Are anxious and mixed depression two sides of the same coin? Similarities and differences in patients with bipolar I, II and unipolar disorders.

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.

Pramipexole Augmentation for Treatment-Resistant Unipolar and Bipolar Depression in the Real World: A Systematic Review and Meta-Analysis.

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.

Efficacy and safety of 24-week pramipexole augmentation in patients with treatment resistant depression. A retrospective cohort study.

Pramipexole is a dopamine agonist with potential antidepressant, neuroprotective, antioxidant and anti-inflammatory activity. In the present study we investigated the 24 weeks effect and safety of traditional AD augmentation with pramipexole for treatment-resistant depression. The study includes 116 patients, 37 (32%) with bipolar disorders and 79 (68%) with major depressive disorder, who failed to respond to at least 2 ADs trials of different classes and that were treated with AD augmented with pramipexole. Mood stabilizers and/or second-generation antipsychotics were added in patients with bipolar or mixed depression. Exclusion criteria were psychotic depression, rapid cycling bipolar course and previous unsuccessful treatment with pramipexole. After 24 weeks of pramipexole augmentation (median max dose 1.05 mg/day, IQR 0.72-1.08) 74.1% of patients responded (≥50% reduction of baseline Hamilton Depression Rating Scale21 total score) and 66.4% remitted (Hamilton Depression Rating Scale21 total score < 7). Global Assessment of Functioning score significantly increase from 53 (50-60) at baseline to 80 (71-81) at 24 weeks (Wilcoxon signed rank test = 8.174, p < 0.001]. Ten patients (8.6%) dropped out (8 due to side effects and 2 for lack of efficacy) and 1 experienced an induced hypomanic switch. No patient committed a suicide attempt, had suicidal ideation, needed hospitalization, reported lethargy, gambling, hypersexuality and compulsive shopping. The limitations of the study are the observational design, the lack of a control group, the inclusion of outpatients only, the unblinded outcomes assessment, and the flexibility of the add-on schedule. The findings of the present study showed that off-label use of pramipexole as augmentation of traditional AD is an effective and safe 24 weeks treatment of resistant unipolar and bipolar depression. These results need confirmation from randomized clinical trials on larger samples.

Which patients with bipolar depression receive antidepressant augmentation? Results from an observational multicenter study.

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.

Is short-term antidepressant treatment effective and safe in bipolar depression? Results from an observational multicenter study.

OBJECTIVES: To investigate the short-term effectiveness and the short-term and long-term safety of acute antidepressant (AD) treatment of bipolar depression in a naturalistic setting. METHODS: Patients with bipolar (n = 86) or unipolar (n = 111) depression were consecutively recruited and treated with AD (combined with mood stabilizer [MS] and/or second-generation antipsychotics in bipolar depression). Exclusion criteria were mixed depression, high mood instability, previous predominantly mixed depression (both bipolar and unipolar depression), rapid cycling course and previous switch AD-emerging (bipolar depression). RESULTS: After 12 weeks of treatment, no difference was found in remission, response and improvement rates between bipolar and unipolar depression. Concerning short-term safety, switching and suicidality did not differ significantly between the two groups, and no suicide attempt was observed. Concerning long-term safety, patients with bipolar depression had a significant reduction of depressive and total recurrences during the year of follow-up, compared to the year before entering the study, without significant changes in (hypo)mania and mixed depression recurrences, and suicide rates. CONCLUSIONS: Acute AD treatment of bipolar depression is effective in the short-term and safe in the short- and long-term, when administered in combination with MSs and/or second-generation antipsychotics, with a low risk of switch, mixed depression and cycle acceleration.

The relationship between depression with anxious distress DSM-5 specifier and mixed depression: a network analysis.

INTRODUCTION: Epidemiological, clinical, and treatment response characteristics of major depression with anxious distress (ADS) are quite similar to those of mixed depression, but no study investigated the symptom interplay of these conditions. OBJECTIVE: To analyze the correlations among symptom criteria for major depression with ADS and for mixed depression using a network analysis. METHODS: Two hundred and forty-one outpatients with major depression were consecutively recruited. DSM-5 criteria for major depression with ADS or with mixed features (MF) and Koukopoulos' criteria for mixed depression (MXD) were assessed using a structured clinical interview. RESULTS: A total of 58.9% of patients met DSM-5 criteria for major depression with ADS, 48.5% for MXD, and 2.5% for major depression with MF, so that the symptoms of this specifier were excluded from the network analysis. The most frequent symptoms were difficulty concentrating due to worries (57.7%), feeling keyed up or on edge (51%) (major depression with ADS), and psychic agitation or inner tension (51%) (MXD). Psychic agitation or inner tension had a central position in the network and bridged MXD to major depression with ADS through feeling keyed up or on edge. CONCLUSIONS: Criteria for major depression with ADS and for MXD are partially overlapping, with psychic agitation or inner tension and feeling keyed up or on edge that feature in both conditions and are difficult to distinguish in clinical practice. The clarification of the relationship between these two psychopathological conditions could bring important implications for diagnosis, prognosis, and treatment of depressive episodes.

Is there a relationship between depression with anxious distress DSM-5 specifier and bipolarity? A multicenter cohort study on patients with unipolar, bipolar I and II disorders.

BACKGROUND: To estimate the prevalence of DSM-5 anxious distress specifier (ADS) in depressed patients with major depressive disorder (MDD) or bipolar I or II disorder (BD), and to compare socio-demographic and clinical characteristics, and response to naturalistic short-term treatment between ADS and non-ADS group. METHODS: 241 outpatients with a major depressive episode (MDE) were consecutively recruited. Outcome were remission (HDRS21 total score < 7), response (≥50% reduction of baseline HDRS21) and improvement (CGI-i score ≤ 2) after 12 weeks of treatment sustained for 4 weeks. RESULTS: ADS was more frequent in BD than in MDD (respectively, 66.9% and 51.2%, χ2 = 6.1, p = 0.013). Compared with those non-ADS, patients with ADS had more severe depressive (respectively, HDRS21 total score 20.0 ±â€¯4.4 and 18.6 ±â€¯3.9, t-test = 2.67, p = 0.008) and mania symptoms (respectively, Y-MRS total score 2.2 ±â€¯2.9 and 1.3 ±â€¯2.3, M-W-test = 2.86; p = 0.004) at intake, a higher rate of BD family history (respectively, 35.2% and 22.2%, Χ2-test 10.4, p = 0.004) and more previous hypomanic episodes (respectively, (median (range) 0 (0-20) and 0 (0-15), MW-test = 2.39 p = 0.017). In the MDD group, patients with ADS had higher scores on hyperthymic temperament and mania symptoms (Y-MRS total score (median (range) 2.2 (0-26) and 0 (0-11), respectively, M-W test 2.071, p = 0.038). ADS and no-ADS patients did not significantly differ on outcome measures. LIMITATIONS: The observational nature of the study and the absence of blinding in outcome assessment. CONCLUSIONS: ADS is the most common DSM-5 specifier for MDE, is more frequent in BD and need a personalized treatment with moderate use of antidepressants, mostly tricyclic.

Treatment of Hypochondriasis in Two Schizophrenia Patients Using Clozapine.

Hypochondriasis (HYPO), an obsessive-compulsive spectrum disorder, is frequent in patients with schizophrenia (SCH) (20%), especially among those treated with clozapine (36.7%). Treatment options for OCS/OCD in patients under clozapine (CLZ) include combining clozapine with amisulpride/aripiprazole or a mood stabilizer, augmenting clozapine with a serotoninergic reuptake inhibitor, adding cognitive behavioural therapy, and gradually reducing dosage. No treatments have been proposed for HYPO in patients using clozapine so we examine these options in 2 cases and report the results. Among treatments delivered, only dosage reduction adequately worked. We recommend caution when thinking about escalating treatment and suggest trying it only when alternative interventions were not successful and weighing risk and benefits of this therapeutic strategy. Further research is needed to confirm the hypothesis that CLZ treatment induces hypochondriac symptoms, to investigate the prevalence of the phenomenon, and, mostly, to identify possible treatment strategies.

Pharmacologic approaches to treatment resistant depression: Evidences and personal experience.

AIM: To review evidence supporting pharmacological treatments for treatment-resistant depression (TRD) and to discuss them according to personal clinical experience. METHODS: Original studies, clinical trials, systematic reviews, and meta-analyses addressing pharmacological treatment for TRD in adult patients published from 1990 to 2013 were identified by data base queries (PubMed, Google Scholar e Quertle Searches) using terms: "treatment resistant depression", "treatment refractory depression", "partial response depression", "non responder depression", "optimization strategy", "switching strategy", "combination strategy", "augmentation strategy", selective serotonin reuptake inhibitors antidepressants (SSRI), tricyclic antidepressants (TCA), serotonin norepinephrine reuptake inhibitors antidepressants, mirtazapine, mianserine, bupropione, monoamine oxidase inhibitor antidepressant (MAOI), lithium, thyroid hormones, second generation antipsychotics (SGA), dopamine agonists, lamotrigine, psychostimulants, dextromethorphan, dextrorphan, ketamine, omega-3 fatty acids, S-adenosil-L-metionine, methylfolat, pindolol, sex steroids, glucocorticoid agents. Other citations of interest were further identified from references reported in the accessed articles. Selected publications were grouped by treatment strategy: (1) switching from an ineffective antidepressant (AD) to a new AD from a similar or different class; (2) combining the current AD regimen with a second AD from a different class; and (3) augmenting the current AD regimen with a second agent not thought to be an antidepressant itself. RESULTS: Switching from a TCA to another TCA provides only a modest advantage (response rate 9%-27%), while switching from a SSRI to another SSRI is more advantageous (response rate up to 75%). Evidence supports the usefulness of switching from SSRI to venlafaxine (5 positive trials out 6), TCA (2 positive trials out 3), and MAOI (2 positive trials out 2) but not from SSRI to bupropione, duloxetine and mirtazapine. Three reviews demonstrated that the benefits of intra- and cross-class switch do not significantly differ. Data on combination strategy are controversial regarding TCA-SSRI combination (positive results in old studies, negative in more recent study) and bupropion-SSRI combination (three open series studies but not three controlled trails support the useful of this combination) and positive regard mirtazapine (or its analogue mianserine) combination with ADs of different classes. As regards the augmentation strategy, available evidences supported the efficacy of TCA augmentation with lithium salts and thyroid hormone (T3), but are conflicting regard the SSRI augmentation with these two drugs (1 positive trial out of 4 for lithium and 3 out of 5 for thyroid hormone). Double-blind controlled studies showed the efficacy of AD augmentation with aripiprazole (5 positive trials out 5), quetiapine (3 positive trials out 3) and, at less extent, of fluoxetine augmentation with olanzapine (3 positive trials out 6), so these drugs received the FDA indication for the acute treatment of TRD. Results on AD augmentation with risperidone are conflicting (2 short term positive trials, 1 short-term and 1 long-term negative trials). Case series and open-label trials showed that AD augmentation with pramipexole or ropinirole, two dopamine agonists, could be an effective treatment for TRD (response rate to pramipexole 48%-74%, to ropinirole 40%-44%) although one recent double-blind placebo-controlled study does not support the superiority of pramipexole over placebo. Evidences do not justify the use of psychostimulants, omega-3 fatty acids, S-adenosil-L-metionine, methylfolate, pindolol, lamotrigine, and sex hormone as AD augmentation for TRD. Combining the available evidences with our experience we suggest treating non-responders to one SSRI bupropion or mirtazapine trial by switching to venlafaxine, and non-responders to one venlafaxine trial by switching to a TCA or, if TCA are not tolerated, combining mirtazapine with SSRI or venlafaxine. In non-responders to two or more ADs (including at least one TCA if tolerated) current AD regimen could be augmented with lithium salts (mainly in patients with bipolar depression or suicidality), SGAs (mostly aripiprazole) or DA-agonists (mostly pramipexole). In patients with severe TRD, i.e., non-responders to combination and augmentation strategies as well as to electroconvulsive therapy if workable, we suggest to try a combination plus augmentation strategy. CONCLUSION: Our study identifies alternative effective treatment strategies for TRD. Further studies are needed to compare the efficacy of different strategies in more homogeneous subpopulations.

Short-term antidepressant treatment of bipolar depression: are ISBD recommendations useful in clinical practice?

OBJECTIVES: The study aimed to test the effectiveness of the ISBD Guidelines for short-term AD treatment of BP depression. METHODS: The study sample included 255 patients with mood disorders (154 UP, 49 BP-I, 52 BP-II). Response was defined as a HDRS21 total score<7 at 12 weeks of treatment and remission as a ≥50% reduction of baseline HDRS21 total score sustained for 8 weeks. RESULTS: Response was achieved by 64.9% of patients with UP disorder, 75.5% of patients with BP-I disorder and 75.0% with BP-II disorder without significant differences (χ²=3.0, p=0.219). The remission rate did not differ significantly among groups (χ²=3.8, p=0.151). The dropout rate was significantly higher for patients with UP (18.2%) than for patients with BP-I (2%) and BP-II (7.7%) disorder (χ²=10.1, p=0.006). Concerning AD safety, one patient with BP-I depression committed a suicide attempt and AD-emerging switch was observed in 2.9% of patients, 2 with BP-I and 1 with BP-II disorder. LIMITATIONS: The observational nature of the study and unblinded outcomes assessment. CONCLUSIONS: Our findings confirm the usefulness of ISBD Guidelines for short-term AD treatment of BP depression. These patients appear to have similar response and remission rate to those observed in UP depression and do not exhibit significant switch rates or risk of suicide. Our results are limited to patients with pure bipolar depression (excluding those with broadly defined mixed states), treated with ADs-mood stabilizers combination. We suggest to partially modify ISBD Recommendations 1 and 4, to include potential responders and to improve safety.

Continuous circular cycling in bipolar disorder as a predictor of poor outcome.

OBJECTIVE: This prospective study aims to determine if patients with bipolar disorder with a continuous circular course (CCC) are significantly different on clinical characteristics and response to long-term treatment from those with a non-continuous circular course (N-CCC). CCC was defined as the alternation of depression and (hypo)mania without a completely free interval, and N-CCC as the presence of free intervals after the sequence mania-depression or depression-mania. METHOD: The study sample includes 140 consecutive patients with bipolar I or II disorder according to DSM-IV criteria, aged 18-65 years and receiving prophylactic treatment for. Treatment was based upon international guidelines and clinical experience at the time of patient's enrollment (from January 1998 to January 2006). Primary outcome was the absence of new episodes during the follow-up. Significance level was set at p<0.05. RESULTS: Twenty-eight percent of the sample has CCC. Compared with N-CCC, CCC patients were older, had a later onset, a higher number of total, depressive and (hypo)manic episodes, and of switches, and spent a higher percentage of time ill in the year before entering the study. Polarity at onset and subsequent recurrences were more frequently mixed in N-CCC than in CCC patients. The proportion of patients in the CCC group who had no recurrences during the follow-up was significantly lower than in the N-CCC group. CONCLUSION: The presence or absence of a free intervals over the course of illness identifies two subtypes of bipolar disorder that differ in clinical presentation, outcome, and response to long-term treatment.

Pregabalin, tiapride and lorazepam in alcohol withdrawal syndrome: a multi-centre, randomized, single-blind comparison trial.

INTRODUCTION: The aim of this trial was to compare lorazepam with non-benzodiazepine medications such as pregabalin and tiapride in the treatment of alcohol withdrawal syndrome (AWS). These drugs were chosen for their inhibitorial effects on the hypersecretion of neurotransmitters usually observed in AWS. Craving reduction and improvement of psychiatric symptoms were the secondary end-points. METHODS: One hundred and ninety subjects affected by current alcohol dependence were considered consecutively: 111 were enrolled and divided into three groups of 37 subjects each. Within a treatment duration of 14 days, medication was given up to the following maximum doses (pregabalin 450 mg/day; tiapride 800 mg/day; lorazepam 10 mg/day). Withdrawal (CIWA-Ar), craving [visual analogue scale (VAS); Obsessive and Compulsive Drinking Scale (OCDS)], psychiatric symptoms [Symptom Check List 90 Revised (SCL-90-R)] and quality of life (QL-index) rating scales were applied. RESULTS: On the CIWA-Ar score, all the groups showed a significant reduction between times (P < 0.001) with a higher reduction for the pregabalin group (P < 0.01) on items regarding headache and orientation. Retention in treatment was lower in the tiapride group (P < 0.05), while the number of subjects remaining alcohol free was higher in the pregabalin group (P < 0.05). Significant reduction between baseline and the end of the treatment was found in all the groups at the OCDS and the VAS for craving, at the SCL-90-R and QL-index (P < 0.001). DISCUSSION: All the medications in the trial showed evidence of safety and efficacy in the treatment of uncomplicated forms of AWS, with some particular differences. The efficacy of pregabalin was superior to that of tiapride, used largely in research trials and, for some measures, to that of the 'gold standard', lorazepam. Accordingly, pregabalin may be considered as a potentially useful new drug for treatment of AWS, deserving further investigation.