Quetiapine and classical mood stabilizers in the long-term treatment of Bipolar Disorder: a 4-year follow-up naturalistic study

BACKGROUND: The aim of this naturalistic study was to compare the effectiveness of quetiapine and classical mood stabilizers, as mono- or combination therapy, in the long-term treatment of Bipolar Disorder (BD). METHODS: 232 DSM-IV BD I (n=91) or BD II (n=141) patients, treated and followed up for four years, were studied. Mood stabilizers were chosen by the treating psychiatrists on the basis of their clinical judgement. The sample was subdivided into 6 treatment groups: quetiapine (n=41), lithium (n=39), sodium valproate (n=73), lamotrigine (n=31), quetiapine plus lithium (n=25), and quetiapine plus sodium valproate (n=23). Throughout the 4-year follow-up period patients were assessed monthly, or whenever a recurrence occurred, by the administration of HAMD-21 and of the YMRS. Primary outcome measures were the duration of euthymia and the cumulative proportion of subjects who maintained euthymia. Kaplan-Meier survival analyses were done to tabulate and compare the differences in survival distributions across the different treatment groups (Log-Rank Mantel-Cox test). RESULTS: The combined treatments with quetiapine plus lithium or sodium valproate were more effective overall in maintaining euthymia, (percentages of patients who maintained euthymia: 29.3% for quetiapine, 46.2% for lithium, 32.9% for sodium valproate, 41.9% lamotrigine, 80% for quetiapine plus lithium, and 78.3% for quetiapine plus sodium valproate). In addition, quetiapine monotherapy was as effective as lithium monotherapy or combination treatment with lithium or sodium valproate in preventing the recurrence of major depressive episodes. LIMITATION: The main limitations of the study are the lack of randomized, controlled conditions and the low doses of quetiapine used. CONCLUSION: If the results from this study will be replicated, there will be important implications for the use of quetiapine in the long-term treatment of BD.     

Intravenous augmentative citalopram versus clomipramine in partial/nonresponder depressed patients: a short-term, low dose, randomized, placebo-controlled study

The aim of the present study was to evaluate the efficacy of short-term low-dose intravenous augmentative citalopram (10 mg/d) versus clomipramine (25 mg/d) versus placebo in a sample of patients with MDE and partial or no response to selective serotonin reuptake inhibitors (SSRIs). Fifty-four patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, MDE and partial or no response to SSRIs per os (21-item Hamilton Depression Rating Scale [HAM-D21] score reduction, <50% or < or =25%, respectively, compared with pretreatment scores) were selected and randomized to citalopram (n = 18), clomipramine (n = 18), or placebo (n = 18) intravenous augmentation. The augmentation regimen lasted 5 days during which patients were maintained on their previous treatment with oral SSRIs. Analyses of variance with repeated measures on HAM-D(21), collected daily in blind-raters design, were performed to detect any change of depressive symptoms between the 3 groups. In addition, the number of responders and remitters was computed in the 3 groups of treatment. At end point, a significant treatment effect (F= 4.57; P = 0.015) and time-by-treatment effect (F = 11.22; P < 0.0001) were found on HAM-D21 total scores in favor of citalopram and clomipramine versus placebo, with a superiority of citalopram over clomipramine on overall symptoms (P = 0.05) as well as on anxiety-somatization symptoms (P = 0.027). The number of responders was significantly superior in the active treatment groups versus the placebo group ([chi](2)(2) = 16.36; P < 0.0001). The same result was found, considering the number of remitters ([chi](2)(2) = 13.50; P < 0.0001). Present findings suggest that both clomipramine and citalopram intravenous augmentation at low doses and for a short period are well tolerated and superior to placebo in major depressives with partial or no response to oral SSRIs with a possible superiority of citalopram over clomipramine with regard to anxiety-somatization symptoms. The lack of double-blind conditions and the limited sample size may limit the confidence in the reported results, and larger randomized controlled trials are warranted to confirm the present findings.     

Augmentative repetitive navigated transcranial magnetic stimulation (rTMS) in drug-resistant bipolar depression

Objectives:  The efficacy of transcranial magnetic stimulation (TMS) has been poorly investigated in bipolar depression. The present study aimed to assess the efficacy of low-frequency repetitive TMS (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) combined with brain navigation in a sample of bipolar depressed subjects.
Methods:  Eleven subjects with bipolar I or bipolar II disorder and major depressive episode who did not respond to previous pharmacological treatment were treated with three weeks of open-label rTMS at 1 Hz, 110% of motor threshold, 300 stimuli/day.
Results:  All subjects completed the trial showing a statistically significant improvement on the 21-item Hamilton Depression Rating Scale (HAM-D), Montgomery-Åsberg Depression Rating Scale, and Clinical Global Impression severity of illness scale (ANOVAs with repeated measures: F  =   22.36, p < 0.0001; F  =   12.66, p < 0.0001; and F  =   10.41, p < 0.0001, respectively). In addition, stimulation response, defined as an endpoint HAM-D score reduction of ≥50% compared to baseline, was achieved by 6 out of 11 subjects, 4 of whom were considered remitters (HAM-D endpoint score ≤ 8). Partial response (endpoint HAM-D score reduction between 25% and 50%) was achieved by 3/11 patients. No manic/hypomanic activation was detected during the treatment according to Young Mania Rating Scale scores (ANOVAs with repeated measures: F  =   0.62, p = 0.61). Side effects were slight and were limited to the first days of treatment.
Conclusions:  Augmentative low-frequency rTMS of the right DLPFC combined with brain navigation was effective and well tolerated in a small sample of drug-resistant bipolar depressive patients, even though the lack of a sham controlled group limits confidence in the results.     

Augmentative quetiapine in partial/nonresponders with generalized anxiety disorder: a randomized, placebo-controlled study

Generalized anxiety disorder (GAD) is a chronic and disabling condition. The aim of this study was to evaluate the effectiveness of low-dose augmentative quetiapine (mean dose=50 mg/day) in patients with GAD and partial/no response to selective serotonin reuptake inhibitors (SSRIs). Twenty patients with GAD and partial/no response to SSRIs were randomized to quetiapine (n=10) or placebo (n=10) for 8 weeks, continuing their treatment with SSRIs. Analyses of variance with repeated measures on Hamilton Anxiety Rating Scale (HAM-A) and Clinical Global Impression (CGIs; severity of illness) were carried out at baseline and after 8 weeks and the number of responders/remitters was computed and compared between the groups. HAM-A scores at baseline were 15.60 (± 4.48) in the placebo group and 18.50 (± 6.59) in the quetiapine group, and at the end-point, HAM-A scores in the placebo group were 10.40 (± 4.88) and 9.20 (± 5.86) in the quetiapine group. A significant time-by-treatment effect was found on the HAM-A (F=5.19, P=0.035) and CGIs scores (F=19.60, P<0.001) in favor of the quetiapine group. The number of responders was numerically superior in the quetiapine group (60 vs. 30%) without reaching statistical significance (χ=1.82, degree of freedom=1, P=0.37, φ=0.30). Remitters were 40% for the quetiapine group versus 20% for the placebo group (χ=0.95, degree of freedom=1, P=0.63, φ=0.22). Low-dose augmentative quetiapine may be an useful treatment option for patients with GAD and partial/no response to SSRIs. The lack of double-blind conditions and the limited sample size may limit the confidence in the reported results. Larger randomized controlled trials are warranted to confirm these data.     

The influence of age at onset and duration of illness on long-term outcome in patients with obsessive-compulsive disorder: A report from the International College of Obsessive Compulsive Spectrum Disorders (ICOCS)

Several studies reported a negative effect of early onset and long duration of illness on long-term outcome in psychiatric disorders, including Obsessive-Compulsive Disorder (OCD). OCD is a prevalent, comorbid and disabling condition, associated with reduced quality of life and overall well-being for affected patients and related caregivers. The present multicenter naturalistic study sought to assess the influence of early onset and duration of illness on long-term outcome in a sample of 376 OCD out-patients worldwide, as part of the “International College of Obsessive-Compulsive Spectrum Disorders” (ICOCS) network. Binary logistic regressions were performed with age at the onset and duration of illness, as continuous independent variables, on a series of different outcome dependent variables, including lifetime number of hospitalizations and suicide attempts, poly-therapy and psychiatric comorbidity. Correlations in terms of disability (SDS) were analyzed as well. Results showed that a longer duration of illness (but not earlier age of onset) was associated with hospitalization (odds ratio=1.03, p=0.01), earlier age at onset with CBT (odds ratio=0.94, p<0.001) and both a later age at onset (odds ratio=1.05, p=0.02) and a shorter duration of illness (odds ratio=0.93, p=0.02) with panic disorder comorbidity. In addition, earlier age at onset inversely correlated with higher social disability (r=?0.12, p=0.048) and longer duration of illness directly correlated with higher disability in work, social and family life (r=0.14, p=0.017; r=0.13, p=0.035; r=0.14, p=0.02). The findings from the present large, multicenter study indicate early onset and long duration of illness as overall negative predictors of long-term outcome in OCD.     

Duration of untreated illness and suicide in bipolar disorder: a naturalistic study

The aim of this naturalistic study was to evaluate the potential influence of the duration of untreated illness (DUI)—defined as the time elapsed between the occurrence of the first mood episode and the first adequate pharmacological treatment with mood stabilizers—on the clinical course of bipolar disorder (BD). Three hundred and twenty outpatients (n = 320) with a DSM-IV diagnosis of BD—either Type I or Type II—were interviewed; their clinical features were collected and they were naturalistically followed-up for 5 years. At the end of the follow-up observation, the sample was subdivided into two groups: one group with a DUI ≤2 years (n = 65) and another group with a DUI >2 years (n = 255). The main demographic and clinical variables were analyzed and compared between the two subgroups of patients using chi-square tests for dichotomous variables or Mann–Whitney U tests for continuous variables. Patients with a longer DUI showed a higher frequency of suicide attempts (Z = −2.11, P = 0.035), a higher number of suicide attempters (χ² = 4.13, df = 1, P = 0.04), and a longer duration of illness (Z = −6.79, P < 0.0001) when compared to patients with a shorter DUI. Moreover, patients with a longer DUI had a depressive first episode more frequently than patients with a shorter DUI (χ² = 11.28, df = 2, P = 0.004). A further analysis performed dividing the total sample into two subgroups on the basis of a DUI of 6 years (corresponding to the median value of the DUI in the study sample) confirmed prior findings. Results indicate a potential association between a longer DUI and a worse outcome in BD, particularly in terms of suicidality, and confirm the clinical relevance of early diagnosis and pharmacological intervention with mood stabilizers in BD.     

Agomelatine for the treatment of generalized anxiety disorder

Introduction: Agomelatine is a melatonergic antidepressant, approved for the treatment of Major Depressive Disorder (MDD) in Europe and Australia, but not in the United States. This compound seems to be promising in the short-term and maintenance treatment of Generalized Anxiety Disorder (GAD).

Areas covered: This paper presents an evaluation of the available data about the clinical efficacy and tolerability of agomelatine in the treatment of GAD.

Expert opinion: First-line GAD treatments are limited by high rates of lack of clinical response. Preliminary data would indicate agomelatine as a safe compound, and with a higher rate of clinical response in the short-term and an earlier improvement of symptoms with respect to Selective Serotonine Reuptake Inhibitors (SSRIs) and Selective Serotonin Noradrenaline Reuptake Inhibitors (SNRIs). In addition, agomelatine has not been associated with potential risk of abuse as in case of pregabalin and with long-term metabolic side effects similar to quetiapine. The major limitation of the results presented is that little data has come from long-term or comparative trials. Furthermore, some caution should be reserved in case of liver impairment (e.g. in subjects with alcohol abuse).     

Short-term intravenous citalopram augmentation in partial/nonresponders with major depression: a randomized placebo-controlled study

Approximately 30-45% of patients with major depressive episode (MDE) do not fully respond to standard recommended treatments and further strategies of intervention, including pharmacological augmentation, have been proposed for these patients. This study was aimed to evaluate the efficacy of short-term, low-dose (10 mg/day) intravenous (i.v.) citalopram augmentation versus placebo in a sample of patients with MDE and partial or no response to selective serotonin reuptake inhibitors (SSRIs). Thirty-six patients with a Diagnostic and Statistical Manual for Mental Disorders, 4th edition, text revision criteria MDE and partial or no response to oral SSRIs were selected and randomly assigned to citalopram (n=18) or to placebo (n=18) i.v. augmentation. The augmentation regimen lasted 5 consecutive days during which the patients were maintained on their current treatment with oral SSRIs. Analyses of variance with repeated measures on Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale total scores, administered daily with blind-raters conditions, were done. With regard to the Hamilton Depression Rating Scale total scores, a significant time effect (F=42.02, P<0.0001) and timextreatment effect (F=21.17, P<0.0001) were found in favor of citalopram. Similar results were obtained from the analysis on Montgomery-Asberg Depression Rating Scale total scores: time effect (F=50.07, P<0.0001), timextreatment effect (F=19.91, P<0.0001), and treatment effect (F=4.07, P=0.05). Even though referred to a small sample, the present findings seem to suggest that short-term, low-dose, i.v. citalopram augmentation may be effective in depressed patients with partial or no response to oral SSRIs. Further controlled studies performed with double-blind conditions are warranted to confirm the present results.