Changes in the pituitary-thyroid axis accompanying major affective disorders

The reports tries to show the intercorrelations between the TRH-test and the peripheric thyroid function during the course of affective disorders. The sample comprised 22 manic (15 follow-up) and 24 depressive (13 follow-up) patients. As parameters serum thyroxine, triiodothyronine, T3-uptake, FT4-index, T3/T4-ratio, TSH basal and 30 min after 200 micrograms TRH i.v. were determined. In a smaller group of patients reverse-T3 was measured, too. During acute mania and depression there is an increase of thyroxine. We observed a stronger conversion of T4 to rT3 with less inactivation of T4 to T3 in mania than in depression. Both groups show attenuated TSH response to TRH stimulation in florid psychoses. Comprehensing all results we come to the conclusion that the changes in the pituitary-thyroid axis accompanying affective psychoses start from the thyroidea and not from the anterior pituitary gland.     

Erythrocyte COMT-activity in patients with affective disorders

COMT enzyme characteristics (K_m, V, ratio of meta/paramethylation) were determined in the red blood cells of 20 patients with endogenous depression, in 20 healthy controls matched as to age and sex, as well as in 10 patients with mania, and 10 patients with neurotic depression. Assessment was done twice, i.e. before and after remission in patients with endogenous depression and in the manic patients. If male and female patients are considered together there was no statistical difference between the COMT charateristics of these patients groups, either before or after remission. Only the bipolar patients showed a higher COMT-activity (V) than their individually matched controls. If, however, only the female patients are taken into consideration, COMT-activity of the patients with endogenous depression vs. controls is significantly increased by 60%. This difference can be demonstrated also after remission (“free interval”) though statistical significance is reached only for the unipolar group. Further in vitro experiments indicate that antidepressant drugs do not possess a relevant influence on COMT-activity. Ranking the mean COMT-values leads to the following order: matched controls < neurotic depression < unipolar depression < biopolar depression, which would be in good agreement with theoretical expectations based on the amine hypothesis of depression. Compared with normal male subjects COMT-activity of female controls is significantly lower. On the other hand, the female patients with endogenous depression show a significantly higher enzyme activity than the corresponding male patients.     

A proton magnetic resonance spectroscopy investigation of the dorsolateral prefrontal cortex in acute mania

BACKGROUND: Several neurochemical abnormalities have been reported in bipolar disorder (BD), but the exact mechanisms that underlie its pathophysiology remain to be elucidated. Proton magnetic resonance spectroscopy (1HMRS) allows in vivo measurements of certain neurometabolites in the human brain. 1HMRS was used to investigate the dorsolateral prefrontal cortex (DLPFC) in bipolar subjects during a manic or mixed phase. N-acetyl-L-aspartate (NAA), choline-containing molecules (Cho), creatine plus phosphocreatine (Cr) and myoinositol (Ino) were measured. METHOD: Ten bipolar patients (nine manic, one mixed), diagnosed by a semi-structured clinical interview (SCID), and ten age- and gender-matched healthy volunteers were studied. Absolute neurometabolites levels were measured from two 8 cm3 voxels placed in left and right DLPFC using a short TE 1HMRS method at 1.5 T. T1- and T2-weighted anatomical magnetic resonance imaging was performed to exclude any neuroanatomical abnormality. RESULTS: No significant differences were found for NAA, Cho, Cr, Ino, NAA/Cr, Cho/Cr or Ino/Cr between patients and controls. Manic/mixed patients had significantly higher left-to-right myoinositol ratios in DLPFC (p = 0.044). CONCLUSIONS: Increased left-to-right myoinositol ratios in the DLPFC in bipolar patients during acute mania may represent a dysfunction in the phosphoinositide-signaling pathway. Longitudinal studies with larger samples of unmedicated patients assessing pre- and post-treatment times will be required for further clarification of the time course of these abnormalities and the relationship with treatment effects.     

Treatment of acute mania--from clinical trials to recommendations for clinical practice

No consensus has been reached with regard to the treatment of bouts of acute mania in various parts of the world. Controlled clinical trials have, at last, provided irrefutable evidence of the activity of lithium, which has long been used alone, as well as that of divalproate or its derivatives and, to a lesser extent, carbamazepine. The new antipsychotic agents have more recently established their efficacy, especially olanzapine, risperidone and aripiprazole. It is paradoxical to note that, in Europe, haloperidol is still the reference substance used in clinical trials despite the fact that it is not officially indicated in the treatment of mania. In the USA, lithium, divalproate or antipsychotics can be prescribed as first‐line treatment. In Europe, lithium remains the first‐line medication, whereas divalproate and atypical antipsychotic agents are used only as second‐line therapy. The conventional antipsychotic agents (such as haloperidol, loxapine or zuclopenthixol) which should no longer be prescribed during manic episodes given the potential risks and side effects associated with these substances (extrapyramidal side effects, depressogenic effect, malignant syndrome) are still prescribed extensively in Europe. Although both types of medication (antipsychotics, normothymic agents and/or anticonvulsants) have proved to be clinically effective in the management of mania by reducing the mania scores overall, the same does not apply, however, to all symptoms of mania. Factorial approaches to mania have all shown that since there are several clinical forms of mania, several lines of manic symptoms can be identified. Antipsychotic and normothymic agents and/or anticonvulsants do not appear to have the same effects on each of these identifiable clusters of symptoms, mainly psychotic features. We believe that it is vitally important for future clinical trials of mania treatment to focus on the treatment effect by adopting a factorial approach to the episode with an appropriate methodological structure provided to this end. These questions highlight the uncertainty shrouding the very structure of manic episodes, namely that these are predominantly of a thymic or psychotic nature. The Europeans undoubtedly consider mania to be more of a thymic episode and prefer lithium as the first‐line treatment, whereas the Americans believe that psychotic symptoms dominate and widely prescribe antipsychotic agents. However, from the standpoint of clinical trials currently available, even though antipsychotic agents are certainly effective in reducing the scores on the mania scales, can they be considered purely as antimania treatments?. Copyright © 2004 John Wiley & Sons, Ltd.     

Assessment of safety,tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar mania: a 46-week,open-label extension following a 6-week double-blind study

Abstract

Objective:

This study evaluated the long-term tolerability and effectiveness of aripiprazole adjunctive to lithium or valproate in partial responders with bipolar mania.     

Targeting glycogen synthase kinase-3 as an approach to develop novel mood-stabilising medications

Historically, success in the pharmacological treatment of bipolar disorder has arisen either from serendipitous findings or from studies with drugs (antipsychotics and anticonvulsants) developed for other indications (schizophrenia and epilepsy, respectively). Lithium has been in widespread clinical use in the treatment of bipolar disorder for > 30 years. Development of lithium-mimetic compounds has the potential to result in a more specific medication, with fewer side effects and a less narrow dose range. However, novel medications based upon a known mechanism of action of this drug are yet to be developed. Increasing evidence suggests that a next-generation lithium compound may derive from knowledge of a direct target of lithium, glycogen synthase kinase-3 (GSK-3). GSK-3 is an intracellular enzyme implicated as a critical component in many neuronal signalling pathways. However, despite the large body of preclinical data discussed in this review, definitive validation of GSK-3 as therapeutically relevant target of lithium will require clinical trials with novel GSK-3 inhibitors. A number of recent reports suggest that it is possible to develop selective, small-molecule GSK-3 inhibitors.     

Comparison of the Internal State Scale to Clinician-Administered Assessments in Patients with Bipolar Disorder and Alcohol Abuse or Dependence

Abstract

Objectives: Self-report measures require less clinician time to administer than clinician-rated assessments. The Internal State Scale (ISS) is a well-validated self-report measure that assesses symptoms of mania and depression in patients with bipolar disorder (BPD). However, the ISS has never been specifically evaluated in patients with BPD and comorbid substance misuse. Substances can induce mood symptoms complicating diagnosis and mood state assessment.

Methods: The ISS was compared with the Hamilton Rating Scale for Depression (HRSD), Young Mania Rating Scale (YMRS), and Brief Psychiatric Rating Scale (BPRS) in 21 patients with BPD and alcohol abuse/dependence at baseline and for up to 16 weeks postbaseline. In addition, ISS-determined mood state was compared to mood state from a structured diagnostic interview.

Results: Significant baseline correlations were observed between the ISS depression subscale and HRSD, ISS activation subscale and YMRS, and ISS perceived conflict subscale and BPRS. Significant correlations of baseline to exit change scores were found between the ISS activation and YMRS, but not ISS depression and HRSD, or ISS perceived conflict and BPRS. All participants had a mixed mood state by structured diagnostic interview. The ISS diagnosed the manic/hypomanic portion of this mood state in 76% of participants but found depression in only 38%.

Conclusions: As in BPD patients without substance abuse, the ISS generally showed correlations with clinician-rated scales at baseline, with less strong correlations observed on change scores. The ISS diagnosis of mania or hypomania appeared to correspond more highly than depression with the findings from a structured diagnostic interview.     

Patterns of cardiorespiratory coordination in young women with recurrent major depressive disorder treated with escitalopram or venlafaxine

Evidence from previous studies suggests autonomic dysregulation in patients with major depressive disorder (MDD). Antidepressant treatment may also affect central autonomic function. We investigated whether the type of antidepressant might be associated with the pattern of cardiorespiratory coordination in non-depressed women with recurrent MDD. Resting electrocardiograms and respiratory signals were simultaneously recorded from 38 euthymic women with recurrent MDD who were treated with either escitalopram (n=19) or venlafaxine (n=19) monotherapy and from 38 healthy women. Linear measures of heart rate variability were extracted to assess cardiac autonomic control. Sample entropy (SampEn) was computed to assess the complexity of heart rate and respiratory signals, and cross-SampEn was calculated to measure the nonlinear interaction of both signals. Significant decreases in the cardiovagal tone and cardiorespiratory coupling of women with recurrent MDD receiving venlafaxine, and tendencies toward lower cardiovagal tone and cardiorespiratory coupling in women with recurrent MDD receiving escitalopram were observed when compared with healthy controls. Effect sizes for these differences were large between women receiving venlafaxine and healthy controls. We found a positive association between cardiorespiratory decoupling and venlafaxine dose. Norepinephrine-enhancement, within a therapeutic dose range, seems to be closely associated with decreased vagal tone and reduced nonlinear coupling between heart rate and respiration in euthymic women with recurrent MDD. However, the effects of serotonin enhancement on cardiovagal tone should be considered. Our results suggest that the pharmacodynamic properties of antidepressants may affect autonomic regulation of women with recurrent MDD even in euthymic state.