Anticonvulsants in bipolar disorder Grunze, Heinz C. R.
Journal of mental health (Abingdon, England),
04/2010, Volume:
19, Issue:
2
Journal Article
Peer reviewed
Anticonvulsant drugs are widely used in psychiatric indications. This includes alcohol and benzodiazepine withdrawal symptoms, panic and anxiety disorders, dementia, schizophrenia, and to some extent ...personality disorders. Besides pain syndromes, their main domain outside epilepsy, however, is bipolar disorder. Carbamazepine, valproate, and lamotrigine are meanwhile recognized mood stabilizers, but several other antiepileptic drugs have also been tried out with diverging or inconclusive results. Understanding the mechanisms of action and identifying similarities between anticonvulsants effective in bipolar disorder may also enhance our understanding of the underlying pathophysiology of the disorder.
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BFBNIB, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Objective: There is growing evidence of cognitive impairment as a trait factor in bipolar disorder. The generalizability of this finding is limited because previous studies have either focussed ...exclusively on bipolar I disorder or have analysed mixed patient groups. Thus, it is still largely unknown whether bipolar II patients perform differently from bipolar I patients on measures of cognitive functioning.
Methodology: A total of 65 patients with bipolar I disorder, 38 with bipolar II disorder, and 62 healthy controls participated in the study. Patients had to be euthymic for at least one month. Clinical and demographic variables were collected in a clinical interview and with the Structured Clinical Interview for DSM‐IV. Cognitive functioning was assessed using a neuropsychological battery. Univariate and multivariate analyses of variance were conducted for analyzing possible differences between the groups.
Results: The multivariate analysis of covariance (MANCOVA) indicated overall differences in neuropsychological performance between the three groups (Pillai Spur: F 1.96, p = 0.003). Post hoc comparisons revealed that patients with bipolar I disorder showed significantly lower scores in psychomotor speed, working memory, verbal learning, delayed memory, and executive functions than healthy controls. Patients with bipolar II disorder showed significant deficits in psychomotor speed, working memory, visual/constructional abilities, and executive functions compared to controls, but not on verbal learning and delayed memory. The two patient groups did not differ significantly from each other on any domain tested.
Conclusion: These results support a similar pattern of cognitive deficits in both subtypes of bipolar disorder.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Many patients with major depressive disorder have treatment-resistant depression, defined as no adequate response to two consecutive courses of antidepressants. Some evidence suggests that ...antiglucocorticoid augmentation of antidepressants might be efficacious in patients with major depressive disorder. We aimed to test the proof of concept of metyrapone for the augmentation of serotonergic antidepressants in the clinically relevant population of patients with treatment-resistant depression.
This double-blind, randomised, placebo-controlled trial recruited patients from seven UK National Health Service (NHS) Mental Health Trusts from three areas (northeast England, northwest England, and the Leeds and Bradford area). Eligible patients were aged 18-65 years with treatment-resistant depression (Hamilton Depression Rating Scale 17-item score of ≥18 and a Massachusetts General Hospital Treatment-Resistant Depression staging score of 2-10) and taking a single-agent or combination antidepressant treatment that included a serotonergic drug. Patients were randomly assigned (1:1) through a centralised web-based system to metyrapone (500 mg twice daily) or placebo, in addition to their existing antidepressant regimen, for 21 days. Permuted block randomisation was done with a block size of two or four, stratified by centre and primary or secondary care setting. The primary outcome was improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation, analysed in the modified intention-to-treat population of all randomly assigned patients that completed the MADRS assessment at week 5. The study has an International Standard Randomised Controlled Trial Number (ISRCTN45338259) and is registered with the EU Clinical Trial register, number 2009-015165-31.
Between Feb 8, 2011, and Dec 10, 2012, 165 patients were recruited and randomly assigned (83 to metyrapone and 82 to placebo), with 143 (87%) completing the primary outcome assessment (69 83% in the metyrapone and 74 90% in the placebo group). At 5 weeks, MADRS score did not significantly differ between groups (21·7 points 95% CI 19·2-24·4 in the metyrapone group vs 22·6 points 20·1-24·8 in the placebo group; adjusted mean difference of -0·51 points 95% CI -3·48 to 2·46; p=0·74). 12 serious adverse events were reported in four (5%) of 83 patients in the metyrapone group and six (7%) of 82 patients in the placebo group, none of which were related to study treatment. 134 adverse events occurred in 58 (70%) patients in the metyrapone group compared with 95 events in 45 (55%) patients in the placebo group, of which 11 (8%) events in the metyrapone group and four (4%) in the placebo group were judged by principle investigators at the time of occurrence to be probably related to the study drug.
Metyrapone augmentation of antidepressants is not efficacious in a broadly representative population of patients with treatment-resistant depression within the NHS and therefore is not an option for patients with treatment-resistant depression in routine clinical practice at this time. Further research is needed to clarify if such augmentation might benefit subpopulations with demonstrable hypothalamic-pituitary-adrenal axis abnormalities.
Efficacy and Mechanism Evaluation (EME) programme, a UK Medical Research Council and National Institute for Health Research partnership.
Antidepressants constitute a central cornerstone in the treatment of depressive syndromes. In bipolar patients, however, there is an ongoing controversy about their usefulness for at least 3 decades. ...Early reports, mainly concerning tricyclic antidepressants, have repeatedly pointed toward unfavorable side effects on the course of the disorder, namely switching into (hypo)mania, induction of rapid cycling, and increased risk of suicide. Most evidence for both unfavorable and favorable effects has been deducted, thus far, from small studies with methodological flaws. More substantiated evidence only recently became available. From this it appears that, at least, the switch risk, and perhaps also the risk for rapid cycling and new-onset suicidality have been overinterpreted. At the same time, these new data raise doubt about the efficacy of antidepressants as a primary-treatment choice in bipolar depression.
Anticonvulsant drugs are widely used in psychiatric indications. These include mainly alcohol and benzodiazepine withdrawal syndromes, panic and anxiety disorders, dementia, schizophrenia, affective ...disorders, bipolar affective disorders in particular, and, to some extent, personality disorders, A further area in which neurology and psychiatry overlap is pain conditions, in which some anticonvulsants, and also typical psychiatric medications such as antidepressants, are helpful. From the beginning of their psychiatric use, anticonvulsants have also been used to ameliorate specific symptoms of psychiatric disorders independently of their causality and underlying illness, eg, aggression, and, more recently, cognitive impairment, as seen in affective disorders and schizophrenia. With new anticonvulsants currently under development, it is likely that their use in psychiatry will further increase, and that psychiatrists need to learn about their differential efficacy and safety profiles to the same extent as do neurologists.
Increased discharge activity of mesopontine cholinergic neurons participates in the production of electroencephalographic (EEG) arousal; such arousal diminishes as a function of the duration of prior ...wakefulness or of brain hyperthermia. Whole-cell and extracellular recordings in a brainstem slice show that mesopontine cholinergic neurons are under the tonic inhibitory control of endogenous adenosine, a neuromodulator released during brain metabolism. This inhibitory tone is mediated postsynaptically by an inwardly rectifying potassium conductance and by an inhibition of the hyperpolarization-activated current. These data provide a coupling mechanism linking neuronal control of EEG arousal with the effects of prior wakefulness, brain hyperthermia, and the use of the adenosine receptor blockers caffeine and theophylline.
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Some patients with depression do not respond to first and second line conventional antidepressants and are therefore characterised as suffering from treatment refractory depression (TRD). On-going ...psychosocial stress and dysfunction of the hypothalamic-pituitary-adrenal axis are both associated with an attenuated clinical response to antidepressants. Preclinical data shows that co-administration of corticosteroids leads to a reduction in the ability of selective serotonin reuptake inhibitors to increase forebrain 5-hydroxytryptamine, while co-administration of antiglucocorticoids has the opposite effect. A Cochrane review suggests that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD and includes a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) is a multicentre randomised placebo controlled trial of metyrapone augmentation of serotonergic antidepressants in a large population of patients with TRD in the UK National Health Service.
Patients with moderate to severe treatment refractory Major Depression aged 18 to 65 will be randomised to metyrapone 500 mg twice daily or placebo for three weeks, in addition to on-going conventional serotonergic antidepressants. The primary outcome will be improvement in Montgomery-Åsberg Depression Rating Scale score five weeks after randomisation (i.e. two weeks after trial medication discontinuation). Secondary outcomes will include the degree of persistence of treatment effect for up to 6 months, improvements in quality of life and also safety and tolerability of metyrapone. The ADD Study will also include a range of sub-studies investigating the potential mechanism of action of metyrapone.
Strengths of the ADD study include broad inclusion criteria meaning that the sample will be representative of patients with TRD treated within the UK National Health Service, longer follow up, which to our knowledge is longer than any previous study of antiglucocorticoid treatments in depression, and the range of mechanistic investigations being carried out. The data set acquired will be a rich resource for a range of research questions relating to both refractory depression and the use of antiglucocorticoid treatments.
Current Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A series of open studies suggests that topiramate has efficacy in bipolar disorder. To further investigate the potential value of topiramate as an antimanic agent, we conducted an open trial in 11 ...manic patients.
Eleven patients with bipolar I disorder with an acute manic episode (DSM-IV) were treated with a mood stabilizer and/or antipsychotics in sufficient and fixed doses. All had a Young Mania Rating Scale (YMRS) score of at least 24 (mean +/- SD = 33.5+/-8.1). Topiramate was added after stable plasma levels of concomitant mood stabilizers had been reached and was titrated within 1 week to a final dose in the range of 25 to 200 mg/day, depending on clinical efficacy and tolerability. Topiramate was discontinued after 10 days, while concomitant medication remained unchanged. After 5 days, topiramate was reintroduced at similar or increased dosages for another 7 days. Patients were assessed with the YMRS; the Clinical Global Impressions scale version for bipolar patients; and the 21-item Hamilton Rating Scale for Depression.
Seven of the 11 patients initially showed a good antimanic response with > 50% reduction in YMRS score. One patient showed psychotic features following rapid increase in topiramate dosage and dropped out on day 10. After discontinuation of topiramate, 7 of the remaining 10 patients worsened (increase of > or = 25% in YMRS score), 2 remained stable, and 1 discontinued follow-up after good recovery. After reintroducing topiramate, all patients improved again within a week, with 8 of 9 meeting the responder criterion of > or = 50% YMRS score reduction when comparing baseline values with those of day 22. With the exception of the patient who developed psychosis, topiramate was well tolerated. Concomitant medication did not interfere with plasma levels of drug, except for carbamazepine level in 1 patient.
The antimanic response among patients in this study appears reproducibly linked to the addition of topiramate.
Bipolar disorder is associated with cognitive impairment. High homocysteine levels seem to have a negative impact on cognition in the elderly. The aim of the present study was to investigate the ...potential relationship of elevated homocysteine levels and cognitive impairment in bipolar patients.
Cognitive functioning of DSM-IV bipolar disorder patients who were euthymic (Hamilton Rating Scale for Depression score < or = 5 and Young Mania Rating Scale score < or = 5) and healthy controls was assessed with the revised Wechsler Adult Intelligence Scale Information Subtest, the Wechsler Adult Intelligence Scale III Letter-Number Sequencing Subtest, the Trail Making Test, and the Repeatable Battery for the Assessment of Neuropsychological Status Form A to examine premorbid IQ, information processing speed, working memory, verbal learning, visuospatial/constructional abilities, delayed memory, and executive functions. Total homocysteine plasma concentration was measured by using high-performance liquid chromatography. Multivariate analyses of variance and multiple regression analyses were conducted to examine group differences and possible associations between cognitive functioning and homocysteine level. The study was conducted from 2002 through 2006.
Seventy-five euthymic bipolar patients and 42 healthy controls participated in the study. Patients performed significantly worse than controls in all cognitive domains tested (Pillai Spur: F = 3.32, p = .038) except premorbid IQ (p = .068). The mean +/- SD homocysteine levels were 10.2 +/- 3.2 microM/L for patients and 8.9 +/- 2.8 microM/L for controls (p = .036). Stepwise regression analyses revealed a significant and independent association of homocysteine levels with verbal learning (p = .002), delayed memory (p = .030), and executive function (p = .011) in the patient group. About 11% of the variance was explained by only the homocysteine level.
Elevated homocysteine levels may have a negative impact on verbal learning, delayed memory, and executive function in euthymic bipolar patients, but further studies are warranted.
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