Augmentative transcranial magnetic stimulation (TMS) combined with brain navigation in drug-resistant rapid cycling bipolar depression : a case report of acute and maintenance efficacy

The efficacy of transcranial magnetic stimulation (TMS) has been poorly investigated in the acute and maintenance treatment of bipolar depression. The present case supports the efficacy of low-frequency repetitive TMS (rTMS) of the right dorsolateral pre-frontal cortex (RDLPFC) combined to brain navigation in a drug-resistant, bipolar depressed subject with rapid cycling. While continuing the pharmacological treatment at stable doses, the patient was stimulated for 3 weeks at 1 Hz, 110% of motor threshold, 300 stimuli/day showing a significant improvement on the Hamilton Depression Rating Scale (HDRS(21)), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression, improvement scale (CGI-I) total scores. On completion of the 3-week rTMS, the patient was treated with periodic maintenance sessions of rTMS at the same parameters of acute phase for an additional 6 months, at the end of which the therapeutic gains were maintained according to rating scales scores. Larger controlled trials assessing the acute and maintenance efficacy of rTMS in bipolar depression are needed

The Noradrenergic Action in Antidepressant Treatments : Pharmacological and Clinical Aspects

Even though noradrenaline has been recognized as one of the key neurotransmitters in the pathophysiology of major depression (MD), noradrenergic compounds have been less extensively utilized in clinical practice, compared to selective serotonin reuptake inhibitors (SSRIs). The development of the first selective noradrenergic reuptake inhibitor (NRI), Reboxetine, has not substantially changed the state of the art. In addition, Atomoxetine, a relatively pure NRI used for the treatment of ADHD, has shown mixed results when administered in augmentation to depressed subjects. Through a Medline search from 2000 to 2010, the present article provides an updated overview of the main pharmacological and clinical aspects of antidepressant classes that, partially or selectively, act on the noradrenergic systems. The noradrenergic action plays an important clinical effect in different antidepressant classes, as confirmed by the efficacy of dual action antidepressants such as the serotonin noradrenaline reuptake inhibitors (SNRIs), the noradrenergic and dopaminergic reuptake inhibitor (NDRI) Bupropion, and other compounds (e.g., Mianserin, Mirtazapine), which enhance the noradrenergic transmission. In addition, many tricyclics, such as Desipramine and Nortriptyline, have prevalent noradrenergic effect. Monoamine oxidase inhibitors (MAOIs), moreover, block the breakdown of serotonin, noradrenaline, dopamine and increase the availability of these monoamines. A novel class of antidepressantsthe triple reuptake inhibitorsis under development to selectively act on serotonin, noradrenaline, and dopamine. Finally, the antidepressant effect of the atypical antipsychotic Quetiapine, indicated for the treatment of bipolar depression, is likely to be related to the noradrenergic action of its metabolite Norquetiapine. Even though a pure noradrenergic action might not be sufficient to obtain a full antidepressant effect, a pronoradrenergic action represents an important element for increasing the efficacy of mixed action antidepressants. In particular, the noradrenergic action seemed to be related to the motor activity, attention, and arousal

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

Slow vs standard up-titration of paroxetine in the treatment of panic disorder : a prospective randomized trial

Aim: Patients with panic disorder (PD) might be sensitive to the stimulating effects of selective serotonin reuptake inhibitors (SSRI), thus requiring low dosages at treatment initiation. The aim of the present study was to assess eventual differences in terms of effectiveness and tolerability between a slow up-titration with paroxetine and a standard one. Methods: In an open randomized, multicenter, primary-care study, 60 patients (44 women and 16 men) with PD with or without agoraphobia were enrolled and randomized to receive a slow up-titration with paroxetine (increments of 2.5 mg/day every 2 days) or a standard one (increments of 10 mg/day every week) up to a maximum daily dose of 20 mg. Repeated-measures anova on sub-items scores of the Panic Attack Anticipatory Anxiety Scale (PAAS) and Dosage Record and Treatment Emergent Symptom Scale (DOTES), respectively, used as outcome measures of effectiveness and tolerability, were performed. Significance level was set at 0.05 and it was not corrected. Results: anova showed no differences between the two treatments in terms of effectiveness and tolerability. Post hoc analysis found only one significant difference in the intensity of spontaneous panic attacks (Panic and Anticipatory Anxiety Scale) in the first 9 days of treatment between the two treatment groups, which was that this item was less intense in the slow-titration group (treatment effect: F = 4.89, P = 0.03, effect size = 0.1). Conclusion: Present findings suggest only a small superiority for a slow up-titration regimen of paroxetine compared to a standard one in the first 9 days of treatment but no differences at end-point

Long-Term Efficacy After Acute Augmentative Repetitive Transcranial Magnetic Stimulation in Bipolar Depression : a 1-Year Follow-Up Study

Background: The efficacy of repetitive transcranial magnetic stimulation (rTMS) has been poorly investigated in the long-term. The present follow-up study was aimed to assess the long-term efficacy and the discontinuation effects of rTMS in a sample of depressed bipolar patients. Methods: After the completion of an acute trial with augmentative, low-frequency, navigated rTMS, 11 drug-resistant depressed bipolar subjects (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [Text Revision] criteria) entered a naturalistic follow-up with monthly evaluations through the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Results: After 1 year of follow-up, results showed that the achievement of remission after acute rTMS was predictive of maintenance of response at 1 year. On the other hand, the absence of acute rTMS response predicted the absence of subsequent response in the long-term. Conclusions: This first report on the long-term discontinuation effects after acute rTMS suggests that immediate remission is predictive of sustained benefit after 1 year. Larger controlled studies are needed to confirm present preliminary findings

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 and 45 years). Methods: Study sample included 508 patients with BD, subdivided into 3 groups of age: 30 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

Mood stabilizers for patients with bipolar disorder : the state of the art

Bipolar disorder (BD) is a prevalent and disabling condition, often comorbid with other medical and psychiatric conditions and frequently misdiagnosed. International treatment guidelines for BD recommend the use of mood stabilizers either in monotherapy or in association as the gold standard in both acute and long-term therapy. Commonly used in the clinical practice of BD, mood stabilizers have represented an evolving field over the last few years. The concept of stabilization, in fact, has been stressed as the ultimate objective of the treatment of BD, given the chronic and recurrent nature of the illness, which accounts for its significant levels of impairment and disability. To date, different compounds are included within the broad class of mood stabilizers, with lithium, anticonvulsants and, more recently, atypical antipsychotics being the most representative agents. This article is aimed at providing an updated review of the available literature in relation to the role of mood stabilizers in BD, with particular emphasis on their mechanism of action, main clinical aspects and specific use in the different phases of BD treatment, according to the most recently published international treatment guidelines

An epidemiologic and clinical overview of medical and psychopathological comorbidities in major psychoses

The presence of comorbidity in major psychoses (e.g., schizophrenia and psychotic subtypes of bipolar disorder and major depressive disorder) seems to be the rule rather than the exception in both DSM-IV and ICD-10. Examining comorbidity in major psychoses, however, requires an investigation into the different levels of comorbidity (either full-blown and subsyndromal) which should be analyzed in both psychopathological and medical fields. On one hand, the high prevalence of psychiatric comorbidity in major psychoses may be the result of the current nosographic systems. On the other hand, it may stem from a common neurobiological substrate. In fact, comorbid psychopathological conditions may share a biological vulnerability, given that dysfunction in specific brain areas may be responsible for different symptoms and syndromes. The high rates of comorbidity in major psychoses require targeted pharmacological treatments in order to effectively act on both the primary diagnosis and comorbid conditions. Nevertheless, few controlled trials in comorbid major psychoses had been carried out and treatment recommendations in this field have mostly an empirical basis. The aim of the present article is to provide a comprehensive and updated overview in relation to epidemiological and clinical issues of comorbidity in major psychoses

The impact of brief depressive episodes on the outcome of bipolar disorder and major depressive disorder : a 1-year prospective study

Background: Brief depressive episodes (BDEs) cause psychosocial impairment and increased risk of suicide, worsening the outcome and long-term course of affective disorders. The aim of this naturalistic observational study was to assess the frequency of BDEs and very brief depressive episodes (VBDEs) and their impact on clinical outcome in a sample of patients with major depressive disorder (MDD) and bipolar disorder (BD). Method: Seventy patients with a diagnosis of MDD or BD were followed up and monthly visited for a period of 12 months, assessing the eventual occurrence of BDEs and/or VBDEs. Clinical and demographic variables of the total sample and of the groups divided according to the presence of BDEs or VBDEs were collected and compared by one-way ANOVAs. Hamilton Depression Rating Scale 21 items (HDRS), Young Mania Rating Scale (YMRS), Clinical Global Impression (severity of illness) (CGIs) and the Short Form Health Survey (SF-36-item 1) were administered at baseline and logistic regression was performed to evaluate whether baseline scores were predictive of the onset of BDEs or VBDEs. Results: BDEs (88.6% of the total sample), VBDEs (44.3% of the total sample) and BDEs + VBDEs (40.0% of the total sample) were found to occur frequently across the sample. BDE patients showed more death thoughts during major depressive episodes (chi(2) = 4.14, df = 1, p = 0.04, Phi = 0.24) compared to patients without BDEs. Indeed VBDE patients showed a higher rate of hospitalization (,chi(2) = 5.71, df = 1, p = 0.031, phi = 0.29), a more frequent prescription of a combined treatment (chi(2) -= 13.07, df = 7, p = 0.03, phi = 0.43) and higher scores at SF-36 item 1 (F = 6.65, p = 0.01) compared to patients without VBDEs. Finally, higher SF-36 kern 1 scores were found to be predictive of VBDEs (odds ratio = 2.81, p = 0.03). Discussion: Major depressives, either unipolar or bipolar, with BDEs or VBDEs showed a worse outcome, represented by a more severe psychopathology and higher rates of hospitalization. VBDEs were predicted by a negative subjective general health perception. Studies with larger samples and longer follow-up are warranted to confirm the results of the present study