Antidepressants and Mood Stabilizers: Novel Research Avenues and Clinical Insights for Bipolar Depression.

The concept of the bipolar-spectrum and of mixed features being a bridge between major depressive disorders and bipolar disorders (BDs) has become increasingly important in mood-disorder diagnoses. Under these circumstances, antidepressants (ADs) and mood stabilizers (MSs) should be used with caution in the treatment of major depressive episodes (MDEs) and to obtain long-term stability in BDs. Before treating MDEs, screening tools, specific symptom evaluation and medical history should be used to distinguish between bipolarity and mixed features in patients for whom AD monotherapy may present a risk. In these patients, a combination of ADs plus MSs or atypical antipsychotics is recommended, rather than AD monotherapy. Studies evaluating MSs for bipolar depression suggest that lamotrigine is the most reliable treatment and lithium has modest effects; there is a lack of clear evidence regarding the efficacy of valproate and carbamazepine. Recently, significant progress has been made with respect to the pathophysiology of mood disorders and the application of potential biomarkers. There is an opportunity to study novel drug mechanisms through the rediscovery of fast-acting drugs such as ketamine. It is anticipated that future research developments will involve the discovery of potential targets for new drugs and their application to personalized treatments.

The predictive value of childhood subthreshold manic symptoms for adolescent and adult psychiatric outcomes.

BACKGROUND: Childhood subthreshold manic symptoms may represent a state of developmental vulnerability to Bipolar Disorder (BD) and may also be associated with other adverse psychiatric outcomes. To test this hypothesis we examined the structure and predictive value of childhood subthreshold manic symptoms for common psychiatric disorders presenting by early adulthood. METHODS: Subthreshold manic symptoms at age 11 years and lifetime clinical outcomes by age 19 years were ascertained in the TRacking Adolescents' Individual Lives Survey (TRAILS), a prospective Dutch community cohort. We used latent class analysis to identify subthreshold manic symptom profiles at baseline. The association between class membership and subsequent clinical diagnoses of BD (comprising BD-I, BD-II, mania and hypomania), depressive, anxiety and substance abuse disorders was determined using Cox proportional-hazard ratio (HR) models. RESULTS: At age 11 years, we identified a normative (n=916; 47%), a mildly symptomatic (n=843; 43%) and a highly symptomatic class (n=198; 10%). Referenced to the normative class, the sex- and age-adjusted risk of new-onset BD by the age of 19 years was significantly increased in the mildly (HR=2.01, 95%CI 1.13-3.59) and highly symptomatic classes (HR=5.02, 95%CI 2.48-10.16). These estimates remained significant after further adjustments for cognitive and family function, parental socioeconomic status, parental psychiatric morbidity, and comorbid disorders at baseline (p-value for linear trend across classes<0.01). Class membership did not show significant associations with incident depressive, anxiety and substance abuse disorders in the fully adjusted regression models. LIMITATIONS: The period of risk for adult-onset BD extends beyond the observational period of the study. CONCLUSIONS: Elevated childhood subthreshold manic symptoms are associated with increased risk of BD by early adulthood and are therefore a potentially useful phenotype for the early identification of at-risk individuals.

Increased rates of events that activate or deactivate the behavioral approach system, but not events related to goal attainment, in bipolar spectrum disorders.

Research indicates that life events involving goal attainment and goal striving trigger hypomania/mania and that negative life events trigger bipolar depression. These findings are consistent with the behavioral approach system (BAS) dysregulation model of bipolar disorders, which suggests that individuals with bipolar disorders are hypersensitive to cues signaling opportunity for reward and cues signaling failure and loss of rewards. However, no studies to date have investigated whether individuals with bipolar spectrum disorders experience increased rates of these BAS-relevant life events, which would place them at double risk for developing bipolar episodes. The present study found that individuals with bipolar II disorder and cyclothymia experience increased rates of BAS-activating and BAS-deactivating, but not goal-attainment, life events. Finally, for bipolar spectrum individuals only, BAS-activating events predicted BAS-deactivating events' rates.

Current alcohol use and risk for hypomania in male students: generally more or more binging?

BACKGROUND: Alcohol use disorders and bipolar disorder are highly comorbid. Some studies suggest that alcohol abuse or misuse might even precede the onset of bipolar disorder, but few studies have looked at the daily drinking pattern beyond diagnostic categories. We therefore examined if risk for hypomania is associated with a specific drinking pattern when using a calendar-based interview. METHOD: A total of 120 students who completed the Hypomanic Personality Scale were independently interviewed with the FORM 90 to assess daily drinking and the Composite Diagnostic Interview to derive Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnoses. RESULTS: Conducting regression analyses, we found that an alcohol-related disorder was related to the amount and frequency of drinking, as expected. Risk for hypomania was specifically related to an unstable drinking pattern and binge drinking, but not generally higher consumption. CONCLUSION: Risk for hypomania was associated with unstable alcohol consumption and binge drinking, even after controlling for alcohol-related disorders. This supports the idea that instability in different areas of behavior is characteristic of vulnerability to hypomania.

Life events and social rhythms in bipolar spectrum disorders: a prospective study.

This study examined the social zeitgeber theory, which suggests that affective symptoms are caused by life events disrupting vulnerable individuals' social and circadian rhythms. Undergraduate participants were selected based on a 2-phase screening process, including a semistructured diagnostic interview. The final sample consisted of 101 bipolar spectrum participants and 100 demographically matched normal controls. Participants who completed up to 3 follow-up visits, approximately every 4 months, as part of a longitudinal study were included in the current study. Life events did not predict social rhythm regularity and social rhythm regularity inconsistently predicted affective symptoms. However, life events, particularly social rhythm disruption (SRD) events, did predict depressive symptoms and episodes, and less consistently predicted hypo(manic) symptoms and episodes. Thus, the current study obtained mixed support for social zeitgeber theory.

[Deep brain stimulation, Parkinson's disease and neuropsychiatric complications]. / Stimulation cérébrale profonde, maladie de Parkinson et complications neuropsychiatriques.

Bilateral high-frequency stimulation of the subthalamic nuclei is now considered as the method of choice for the treatment of severe and advanced forms of Parkinson's disease. The technique improves patients' quality of life, disability, motor complications and allows the dose of dopaminergic treatment to be reduced. The dramatic motor benefits provided by the technique were firstly accompanied by a number of psychiatric complications--depression hypomania or mania, anxiety disorders or behavioural disorders--reflecting both the deleterious effect of modulation of the limbic circuit and the (inappropriate) selection of patients with past history of severe psychiatric disorders. Following a number of prospective studies, it is now considered that the rate of severe psychiatric side effects induced by deep brain stimulation is low, provided that the patients are well selected, the electrodes adequately placed and the postoperative follow-up appropriately performed. Interestingly, the favourable effects of the technique on both anxiety disorders (particularly obsessive compulsive disorders) and some behavioural disorders (mainly repetitive behaviour), strongly suggests that deep brain stimulation-associated modulation of associative and limbic circuits--through the basal ganglia--might be the method of choice for the future treatment of severe and medically refractory neuropsychiatric disorders such as Tourette's syndrome, obsessive compulsive disorders and addiction disorders.

Manic/hypomanic switch during acute antidepressant treatment for unipolar depression.

A significant proportion of patients with unipolar depression clinically develop manic or hypomanic switch during acute antidepressant treatment. Elucidation of its prevalence and predicting factors is of clinical relevance during acute antidepressant treatment of such patients. We retrospectively studied patients with unipolar depression who were admitted to our department during the 6-year period from 1997 to 2002 and who had fewer than 3 previous episodes before admission. The clinical background of the consecutive patients with manic/hypomanic switch (n = 37) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria was compared with that of patients without manic/hypomanic switch (n = 245). The prevalence rate of manic/hypomanic switch was 13.1%. The switch group was composed of 23 men and 14 women, whose average age was 48.8 +/- 12.3 years (range, 26-78 years). Manic/hypomanic switch was most frequently observed between 2 and 3 weeks after the antidepressant was increased to the ongoing dose. Antidepressants were decreased in 13 patients and discontinued in 23. Manic/hypomanic episodes lasted from 1 to 8 weeks. The patients in the switch group included a greater proportion of male subjects and had a higher frequency of family history of bipolar disorders than those in the nonswitch group. The mean doses of antidepressants were not significantly different between these groups. The higher frequency of manic/hypomanic switch occurring around the period when antidepressants begin to show clinical effects and the higher frequency of family history of bipolar disorders might suggest a biological susceptibility to antidepressants in patients of the switch group.

Rapid-cycling bipolar disorder. An overview of research and clinical experience.

Although many studies of RCBD have been reported over the last 2 decades, knowledge remains limited. Higher incidence in women is the sole clearly replicated finding in most studies. This finding might be mediated by cyclothymia, a temperament that is of higher prevalence in women and that might be considered as a normal variant of RC. Many questions remain unanswered. Review of putative risk factors, such as hypothyroidism and treatment with antidepressants, provides no conclusive answers. There is clinical evidence to implicate both factors. In principle, the thyroid connection can be approached rationally, yet there seems to be no relationship between thyroid status and response to thyroid augmentation. For this reason and given the potential risks of long-term thyroid use, this strategy should not be the first one to be tried in RC. Cumulatively, naturalistic studies over the past 30 years have strongly implicated antidepressants in switching and cycle acceleration, yet the double-blind, controlled, prospective studies that are needed to provide definitive answers are unlikely to be conducted for ethical reasons discussed in this article. Bipolar family history of RC probands appears indistinguishable from non-RC probands, indicating that most likely RCBD does not breed true. Although RC seems to be more lithium resistant with less likelihood of being symptom-free after 2 to 5 years of follow-up, many of these patients nonetheless have resolution of the RC course. There is no marked difference in suicide rates. An association of RC with bipolar type II, D-M-I pattern and those who switch into mania or hypomania on antidepressants is a provocative possibility: Antidepressants might introduce RC by first inducing a switch during a depressive episode, creating a D-M-I pattern, a pattern that is poorly responsive to lithium, which eventually degenerates into RC. Again, this sequence might be mediated by the high prevalence of cyclothymia in bipolar II patients. Thus, data from phenomenology, family history, and long-term outcome do not support RC as a separate entity. RC appears to be a temporary complicated phase in the illness, not a stable feature. This was noted by Kraepelin: I think I am convinced that that kind of classification must of necessity wreck on the irregularity of the disease. The kind and duration of the attacks and the intervals by no means remain the same in the individual case but may frequently change, so that the case must be reckoned always to new forms. Data by Gottschalk et al testify to the chaotic mood swings of contemporary bipolar disorder. Moreover RC is seen in other medical diseases, such as epilepsy, in which patients have phases of increase in frequency of episodes (seizures) that become refractory to treatment. Further longitudinal prospective studies are required to understand the complexity of this intriguing phenomenon and to provide better treatments. Algorithms deriving from tertiary research or university-based clinical experience may not generalize to RC or otherwise treatment-resistant bipolar patients seen in more routine practice. Illness severity in RCBD generally precludes double-blind controlled investigations. Meanwhile, clinicians may rely on discontinuing antidepressants, maintaining patients on combined mood stabilizers--of which valproate is probably the most useful--and making judicious use of atypical neuroleptics. Benzodiazepines and alcohol (which produce withdrawal), caffeine, stimulants, exposure to bright light, and sleep deprivation during excited phases should be avoided. Thyroid and nimodipine augmentation can be considered in those with the most malignant course. These are patients who need the maximal support that their psychiatrist can provide them. Office visits must be arranged as the last appointment of the day.

Seasonal cyclothymia to seasonal bipolar affective disorder: a double switch after stroke.

The appearance of bipolar affective disorder after stroke depends on the presence of two factors: a predisposing factor of either genetic loading or subcortical atrophy, and a lesion of specific corticolimbic pathways involving the right hemisphere. Whether cyclothymia and seasonal affective disorder further predispose to poststroke affective disorder is not clear. A case is described which highlights these issues. The aetiological factors, pathophysiology, and diagnosis are discussed.

Seasonal affective disorder following brain injury.

Seasonal affective disorder has not previously been linked with neuroanatomical abnormalities despite its relationship to biological rhythms. A 45-year-old woman is described with an arteriovenous abnormality in the right frontotemporal region who developed recurrent winter depression and summer hypomania.

Developmental considerations in the concept of affective illness.

A spectrum exists from change, to crisis, to turmoil, and, at times, to illness at watersheds in the life cycle. Affective experience can be a mobilizing factor and emotional catalyst in the growth experience or a devastating psychotic mood disturbance when predisposing life events and genetic disposition are operational. This paper reviews the dynamics of biologic systems, chronobiology, and time-related transitions of the developmental experience. The relationship of a developmental time clock to affective phenomenology and clinical affective disorder is discussed and presented in two case vignettes. Developmental theory and the interface between life events, stress, and affective illness are reviewed and a concept of development as a sequence of affective cycles is presented.

[Cyclothymia and the brain stem. The question of symptomatic cyclothymia on the basis of observations in insufficiency of the basilar arterial system]. / Zyklothymie und Hirnstamm. Ein Beitrag zur Frage der Symptomatischen Zyklothymie aufgrund von Beobachtungen bei Basilarisinsuffizienz.

Seven patients with an insufficiency in the basilar arterial system showed a typical endogenous depression. We assumed that the temporal coincidence of neurological and psychial syndromes was not accidental but both were caused by a circulation disturbance in the cerebral stem structures.