Massimiliano Buoli

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-Asberg 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 > or =50% compared to baseline, was achieved by 6 out of 11 subjects, 4 of whom were considered remitters (HAM-D endpoint score < or = 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.

Age at onset and latency to treatment (duration of untreated illness) in patients with mood and anxiety disorders: A naturalistic study

This study was designed to investigate and compare demographic and clinical features with specific emphasis on age at onset, age at first treatment and, in particular, on duration of untreated illness (DUI), in patients with different mood and anxiety disorders. Study sample included 729 outpatients with the following diagnoses: major depressive disorder (n=181), bipolar disorder type I (BD I, n=115) and II (BD II, n=186), generalized anxiety disorder (n=100), panic disorder (n=96), and obsessive–compulsive disorder (n=51). Main demographic and clinical variables of the sample were compared among the diagnostic groups using one-way analysis of variance or χ2 tests. The diagnostic groups showed significant differences in relation to age at onset and age at first pharmacological treatment and in relation to latency to treatment. In particular, patients with major depressive disorder showed the shortest DUI (39.08 months), whereas patient with BD II showed the longest DUI (97.2 months) in comparison with the other groups. Within the group with anxiety disorders (F=7.512, P<0.001), patients with panic disorder showed the shortest DUI (44.35 months), whereas patients with obsessive–compulsive disorder showed the longest DUI (90.57 months). The present findings suggest that patients with different mood and anxiety disorders show significant differences in terms of age at onset, age at first treatment and, consequently, DUI, which potentially reflect different reasons influencing treatment delay.

Serotonin norepinephrine reuptake inhibitors (SNRIs) in anxiety disorders: a comprehensive review of their clinical efficacy

Anxiety disorders are common psychiatric conditions that typically require long‐term treatment. This review summarizes current knowledge of the pharmacological treatment of anxiety disorders with serotonin norepinephrine reuptake inhibitors (SNRIs) with specific emphasis on the findings of recent randomized clinical trials and relevant neurobiological investigations. It is now well established that gabaergic, noradrenergic and serotonergic systems play a critical role in the pathophysiology of anxiety disorders, abnormalities in these systems being related to structural and functional alterations in specific brain areas such as the amygdala, prefrontal cortex, locus coeruleus and hippocampus, as repeatedly shown by neuroimaging studies. SNRIs selectively inhibit norepinephrine and serotonin reuptake and have shown to be efficacious and generally well tolerated treatments in patients with anxiety disorders, with some potential clinical advantages over selective serotonin reuptake inhibitors (SSRIs), which are considered by many to represent first‐line pharmacological treatments in patients with anxiety disorders. Anxiety disorders are characterized by a typically chronic course, high rates of comorbidity and frequent partial response to standard treatments, and the increasing use of SNRIs reflects currently unmet clinical need, in terms of overall response, remission rates and treatment tolerability. Copyright

Misdiagnosis, duration of untreated illness (DUI) and outcome in bipolar patients with psychotic symptoms: A naturalistic study.

BACKGROUND A number of data show the negative role of duration of untreated illness (DUI) on outcome in mood disorders, but no investigation has been carried out about the impact of this variable in bipolar disorder (BD) with psychotic symptoms. Clinical experience shows that many bipolar patients with psychotic symptoms receive other diagnoses and often are chronically treated with first generation antipsychotics, with the effect to reduce duration of untreated psychosis/untreated episode with psychotic symptoms (DUP), but not DUI. Purpose of the study was to define the rate of misdiagnosis and the impact of DUP/DUI on outcome of bipolar patients with psychotic symptoms. METHOD Clinical information (DUP, DUI, first received diagnosis) about bipolar outpatients with psychotic symptoms (N=240) were extrapolated through a retrospective review of the clinical charts, Lombardy database and, if necessary, through clinical interviews with patients and their relatives. Outcome measures included psychiatric and substance abuse comorbidity, occupational status, Global Assessment of Functioning (GAF), number of hospitalizations and of suicidal attempts, number of depressive/manic recurrences. Patients were divided in two groups according to the DUP (1 year) and DUI (8 years) median, and the groups were compared through analyses of variance (ANOVAs) for continuous variables or χ(2) tests for dichotomous ones. Multivariate analysis of variance (MANOVA) with duration of illness as covariate was then performed to eliminate the effect of this variable. Finally, binary logistic regressions were performed considering age at onset, DUI, DUP as independent variables and outcome variables as dependent ones (presence of hospitalizations/suicidal attempts, GAF scores<50, occupational status). RESULTS Most of patients (61.5%) received a first diagnosis different from BD with the most frequent DSM-diagnosis being delusional disorder (17.9%). Patients with longer DUP were not different in outcome measures with respect to patients with shorter DUP. Patients with a DUI >8 years presented higher number of hospitalizations (F=6.04, p=0.015), higher number of manic recurrences (F=5.25, p=0.023), higher number of depressive recurrences (F=7.13, p=0.008) and lower GAF scores (F=17.74, p<0.001). Statistical significance persisted for number of hospitalizations (p<0.001) and GAF scores (p=0.003) after MANOVA. Finally binary logistic regression showed that a longer DUI was predictive of GAF scores<50 (F=17.74, p<0.001). DISCUSSION More than half of bipolar patients with psychotic symptoms receive a different diagnosis at first contact with psychiatric services. DUI (but not DUP) is a predictor of outcome in bipolar patients with psychotic symptoms. This indicates that an early diagnosis and proper treatment with a mood stabilizer (or an atypical antipsychotic with mood stabilizing effects) may improve long-term outcome of these patients. In the light of the naturalistic design of the present paper, these results have to be considered as preliminary and have to be confirmed by prospective controlled studies.

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.

Role of immunological factors in the pathophysiology and diagnosis of bipolar disorder: Comparison with schizophrenia

Several lines of evidence point to the key role of neurobiological mechanisms and shared genetic background in schizophrenia and bipolar disorder. For both disorders, neurodevelopmental and neurodegenerative processes have been postulated to be relevant for the pathogenesis as well as dysregulation of immuno‐inflammatory pathways. Inflammation is a complex biological response to harmful stimuli and it is mediated by cytokines cascades, cellular immune responses, oxidative factors and hormone regulation. Cytokines, in particular, are supposed to play a critical role in infectious and inflammatory processes, mediating the cross‐talk between the brain and the immune system; they also possibly contribute to the development of the central nervous system. From this perspective, even though mixed results have been reported, it seems that both schizophrenia and bipolar disorder are associated with an imbalance in inflammatory cytokines; in fact, some of these could represent biological markers of illness and could be possible targets for pharmacological treatments. In light of these considerations, the purpose of the present paper was to provide a comprehensive and critical review of the existing literature about immunological abnormalities in bipolar disorder with particular attention to the similarities and differences with schizophrenia.

Duration of Untreated Illness as a Predictor of Treatment Response and Remission in Obsessive–Compulsive Disorder

Abstract Objectives. The Duration of Untreated Illness (DUI), defined as the time elapsing between the onset of a disorder and the beginning of the first pharmacological treatment, has been increasingly investigated as a predictor of outcome and course across different psychiatric disorders. Purpose of this naturalistic study was to evaluate the influence of DUI on treatment response and remission in a sample of patients with obsessive–compulsive disorder (OCD). Methods. Sixty-six outpatients with a DSM-IV diagnosis of OCD were included in the study. Patients received, according to their clinical conditions, an open pharmacological treatment of 12 weeks and were evaluated by the administration of the Yale Brown Obsessive Compulsive Scale (Y-BOCS) at baseline and endpoint. Treatment response was defined as a decrease .25% on Y-BOCS score compared to baseline, while remission was defined as an endpoint Y-BOCS total score #10. A logistic regression was performed considering DUI as the independent continuous variable and treatment response and remission as the dependent variables. Moreover, the sample was divided into two groups according to a categorical cut-off for the DUI of 24 months and odds ratios (OR) were calculated on the basis of the same variables. Results. DUI, considered as a continuous variable, was not predictive of treatment response (OR51.00, P50.15) nor remission (OR51.00, P50.59). When considered as a categorical variable, however, a DUI # 24 months was predictive of treatment response (OR50.27, P50.03). Conclusions. Results from the present naturalistic study suggest a complicated relationship between DUI and treatment outcome in OCD encouraging further investigation with larger samples in order to better define long versus short DUI in this condition.

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 (&khgr;2=1.82, degree of freedom=1, P=0.37, &phgr;=0.30). Remitters were 40% for the quetiapine group versus 20% for the placebo group (&khgr;2=0.95, degree of freedom=1, P=0.63, &phgr;=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.

New approaches to the pharmacological management of generalized anxiety disorder

Introduction: Selective serotonin reuptake inhibitors (SSRIs) and serotonine reuptake Inhibitors (SNRIs) together with pregabalin are actually considered by international guidelines as the first-line choice for generalized anxiety disorder (GAD) treatment. However, 50% of GAD patients have poor response to first-line treatments and different molecules, such as atypical antipsychotics and mood stabilizers, have been used for treating this condition. Purpose of the present article is to provide an overview of the most recent pharmacological approaches for the treatment of GAD and the rationale for their use. Areas covered: A research in the main database sources has been conducted to obtain an overview of the new pharmacological approaches in GAD (anticonvulsants, atypical antipsychotics, agomelatine, memantine, ondansetron and riluzole). Expert opinion: Among unlabelled molecules, quetiapine seems to have the most robust evidence of efficacy in GAD. Valproic acid and agomelatine appear to be effective in GAD patients, but the data are preliminary and need to be confirmed by future studies. Quetiapine is a promising molecule for GAD treatment but its use would be complicated by long-term metabolic side effects. Future research will have the objective to find more targeted molecules for the treatment of this disorder in light of its specific etiology.

Patterns of Axis I comorbidity in relation to age in patients with Bipolar Disorder: A cross-sectional analysis

BACKGROUND Several data indicate that the clinical course and treatment response of Bipolar Disorder (BD) is influenced by comorbidity. However, whether differences in comorbidity patterns exist in relation to classes of age remains debated. The present study was aimed to evaluate differences in terms of cross-sectional Axis I comorbidity among young (≤30 years), adult (>30 and ≤45 years) and older adult patients with BD (>45 years). METHODS Study sample included 508 patients with BD, subdivided into 3 groups of age: ≤30 years (n=52), >30 and ≤45 years (n=186) and >45 years (n=270). Demographic and clinical variables, with specific emphasis on Axis I comorbidity, were compared across the different groups using chi-square tests. Furthermore, a binary logistic regression was performed. RESULTS Two-hundred eleven patients (41.5%) showed at least another concomitant Axis I disorder. The 3 groups were homogenous in terms of type of diagnosis (type 1 or 2 BD) and gender. However, they were different in terms of cross-sectional Axis I comorbidity (p=0.001) with a higher frequency of substance abuse (p=0.04) and Anorexia (p=0.014) in young patients, and of Obsessive Compulsive Disorder in adult patients (p=0.001). In addition, young patients showed more frequently the presence of a second comorbid Axis I condition compared to the other sub-groups (p=0.05). With regard to the type of abuse, young subjects were more frequently cannabis (p<0.001) and cocaine abusers (p<0.001) compared to the other subgroups. LIMITATIONS Lifetime Axis I and Axis II and cross-sectional Axis II comorbidity patterns were not analyzed. CONCLUSIONS Preliminary results from the present exploratory study seem to suggest different profiles of cross-sectional Axis I comorbidity and abuse in bipolar patients in relation to age. This aspect should be taken into account for the choice of pharmacological treatments and global management in clinical practice.