Adjunctive valproate in panic disorder patients with comorbid bipolar disorder or otherwise resistant to standard antidepressants: a 3-year "open" follow-up study.

The aim of the study was to report on the clinical utility of naturalistic adjunctive treatment with valproate (VPA) in a group of panic disorder (PD) patients with comorbid bipolar disorder (BD) or otherwise resistant to antidepressants. The hypothesis was that these patients might not respond because of coexisting low-grade mood instability and adjunctive VPA treatment might ameliorate PD symptoms. A group of 47 patients with lifetime comorbid BD (n = 35, 74.5%) or otherwise resistant to antidepressants (n = 12, 25.6%), from a population of 326 consecutive outpatients with PD-Agoraphobia evaluated and treated at the Psychiatric Institute of the University of Pisa from 1991 to 1995, and followed for a period of 3 years. All patients were evaluated at baseline and at least every 2 months by means of an intensive interview including semi-structured and structured instruments (SCID, Life-Up, and Panic Disorder/Agoraphobia Interview). Mean dosage was 687 (SD = 234) mg/day (min 400, max 1,500 mg/day). Adjunctive treatment with VPA was well tolerated by all subjects, and there was no treatment interruption because of side effects or adverse events. All antidepressants-resistant subjects and 31 of 35 (88.6%) patients with bipolar comorbidity achieved symptomatological remission. During the observation period, 7 (58.3%) among resistant subjects and 17 (48.6%) of bipolar patients had a relapse of panic disorder after remission. Survival analysis of remission durations and onset relapses for PD and Agoraphobia did not show significant differences between the two groups. Relapses of Agoraphobia were less frequent and more delayed than those for panic. According to the results, VPA seems to be an effective and a well-tolerated adjunctive treatment in PD patients who were resistant to antidepressant therapy or had BD in comorbidity. The results of the study support the hypothesis of resistance to antidepressant treatment being related to mood instability.

The clinical-familial correlates and naturalistic outcome of panic-disorder-agoraphobia with and without lifetime bipolar II comorbidity.

BACKGROUND: Much of the literature on panic disorder (PD)-bipolar disorder (BP) comorbidity concerns BP-I. This literature emphasizes the difficulties encountered in pharmacologic treatment and outcome when such comorbidity is present. The present report explores these issues with respect to BP-II. METHODS: The sample comprised 326 outpatients (aged 34.5 +/- 11.5 years old; 222 females) with Diagnostic and Statistical Manual of Mental Disorders 3rd edn, revised (DSM-III-R) PD-agoraphobia; among them 52 subjects (16%) were affected by lifetime comorbidity with BP-II. Patients were evaluated by means of the Structured Clinical Interview for DSM-IV (SCID), the Panic-Agoraphobia Interview, and the Longitudinal Interview Follow-up Examination (Life-Up) and treated according to routine clinical practice at the University of Pisa, Italy, for a period of 3 years. Clinical and course features were compared between subjects with and without BP-II. All patients received the clinicians' choice of antidepressants and, in the case of the subsample with BP-II, mood stabilizers (for example, valproate, lithium) were among the mainstays of treatment. RESULTS: In comparison to patients without bipolar comorbidity, those with BP-II showed a significantly greater frequency of social phobia, obsessive-compulsive disorder, alcohol-related disorders, and separation anxiety during childhood and adolescence. Regarding family history, a significantly greater frequency of PD and mood disorders was present among the BP-II. No significant differences were observed in the long-term course of PD or agoraphobic symptoms under pharmacological treatment or the likelihood of spontaneous pharmacological treatment interruptions. CONCLUSION: Although the severity and outcome of panic-agoraphobic symptomatology appear to be similar in patients with and without lifetime bipolar comorbidity, the higher number of concomitant disorders in our PD patients with BP-II does indicate a greater complexity of the clinical picture in this naturalistic study. That such complexity does not seem to translate into poorer response and outcome in those with comorbid soft bipolarity probably reflects the fact that we had brought BP-II under control with mood stabilizers. We discuss the implications of our findings as further evidence for the existence of a distinct anxious-bipolar diathesis.

Diagnosis and treatment of agoraphobia with panic disorder.

Agoraphobia with panic disorder is a phobic-anxious syndrome where patients avoid situations or places in which they fear being embarrassed, or being unable to escape or get help if a panic attack occurs. During the last half-century, agoraphobia has been thought of as being closely linked to the recurring panic attack syndrome, so much so that in most cases it appears to be the typical development or complication of panic disorder. Despite the high prevalence of agoraphobia with panic disorder in patients in primary-care settings, the condition is frequently under-recognised and under-treated by medical providers. Antidepressants have been demonstrated to be effective in preventing panic attacks, and in improving anticipatory anxiety and avoidance behaviour. These drugs are also effective in the treatment of the frequently coexisting depressive symptomatology. Among antidepressant agents, SSRIs are generally well tolerated and effective for both anxious and depressive symptomatology, and these compounds should be considered the first choice for short-, medium- and long-term pharmacological treatment of agoraphobia with panic disorder. The few comparative studies conducted to date with various SSRIs reported no significant differences in terms of efficacy; however, the SSRIs that are less liable to produce withdrawal symptoms after abrupt discontinuation should be considered the treatments of first choice for long-term prophylaxis. Venlafaxine is not sufficiently studied in the long-term treatment of panic disorder, while TCAs may be considered as a second choice of treatment when patients do not seem to respond to or tolerate SSRIs. High-potency benzodiazepines have been shown to display a rapid onset of anti-anxiety effect, having beneficial effects during the first few days of treatment, and are therefore useful options for short-term treatment; however, these drugs are not first-choice medications in the medium and long term because of the frequent development of tolerance and dependence phenomena. Cognitive-behavioural therapy is the best studied non-pharmacological approach and can be applied to many patients, depending on its availability.

Obsessive-compulsive disorder and body dysmorphic disorder: a comparison of clinical features.

Body dysmorphic disorder (BDD) is currently classified as a somatoform disorder in DSM-IV, but has been long noted to have some important similarities with obsessive-compulsive disorder (OCD). In addition, BDD and OCD have been often reported to be comorbid with each other. In the present study, we compared demographic characteristics, clinical features and psychiatric comorbidity in patients with OCD, BDD or comorbid BDD-OCD (34 subjects with BDD, 79 with OCD and 24 with BDD-OCD). We also compared the pattern of body dysmorphic concerns and associated behaviors in BDD patients with or without OCD comorbidity. In our sample, BDD and OCD groups showed similar sex ratio. Both groups with BDD and BDD-OCD were significantly younger, and experienced the onset of their disorder at a significantly younger age than subjects with OCD. The two BDD groups were also less likely to be married, and more likely to be unemployed and to have achieved lower level degree, than OCD subjects even when controlling for age. The three groups were significantly different in the presence of comorbid bulimia, alcohol-related and substance-use disorders, BDD-OCD patients showing the highest rate and OCD the lowest. BDD-OCD reported more comorbid bipolar II disorder and social phobia than in the other two groups, while generalized anxiety disorder was observed more frequently in OCD patients. Patients with BDD and BDD-OCD were similar as regards the presence of repetitive BDD-related behaviors, such as mirror-checking or camouflaging. Both groups also did show a similar pattern of distribution as regards the localization of the supposed physical defects in specific areas of the body. The only significant difference concerned the localization in the face, that was more frequent in the BDD group. Our results do not contradict the proposed possible conceptualization of BDD as an OCD spectrum disorder. However, BDD does not appear to be a simple clinical variant of OCD and it seems to be also related to social phobia, mood, eating and impulse control disorders. The co-presence of BDD and OCD features appears to possibly individuate a particularly severe form of the syndrome, with a greater load of psychopathology and functional impairment and a more frequent occurrence of other comorbid mental disorders.

Open-label evaluation of venlafaxine sustained release in outpatients with generalized anxiety disorder with comorbid major depression or dysthymia: effectiveness, tolerability and predictors of response.

In a setting of routine clinical practice, 32 outpatients with generalized anxiety disorder (GAD) and major depression (MD) (n = 21) or dysthymia (n = 11), according to DSM-IV criteria, were consecutively treated with flexible dosages of sustained-release venlafaxine (SR-VF) for at least 8 weeks. In a 16-week follow-up, SR-VF daily dose could be modified on the basis of the therapeutic response and of the side effect profile. Symptomatological modifications were explored by means of the Clinical Global Impression (CGI) scale, Hamilton Rating Scale for Depression (HAM-D), and Hamilton Anxiety Scale (HAM-A). SR-VF was well tolerated and only 2 patients interrupted the treatment before 24 weeks; the mean final dose +/- SD was 135.5 +/- 71.8 mg (range 75-225); in 26 (81.2%) patients, a statistically significant response was observed in depressive symptomatology within the first 8 weeks. The mean total score of HAM-D showed a significant reduction during the first 8 weeks of treatment, while the mean total score of HAM-A did not present a significant reduction until week 24. In patients with MD, a statistically significant response was observed after the first 8 weeks, while the reduction of the anxiety scores required more time and, in some cases, did not appear at all. Conversely, in patients with GAD and dysthymia, anxious and depressive symptomatology improved simultaneously. Stepwise multiple regression indicated that the improvement of depression is negatively related to a high score of CGI anxiety severity, and the improvement of anxiety is related to the presence of dysthymia and, to a lesser extent, to a short duration of the illness. Our data confirm the effectiveness and tolerability of SR-VF in mixed anxiety-depressive states. The differential response suggests a pathophysiologic and clinical distinction between GAD with comorbid MD or dysthymia.

Effectiveness of adjunctive gabapentin in resistant bipolar disorder: is it due to anxious-alcohol abuse comorbidity?

We evaluated effectiveness and predictors of response of gabapentin (GBP) as adjunctive treatment in a sample of 43 subjects with DSM-III-R bipolar disorder who were resistant to standard mood stabilizers. Diagnostic evaluation was performed by means of the Semistructured Interview for Mood Disorder. Clinical evaluation was performed at the beginning and end of the observation period by means of the Hamilton Rating Scale for Depression (HAM-D), the Young Mania Rating Scale, and the Clinical Global Impression Scale. GBP was administered as an adjunctive treatment for an 8-week period in combination with other mood stabilizers, benzodiazepines, antidepressants, and neuroleptics. Mean dosage +/- SD at week 8 was 1270 +/- 561.4 mg (range, 600-2400 mg). Adjunctive treatment with GBP was well tolerated by almost all the subjects; only three patients had to interrupt treatment before week 8, two because of inefficacy and one because of the appearance of side effects (ataxia and irritability); in other patients, the most frequent side effects were sedation, irritability, tremor, ataxia or motor instability, and nausea. Eighteen (41.9%) of 43 patients who began treatment were considered responders. Mean total HAM-D score showed a significant reduction during the 8 weeks of treatment. Analysis of the various HAM-D dimensions showed that the anxiety-somatization factor was the one with the greatest change. Seventeen of the 18 responder patients remained in remission for a period ranging from 4 to 12 months without clinically significant side effects or adverse events. One patient had to interrupt GBP treatment and be administered neuroleptics because of the reappearance of manic symptoms. Regarding response predictors, logistical regression analysis showed that the presence of panic disorder and alcohol abuse was associated with positive response. The results of the present study replicate prior studies indicating that GBP is an effective and well tolerated treatment in a large proportion of bipolar patients who are resistant to traditional mood stabilizers. More specifically, this drug appears to have antidepressant and anxiolytic properties. What is new in the present report is the suggestion that the utility of GBP in resistant bipolar disorder resides in its effectiveness against comorbid panic disorder and alcohol abuse.

Alcohol abuse in social phobic patients: is there a bipolar connection?

BACKGROUND: Epidemiological and clinical studies have reported the frequent co-occurrence of social phobia (SP) and alcohol use disorders. Patients with SP often use alcohol to cope with the social situations they fear, and to lessen anticipatory anxiety, behavioral inhibition, and phobic avoidance. We investigated whether the presence of lifetime comorbidity with alcohol abuse was associated with significant differences as regards demographic and clinical features, family history and pattern of comorbidity in a large clinical sample of SP outpatients. METHOD: The sample comprised 153 outpatients who met DSM-III-R diagnostic criteria for SP. Demographic, family history and course characteristics were investigated by a semi-structured interview. Social phobic symptoms and the severity of the illness have been assessed by the Liebowitz Social Anxiety Scale (LSAS) and the Liebowitz Social Phobic Disorders Rating Scale, Severity (LSPDRS). Patients completed the Hopkins Symptom Checklist (HSCL 90). RESULTS: Thirty-four patients (22.2%) had a past or current history of alcohol abuse for at least 1 year. There were no significant differences between these patients and those without a history of alcohol abuse, as regards demographic features and lifetime comorbidity with major depression and other anxiety disorders. Bipolar disorder type II was found almost exclusively among patients with alcohol abuse, as well as family history for bipolar disorders. LIMITATIONS: Retrospective study. CONCLUSIONS: Our data indicate a strong relationship between bipolar II disorder and alcohol abuse comorbidity in patients with SP. The socializing and disinhibiting effect that many social phobics report might be mediated by mood elation induced by alcohol. The presence of bipolar diathesis in patients presenting with social anxiety might explain their increased susceptibility to alcohol, as they might undertake alcohol abuse as an attempt to overcome social difficulties.

Obsessive-compulsive-bipolar comorbidity: a systematic exploration of clinical features and treatment outcome.

BACKGROUND: Notwithstanding the emerging literature on comorbidity between obsessive-compulsive disorder (OCD) and bipolar disorder, relatively few systematic data exist on the clinical characteristics of this interface and its treatment. The aim of the present study is to address this challenge as it appears in a setting of routine clinical practice. METHOD: The sample comprised 68 patients with comorbid DSM-IV diagnoses of OCD and major depressive episode admitted and treated at the day-hospital in the Department of Psychiatry at the University of Pisa (Pisa, Italy) during a 3-year period (January 1995-December 1998). Thirty-eight patients (55.8%) showed lifetime comorbid bipolar disorder (12 [31.6%] bipolar I and 26 [68.4%] bipolar II). Diagnoses and clinical features were collected by means of structured (Structured Clinical Interview for DSM-IV) and semistructured interviews (OCD-Interview). Assessments of drug treatments, clinical outcome, and adverse effects were made prospectively as part of routine clinical care throughout the course of their day-hospitalization. RESULTS: In contrast with non-bipolar OCD patients, OCD-bipolar patients showed a more episodic course with a greater number of concurrent major depressive episodes. They reported a significantly higher rate of sexual obsessions and significantly lower rate of ordering rituals. Furthermore, they reported more frequent current comorbidity with panic disorder-agoraphobia and abuse of different substances (alcohol, sedatives, nicotine, and coffee). Drug treatment with clomipramine and, to a lesser extent, with selective serotonin reuptake inhibitors was associated with hypomanic switches in OCD-bipolar patients, especially in those not concomitantly treated with mood stabilizers. A combination of multiple mood stabilizers was necessary in 16 OCD-bipolar patients (42.1%) and a combination of mood stabilizers with atypical antipsychotics was required in 4 cases (10.5%). OCD-bipolar patients tended to show a less positive outcome for mood symptomatology and general functioning. Three patients required hospitalization for severe mixed episode. CONCLUSION: In a tertiary care center, comorbidity between OCD and bipolar disorder is a significant clinical problem affecting a large number of patients and has a substantial impact on the clinical characteristics and treatment outcome of both disorders.