help differentiate between ADS-D and KMX-D in patients meeting both conditions and to select the appropriate treatment. However, the small sample size may have limited the power to detect differences between the groups. Further research is needed to confirm the results of present study.

Background: Pramipexole is a dopamine full agonist approved for the treatment of Parkinson’s disease and restless legs syndrome. Its high affinity for the D3 receptor and neuroprotective, antioxidant, and anti-inflammatory activity provides a rationale for the treatment of depression. In this paper, we review studies on the effectiveness and safety of antidepressant pramipexole augmentation in treatment-resistant depression. Methods: This comprehensive systematic review and meta-analysis of observational studies on pramipexole–antidepressant augmentation included patients with resistant unipolar and bipolar depression. The primary outcome measure was the treatment response, measured at the study endpoint. Results: We identified 8 studies including 281 patients overall, 57% women and 39.5% with bipolar disorder and 60.5% with major depressive disorder. The mean follow-up duration was 27.3 weeks (range 8–69). The pooled estimate of treatment response was 62.5%, without significant differences between unipolar and bipolar depression. Safety was good, with nausea and somnolence the most frequent side effects. Conclusions: The findings of this systematic review, needing further confirmation, show that off-label use of pramipexole as augmentation of antidepressant treatment could be a useful and safe strategy for unipolar and bipolar treatment-resistant depression.

Six in ten patients with obsessive-compulsive disorder (OCD) do not respond to the first-line treatments with serotonin reuptake inhibitor (SRI) or cognitive behavioural therapy including exposure and response prevention (CBT/ERP), and several do not respond to second-line treatments, i.e., SRI-second generation antipsychotic (SGA) or SRI-CBT/ERP augmentation. Evidence on third-line treatments is inconsistent. We investigated the 1-year response to SRI-CBT/ERP-SGA combination in patients with severe treatment-resistant OCD, who failed to respond to SRI and to SRI-SGA or SRI-CBT/ERP augmentation. Twenty-eight patients were consecutively recruited and treated with SRI (drug(s) and doses previously administered), SGA (risperidone median dosage 1 mg/day in 14 cases, aripiprazole median dosage 3 mg/day in 14 cases) and CBT/ERP (median hours 32.5). Exclusion criteria: mental retardation and organic brain syndrome. The mean Y-BOCS total score reduction at 12 months was 28.2%, 60.7% of patients improved, 46.4% partially responded, 32.1% responded, and 28.6% remitted. Patients previously resistant to SRI-SGA and SRI-CBT/ERP did not significantly differ in the rates of improvement, partial response, response and remission. This study suggests that SRI-SGA-CBT/ERP combination could be useful for severe treatment-resistant OCD. Small sample size is a limitation.

Background: To identify demographic and clinical characteristics of bipolar depressed patients who require antidepressant (AD) augmentation, and to evaluate the short- and long-term effectiveness and safety of this therapeutic strategy.Methods: One hundred twenty-two bipolar depressed patients were consecutively recruited, 71.7% of them received mood stabilizers (MS)/second-generation antipsychotics (SGA) with AD-augmentation and 28.3% did not. Patients were evaluated at baseline, and after 12 weeks and 15 months of treatment.Results: The AD-augmentation was significantly higher in patients with bipolar II compared with bipolar I diagnosis. Patients with MS/SGA + AD had often a seasonal pattern, depressive polarity onset, depressive index episode with anxious features, a low number of previous psychotic and (hypo)manic episodes and of switch. They had a low irritable premorbid temperament, a low risk of suicide attempts, and a low number of manic symptoms at baseline. After 12 weeks of treatment, 82% of patients receiving ADs improved, 58% responded and 51% remitted, 3.8% had suicidal thoughts or projects, 6.1% had (hypo)manic switch, and 4.1% needed hospitalization. During the following 12 months, 92% of them remitted from index episode, 25.5% did not relapse, and 11% needed hospitalization. Although at the start advantaged, patients with AD-augmentation, compared with those without AD-augmentation, did not significantly differ on any outcome as well on adverse events in the short- and long-term treatment.Conclusion: Our findings indicate that ADs, combined with MS and/or SGA, are short and long term effective and safe in a specific subgroup for bipolar depressed patients.

Background and Objectives: This observational prospective study aims to examine the psychological and psychopathological impact of the pandemic stress on patients with pre-existing mood, anxiety and obsessive–compulsive disorders. Materials and Methods: The study includes 386 consecutive patients recruited from 10 March to 30 June 2020 among those being treated at the Institute of Psychopathology in Rome (Italy) with an age ≥18 years and meeting DSM-5 criteria for major depressive disorder (MDD) (35.2%), bipolar I (BD-I) (21.5%) or II (BD-II) (28.8%) disorder, obsessive–compulsive disorder (OCD) (7.5%), panic disorder (PD) (7.0%) or social anxiety (SA). A total of 34.2% had lifetime comorbid Axis I disorders and 15.3% had alcohol/drug abuse disorders. Using a semi-structured interview, we investigated if the impact of COVID-19 stress for patients has been similar, higher or lower than that of their family and friends and, for patients with relapse/symptoms worsening, if there was a relationship between the clinical condition worsening and the pandemic stress. Results: Compared with that experienced by their family members and friends, the psychological impact of pandemic stress was similar in 52.1% of the sample, better in 37.1% and worse in 10.8%. In 21 patients (5.4%), the stress triggered a recurrence or worsened the symptoms. Patients with OCD had a higher rate of worsening due to pandemic stress compared to patients with MDD (p = 0.033), although, overall, the χ² test was not significant among primary diagnoses (χ² = 8.368; p = 0.057). Conclusions: The psychological and psychopathological consequences of COVID-19 stress in our outpatients were very modest. The continuity of care offered during the lockdown could explain the results.