Laura Musetti

Psychopathology, Temperament, and Past Course in Primary Major Depressions. 1. Review of Evidence for a Bipolar Spectrum

In reviewing recent findings on affective conditions in the interface of unipolar and bipolar disorders, we find evidence favoring a partial return to Kraepelins broad concept of manic-depressive illness, which included many recurrent depressives and temperamental variants. This review addresses methodologic, clinical, and familial considerations in the definition and characterization of a proposed spectrum of bipolar disorders which subsumes episodic and chronic forms. Episodic bipolar disorders are subclassified into bipolar schizoaffective, and bipolar I and II, and bipolar III or pseudo-unipolar forms. Chronic bipolar disorders could be either intermittent or persistent, and are subclassified into chronic mania, protracted mixed states, and rapid-cycling forms, as well as the classical temperaments (cyclothymic, hyperthymic, irritable and dysthymic).

Depressive comorbidity of panic, social phobic, and obsessive–compulsive disorders re-examined: is there a bipolar ii connection?

Utilizing the DSM-III-R schema, we have investigated lifetime comorbidity between panic disorder with or without agoraphobia (PD), social phobia (SP) and obsessive-compulsive disorder (OCD) on the one hand, and mood disorder on the other. Compared with PD, the results for SP and OCD showed significantly higher numbers of comorbid anxiety and mood disorders. In addition, SP and OCD were significantly more likely to cooccur with each other than with PD. The complexity of these comorbid patterns is underscored by the finding of significantly higher numbers of anxiety disorders in those with lifetime comorbidity with bipolar (especially bipolar II) disorder. We conclude that the comorbidity between anxiety and mood disorders - conventionally conceived as the relationship between anxiety and unipolar depressive states -- might very well extend into the domain of bipolar spectrum disorders in a subset of these disorders. Among the latter, the spontaneous or antidepressant-induced switches into brief disinhibited (hypomanic) behavior can be conceptualized to lie on a dimensional continuum with the temperamental inhibition (or constraint) underlying the anxiety disorders under discussion. These findings and theoretical considerations have important therapeutic implications.

Psychopathology, Temperament, and Past Course in Primary Major Depressions. 2. Toward a Redefinition of Bipolarity with a New Semistructured Interview for Depression

We report on the utility of a new instrument to identify subtypes of major depressive episodes with special reference to pseudo-unipolar conditions. By incorporating reliable measures of depressive and hyperthymic temperamental characteristics in subtype definitions, we achieve the sharpest possible demarcation between unipolar and bipolar disorders. The new procedures also reveal that 1 out of 3 primary depressives in a consecutive series of 405 patients belong to the bipolar spectrum. Furthermore, among bipolars, bipolar II disorder (redefined as major depressions with hypomania or hyperthymic temperament) represents the most common variant. We discuss the nosologic, therapeutic, methodologic and theoretical implications of these considerations on the unipolar-bipolar dichotomy. Given that major depression emerges as the final common clinical expression of a heterogeneous group of disorders, it underscores the importance of focusing on temperament and course of illness in subclassification efforts such as attempted here.

Clomipramine for panic disorder: I. the first 10 weeks of a long-term comparison with imipramine

Clomipramine and imipramine treatments were compared in a sample of 152 panic disorders. Diagnosis was according to the positive criteria of DSM-III-R, but without exclusion of comorbid affective or personality disorders. The 2-year design provides non-blind treatment under typical clinical practice conditions, and it includes random assignment, periodic assessment with standardized measures, and comparable, flexible drug dosages. Findings on six outcome measures in the first 59 cases to complete 10 weeks showed both tricyclics to be markedly and equally effective for blocking panic attacks, alleviating phobic avoidance, and reducing nonspecific aspects of anxiety. Clomipramines predominantly serotonergic action seemed not to determine a different action spectrum. During the first 2 weeks, clomipramine was significantly and unexpectedly superior to imipramine in both antipanic and antiphobic actions. These results require replication under double-blind conditions.

THE IMPORTANCE OF MEASURES OF AFFECTIVE TEMPERAMENTS IN GENETIC STUDIES OF MOOD DISORDERS

Collaboration between the University of Pisa, Italy, and the University of Tennessee, Memphis, U.S.A., on patients presenting with major depressive episodes (in the absence of nonaffective psychiatric illness) focused on the detection of depressive and hyperthymic temperaments. From our data on symptomatology, family history and course of 538 such patients, several findings emerge of cardinal relevance to genetic studies. Hyperthymic temperament, observed more commonly in men, appears as one pole of an attenuated form of manic-depressive illness. Thus, major depressives with this temperament have high rates of bipolar family history, even in the absence of hypomanic and manic episodes. The depressive temperament, more prevalent in women, is correlated with earlier onset and higher number of depressive episodes, greater severity of the Hamilton Rating Scale for Depression (HAM-D), as well as higher familial loading for mood disorders, compared with major depressives without this temperament. Building on Akiskals latest model on the multifactorial origin of mood disorders, we submit that these temperamental dysregulations constitute the intermediate step between predisposing familial-genetic factors in affective illness and gender-related clinical expressions of mood disorders. The authors recommend that future high-risk prospective studies and genetic investigations should include measures of affective temperament.

Oxcarbazepine as add-on treatment in patients with bipolar manic, mixed or depressive episode.

OBJECTIVES The aim of this preliminary open-label trial was to evaluate the efficacy and safety of oxcarbazepine (OXC) as adjunctive therapy in 18 patients with bipolar disorder who did not respond satisfactorily to lithium. METHODS Eighteen patients with bipolar I (n=16) and bipolar II (n=2) disorder were treated openly with OXC for a 8-week period as add-on treatment to the existing lithium regimen. After the 8-week trial, all patients continued the treatment with OXC, and were followed-up prospectively. Outcome measures included the Clinical Global Impression-Bipolar Version Scale, the Bech-Rafaelsen Mania-Melancholia Scale and the Brief Psychiatric Rating Scale. These scales were administered at baseline and at the end of weeks 2, 4 and 8. Patients were subsequently assessed every 4 months for a period of time ranging from 4 to 12 months with the Longitudinal Interval Follow-up Evaluation. RESULTS The mean dose of OXC at the end of week 8 was 919.4 mg/day (SD+/-335.7). Eleven of the 18 patients were considered responders. The remaining seven patients were rated as nonresponders. Of the eleven responders to the 8-week trial, seven patients remained mood-stabilized for the entire period of follow-up. CONCLUSIONS OXC appeared to be significantly effective as add-on strategy in 60% of patients after 8 weeks of treatment. A substantial proportion (66.3%) of the 8-week trial responders maintained a satisfactory mood stabilization during the follow-up. Despite several limitations, our study suggests the potential usefulness of OXC as adjunctive therapy to lithium both in acute and long-term treatment of bipolar disorder.

Delineating a putative phobic-anxious temperament in 126 panic-agoraphobic patients: toward a rapprochement of European and US views.

BACKGROUND The current US official position, since DSM-III, is that panic attacks represent the hallmark of panic disorder and play a major role in the development of the agoraphobic syndrome. The more favoured view in the European tradition is that neurotic personality and/or prodromal features such as mild depression and excessive worries precede the illness. METHOD We studied 126 consecutive cases of panic disorder with or without agoraphobia by DSM-III-R criteria, evaluated by relevant structured and semi-structured interviews. RESULTS We provide evidence that characterological and prodromal antecedents represent a putative phobic-anxious temperamental substrate occurring in at least 30% of our sample. This temperament consists of three or more of the following traits: (1) increased sympathetic activity with repeated sporadic and isolated autonomic manifestations; (2) marked fear of illness; (3) hypersensitivity to separation; (4) difficulty to leave familiar surroundings; (5) marked need for reassurance; (6) oversensitivity to drugs and substances. Our data further suggest that these attributes are of familial origin, as a result of which the illness tends to declare itself earlier. LIMITATION The present investigation is largely correlational without a prospective component; however, the key validating familial data were obtained blindly. CONCLUSION Our data support a pathogenetic model whereby genetic diathesis unfolds from subclinical to clinical manifestations along temperamental, panic, phobic and avoidant patterns. We submit that the delineation of the phobic-anxious temperament will be useful in more completely charting the life course of the panic-agoraphobic spectrum; avoidant and dependent (Axis II) patterns appear more distal in the pathogenetic chain and, in many cases, can be conceptualized to be epiphenomenal to the disease process.

The nature of depression presenting concomitantly with panic disorder

Our data, along with the literature review we have undertaken, suggest that depression seen in the course of panic disorder most commonly represents symptomatic elaboration or complication of panic disorder. Less often it represents an associated independent entity or, more hypothetically, an alternative clinical expression of a shared underlying diathesis for both conditions. Future prospective research efforts, especially along familial-genetic lines, are needed to clarify the precise nature of the cross-sectional and longitudinal overlap of anxiety and depressive states.

Gender differences in bipolar disorder type 1: a 48-week prospective follow-up of 72 patients treated in an Italian tertiary care center.

To explore gender differences in bipolar I disorder, we compared the longitudinal treatment outcome and baseline demographic and clinical characteristics of 27 male and 45 female adult subjects who were treated for an acute affective episode and longitudinally followed for a period of up to 48 weeks. Females were more likely to report a history of suicidal gestures and a comorbid panic disorder; males were more likely to present with a comorbid obsessive-compulsive disorder, and there was a trend for a more frequent history of alcohol or substance abuse. No significant differences were found between the genders for the time to remission from the index episode, number of recurrences, and time spent with any clinical or subclinical mood symptom during the 48 weeks of maintenance treatment. Although differences may exist between bipolar I male and female subjects, prospective course does not seem to reveal differences in a 48-week period, at least when similar treatment strategies are adopted.

A new look at an old drug: neuroprotective effects and therapeutic potentials of lithium salts.

Increasing evidence highlights bipolar disorder as being associated with impaired neurogenesis, cellular plasticity, and resiliency, as well as with cell atrophy or loss in specific brain regions. This has led most recent research to focus on the possible neuroprotective effects of medications, and particularly interesting findings have emerged for lithium. A growing body of evidence from preclinical in vitro and in vivo studies has in fact documented its neuroprotective effects from different insults acting on cellular signaling pathways, both preventing apoptosis and increasing neurotrophins and cell-survival molecules. Furthermore, positive effects of lithium on neurogenesis, brain remodeling, angiogenesis, mesenchymal stem cells functioning, and inflammation have been revealed, with a key role played through the inhibition of the glycogen synthase kinase-3, a serine/threonine kinase implicated in the pathogenesis of many neuropsychiatric disorders. These recent evidences suggest the potential utility of lithium in the treatment of neurodegenerative diseases, neurodevelopmental disorders, and hypoxic–ischemic/traumatic brain injury, with positive results at even lower lithium doses than those traditionally considered to be antimanic. The aim of this review is to briefly summarize the potential benefits of lithium salts on neuroprotection and neuroregeneration, emphasizing preclinical and clinical evidence suggesting new therapeutic potentials of this drug beyond its mood stabilizing properties.