Nikolaus Michael

Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression.

BACKGROUND The dorsolateral prefrontal cortex (DLPFC) is involved in the pathophysiology of major depression. In particular, metabolic (functional hypometabolism) and structural alterations have been described. In this study metabolic changes within the DLPFC of severely depressed patients before and after electroconvulsive therapy (ECT) were evaluated by proton STEAM spectroscopy (1H-MRS). METHOD Twelve severely depressed patients with a diagnosis of major depressive episode, unipolar with melancholic features (DSM-IV), were enrolled, and the left dorsolateral prefrontal cortex (DLPFC) was investigated before and after unilateral ECT by 1H-MRS. Three of the four non-responding patients were remeasured a third time after a combined ECT/antidepressant pharmacotherapy. The results were compared with 12 age- and gender-matched controls. RESULTS In depressed patients reduced glutamate/glutamine (Glx) levels were measured pre-ECT; Glx concentrations correlated negatively with severity of depression. After successful treatment, Glx increased significantly and levels no longer differed from those of age-matched controls. CONCLUSIONS Our results indicate that major depressive disorder is accompanied by state-dependent metabolic alterations, especially in glutamate/glutamine metabolism, which can be reversed by successful ECT.

Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex

RationaleThe dorsolateral prefrontal cortex (DLPFC) participates in the pathophysiology of mania. In particular, left-sided structural and metabolic abnormalities have been described.ObjectivesClinical symptoms may be due to hyperactivity of cortical glutamatergic neurons, resulting in increased excitatory neurotransmitter flux and thus enhanced Glx levels.MethodsGlutamate/glutamine (Glx) levels were assessed by proton magnetic resonance spectroscopy (1H-MRS) in eight acute manic patients compared with age- and gender-matched controls.ResultsManic patients had significantly elevated Glx levels (t-test; t=–3.1, P=0.008) within the left DLPFC.ConclusionsOur results indicate that the prefrontal cortical glutamatergic system is involved in the pathophysiology of acute mania. This may have implications for the treatment of mania.

Neurotrophic effects of electroconvulsive therapy: A proton magnetic resonance study of the left amygdalar region in patients with treatment-resistant depression

Negatively balanced neurotrophic factors may be important in precipitating clinical depression. Recently, it has been reported that antidepressant therapy may exert positive neurotrophic effects. The aim of this study was to detect probable neurotrophic changes during electroconvulsive therapy (ECT). For this purpose, N-acetylaspartate (NAA), an amino acid exclusively located in neurons, and other brain metabolites such as glutamine/glutamate (Glx), choline (Cho), and creatine (Cr) were measured in patients by localized proton magnetic resonance spectroscopy. A total of 28 severely depressed patients (DSM-IV) were enrolled, and the left amygdalar region was investigated by proton STEAM spectroscopy before and after unilateral ECT. The results were compared with 28 age- and gender-matched controls using nonparametric paired and unpaired tests. A significant increase in NAA was observed only in ECT responders (n=14; p=0.019). Five out of 14 nonresponders to ECT monotherapy were remeasured following a clinical improvement after continued ECT combined with antidepressants and were then found also to present a significant increase in NAA. In all successfully treated patients, parallel observations, that is, increased levels, were made for Glx, whereas Cho and Cr were unchanged. In conclusion, our preliminary finding of increased NAA concentrations after successful ECT may indicate a probable neurotrophic effect of ECT.

Metabolic changes after repetitive transcranial magnetic stimulation (rTMS) of the left prefrontal cortex: a sham‐controlled proton magnetic resonance spectroscopy (1H MRS) study of healthy brain

Rapid transcranial magnetic stimulation is being increasingly used in the treatment of psychiatric disorders, especially major depression. However, its mechanisms of action are still unclear. The aim of this study was to assess metabolic changes by proton magnetic resonance spectroscopy following high‐frequency rapid transcranial magnetic stimulation (20 Hz), both immediately after a single session and 24 h after a series of five consecutive sessions. Twelve healthy volunteers were enrolled in a prospective single‐blind, randomized study [sham (n = 5) vs. real (n = 7)]. Three brain regions were investigated (right, left dorsolateral prefrontal cortex, left anterior cingulate cortex). A single as well as a series of consecutive rapid transcranial magnetic stimulations affected cortical glutamate/glutamine levels. These effects were present not only close to the stimulation site (left dorsolateral prefrontal cortex), but also in remote (right dorsolateral prefrontal cortex, left cingulate cortex) brain regions. Remarkably, the observed changes in glutamate/glutamine levels were dependent on the pre‐transcranial magnetic stimulation glutamate/glutamine concentration, i.e. the lower the pre‐stimulation glutamate/glutamine level, the higher the glutamate/glutamine increase observed after short‐ or long‐term stimulation (5 days). In general, the treatment was well tolerated and no serious side‐effects were reported. Neither transient mood changes nor significant differences in the outcome of a series of neuropsychological test batteries after real or sham transcranial magnetic stimulation occurred in our experiment. In summary, these data indicate that rapid transcranial magnetic stimulation may act via stimulation of glutamatergic prefrontal neurons.

Studies on a German (Münster) version of the temperament auto-questionnaire TEMPS-A: construction and validation of the briefTEMPS-M

BACKGROUND Based on classic German concepts of a continuum between depressive, hyperthymic, cyclothymic, and irritable temperaments and affective disorder (and adding an anxious type to the four), Akiskal and co-workers developed the Temperament Evaluation of Memphis, Pisa, Paris and San Diego both in interview (TEMPS-I) and auto-questionnaire (TEMPS-A) versions. It is the aim of the present analyses to validate a brief German version of TEMPS-A. METHODS A total of 1056 students of the Westfalische-Wilhelms-Universitat in Munster, Germany, filled out the long 110-item version of the TEMPS-A (Munster translation by Erfurth: TEMPS-M) modified into a five gradation Likert format and with the items randomized. Based on this data we constructed a brief version of the TEMPS-M. In a second study, a sample of 151 students were recruited who filled out the briefTEMPS-M twice, approximately 1 month apart. RESULTS Our psychometric procedures resulted in the retention of 35 items from the original 110. The proposed five-factor structure of the original TEMPS-A was upheld, with relatively few item reclassification (mainly due to some overlap between depressive and anxious traits). Internal consistency (Cronbach alpha values ranging from 0.69 to 0.84) and test-retest reliability were shown. Most importantly, all temperaments in the briefTEMPS-M correlated quite well (Pearson r values ranging from 0.49 to 0.72) with their respective original versions in the longer TEMPS-M. As for construct validity, significant correlation was shown with the Beck Depression Inventory for all but the hyperthymic temperament; the hyperthymic, cyclothymic and irritable correlated highest with the self-report Manic Inventory. LIMITATIONS The study sample of university students was selective. CONCLUSIONS We were able to construct a brief German version of the TEMPS-A auto-questionnaire. We submit this shorter version will be suitable for both clinical (psychiatric and general medical) and neurobiological research, as well as in studies on temperament features in selected populations, e.g., allowing comparisons between regions or different (German-speaking) countries.

N-acetylaspartate levels of left frontal cortex are associated with verbal intelligence in women but not in men: a proton magnetic resonance spectroscopy study

The left frontal cortex plays an important role in executive function and complex language processing inclusive of spoken language. The purpose of this work was to assess metabolite levels in the left and right prefrontal cortex and left anterior cingulum by proton magnetic resonance spectroscopy and relate results to verbal intelligence (Wechsler Adult Intelligence Scale revised) in a sample of college-educated healthy volunteers (dorsolateral prefrontal cortex [DLPFC]: n=52, 23 females, and left anterior cingulum: n=62, 22 females; age range: 20-75 years). In women only, N-acetylaspartate in the DLPFC and in the left anterior cingulate cortex was positively correlated with vocabulary scores. Our data support the hypothesis of existing gender differences regarding the involvement of the left frontal cortex in verbal processing as reflected in different correlations of specific metabolites with verbal scores.

Treatment of bipolar mania with right prefrontal rapid transcranial magnetic stimulation.

Background: Transcranial magnetic stimulation (TMS) has been suggested for the treatment of a variety of CNS disorders including depression and mania. Methods: Nine bipolar (I) in-patients diagnosed with mania were treated with right prefrontal rapid TMS in an open and prospective study. Eight of nine patients received TMS as add-on treatment to an insufficient or only partially effective drug therapy. Results: During the 4 weeks of TMS treatment a sustained reduction of manic symptoms as measured by the Bech-Rafaelsen mania scale (BRMAS) was observed in all patients. Limitations: Due to the open and add-on design of the study, a clear causal relationship between TMS treatment and reduction of manic symptoms cannot be established. Conclusions: Our data suggest that right prefrontal rapid TMS is safe and efficacious in the add-on treatment of bipolar mania showing laterality opposed to the proposed effect of rapid TMS in depression.

Bupropion as add-on strategy in difficult-to-treat bipolar depressive patients.

Bupropion, a selective norepinephrine and dopamine reuptake inhibitor, has been suggested for the treatment of bipolar depression, not only because of its efficacy, but also because of a probably lower risk of inducing switches to hypomania or mania. Most studies on bupropion treatment in bipolar patients have been performed in moderately ill out-patients. In contrast, we report on a sample of difficult-to-treat, predominantly severely ill, co-morbid, psychotic or therapy-refractory bipolar depressive in-patients. In this open and prospective study, 13 patients were treated with bupropion as an add-on strategy mainly to other antidepressants and to various mood stabilizers. Our data support the idea that bupropion is a first-line antidepressant in the treatment of severe bipolar depression. Eight of 13 patients showed a >50% reduction of Montgomery-Asberg Depression Scale ratings within 4 weeks. Co-medication with drugs commonly used in treatment-resistant bipolar disorder including venlafaxine, clozapine, lithium, topiramate and sodium valproate was safe in our small sample. While adhering to the suggestion of Goren and Levin not to exceed a daily dose of 450 mg of bupropion when treating bipolar depressed patients, we did not observe any switch from depression to hypomania or mania.

Dissociative disorders and traumatic childhood experiences in transsexuals.

In this first prevalence study of dissociative symptoms and different forms of childhood experiences among transsexuals, 41 transsexuals and 115 psychiatric inpatients were compared by means of the Interview for Dissociative Disorders (SCID-D-R), the Dissociative Experiences Scale (DES), and the Childhood Trauma Questionnaire (CTQ). The total score for the dissociative symptoms revealed no significant differences between the transsexuals and the psychiatric inpatients. However, the higher DES score among transsexuals compared with a normal population was found to be due largely to one item. A surprisingly high prevalence of emotional maltreatment was recorded. The results suggest that both the DES and the SCID-D-R have limited validity as instruments for screening and diagnosing dissociative disorders in transsexuals. Psychiatrists should be mindful of the possible existence of dissociative disorders in transsexual patients. Further investigations are needed to clarify the effects of traumatic childhood experiences on sexual identity in transsexuals and to throw more light on the phenomenological correlation between transsexualism and dissociative identity, using taxometric analyses.

Electroconvulsive therapy exerts mainly acute molecular changes in serum of major depressive disorder patients

Electroconvulsive therapy (ECT) is mainly used to treat medication resistant major depressive disorder (MDD) patients, with a remission rate of up to 90%. However, little is known about the serum molecular changes induced by this treatment. Understanding the mechanisms of action of ECT at the molecular level could lead to identification of response markers and potential new drug targets for more effective antidepressant treatments. We have carried out a pilot study which analysed serum samples of MDD patients who received a series of ECT treatments over 4 weeks. Patients received only ECT treatments over the first two weeks and a combination of ECT and antidepressant drugs (AD) over the subsequent two weeks. Blood serum analyses were carried out using a combination of multiplex Human MAP® immunoassay and liquid-chromatography mass spectrometry (LC-MS(E)) profiling. This showed that ECT had a predominant acute effect on the levels of serum proteins and small molecules, with changes at the beginning of ECT treatment and after administration of the ECT+AD combination treatment. This suggested a positive interaction between the two types of treatment. Changed molecules included BDNF, CD40L, IL-8, IL-13, EGF, IGF-1, pancreatic polypeptide, SCF, sortilin-1 and others which have already been implicated in MDD pathophysiology. We conclude that ECT appears to exert mainly acute effects on serum molecules.