H¹-MR-spectroscopy of cerebellum in adult attention deficit/hyperactivity disorder.

INTRODUCTION: Neurobiological research has implicated the cerebellum as one possible site of neurophysiological dysfunction in ADHD. Latest theoretical conceptualizations of the cerebellum as core site of the brain to model motor as well as cognitive behavior puts further weight to the assumption that it might play a key role in ADHD pathophysiology. METHODS: 30 medication free adult ADHD patients and 30 group matched (gender, age and education) healthy controls were investigated using the method of chemical shift imaging (CSI) of the cerebellum. The vermis, left and right cerebellar hemispheres were processed separately. RESULTS: We found significantly increased glutamate-glutamine (Glx) to creatine (Cre) ratios in the left cerebellar hemisphere. No other differences in measured metabolite concentrations were observed. DISCUSSION: To our knowledge this is the first evidence for neurochemical alterations in cerebellar neurochemistry in adult ADHD. They relate well to recent hypotheses that the cerebellum might control mental activities by internal models.

Evidence of disturbed amygdalar energy metabolism in patients with borderline personality disorder.

In order to detect possible links between structural and neurochemical brain abnormalities we applied high resolution morphometric imaging and short-echo time absolute-quantification magnetic resonance spectroscopy (MRS) at the left hand side to the amygdala in 12 patients with borderline personality disorder (BPD) and 10 group-matched healthy controls. Confirming earlier reports we found a significant 11-17% reduction of amygdalar volumes in patients with BPD. In addition there was a significant 17% increase of left amygdalar creatine concentrations in BPD patients. Left amygdalar creatine concentration correlated positively with measures of anxiety and negatively with amygdalar volume. This pilot study of simultaneous amygdalar morphometry and spectroscopy in BPD reveals a possible link between amygdalar volume loss, psychopathology and neurochemical abnormalities in terms of creatine signals.

Reduced cingulate glutamate/glutamine-to-creatine ratios in adult patients with attention deficit/hyperactivity disorder -- a magnet resonance spectroscopy study.

BACKGROUND: The dopaminergic system is thought to be essentially involved in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). However, there is also evidence for abnormalities in the glutamatergic system and recent theories focus on a disturbed interaction between the two systems as the essential pathogenetic mechanism of ADHD. In the present study, we wanted to test the hypothesis that prefrontal glutamate signals indirectly indicate dopaminergic dysfunction in adult patients with ADHD. METHODS: Twenty-eight adult patients with ADHD and 28 group-matched healthy volunteers were studied clinically and using chemical-shift MR spectroscopy (MRS) of the prefrontal cortex covering the anterior cingulate gyrus. RESULTS: A significant reduction of the combined glutamate/glutamine to creatine ratio in the right anterior cingulate cortex in patients with ADHD was found. DISCUSSION: Glutamatergic alterations as measured with MRS might play a role in the pathogenesis of adult patients with ADHD.

A voxel-based morphometric MRI study in female patients with borderline personality disorder.

Subtle prefrontal and limbic structural abnormalities have been reported in borderline personality disorder (BPD). In order to further validate the previously reported findings and to more precisely describe the nature of the structural change we performed a voxel-based morphometric (VBM) study in patients with BPD. Twenty female patients with BPD and 21 female healthy controls were investigated. High-resolution 3-D datasets were acquired and analyzed following an optimized protocol of VBM in the framework of statistical parametric mapping (SPM99). Gray matter volume loss was found in the left amygdala. No other differences in gray or white matter volume or density were found anywhere else in the brain. Our findings support the hypothesis that temporolimbic abnormalities play a role in the pathophysiology of BPD. Prefrontal structural alterations in BPD were not observed in this study.

Positron emission tomography in female patients with borderline personality disorder.

The pathology of Borderline personality disorder (BPD) is poorly understood and its biological basis remains largely unknown. One functional brain imaging study using [(18)F]Deoxyglucose-PET previously reported frontal and prefrontal hypometabolism. We studied brain metabolism at baseline in 12 medication-free female patients with BPD without current substance abuse or depression and 12 healthy female controls by [(18)F]Deoxyglucose-PET and statistical parametric mapping. We found significant frontal and prefrontal hypermetabolism in patients with BPD relative to controls as well as significant hypometabolism in the hippocampus and cuneus. This study demonstrated limbic and prefrontal dysfunction under resting conditions in patients with BPD by FDG-PET. Dysfunction in this network of brain regions, which has been implicated in the regulation of emotion, may underlie symptoms of BPD.

A psychopathological study into the relationship between attention deficit hyperactivity disorder in adult patients and recurrent brief depression.

OBJECTIVE: Clinical and epidemiological observations and neurobiological data suggest that there might be an inherent link between attention deficit hyperactivity disorder (ADHD) and recurrent brief depression (RBD). In this psychopathological study, we investigated the comorbidity between these two conditions. METHOD: Using an index patient approach 40 adult out-patients fulfilling the criteria for ADHD were investigated for lifetime history of RBD and another 40 out-patients with the primary diagnosis of RBD were investigated for a lifetime history of ADHD. RESULTS: We found a high prevalence of RBD in patients with ADHD (70%) while the prevalence of ADHD in the index sample with RBD was smaller (about 40%). CONCLUSION: In terms of comorbidity ADHD was the second commonest psychiatric disorder in patients with RBD next to other affective disorders. The psychopathological pattern of lifetime comorbidity might be of clinical relevance in terms of medical treatment.

Different striatal dopamine D2 receptor occupancy in alcohol dependent patients with or without physical withdrawal symptoms --a study using IBZM-SPECT.

Ten male patients with type I alcohol dependency fulfilling DSM-IV criteria for alcohol dependency were investigated twice using IBZM-SPECT after alcohol withdrawal (day 2 and day 28 after withdrawal). Five patients had a history of physical withdrawal symptoms, 5 patients had no such history. The group with physical withdrawal symptoms showed higher IBZM binding in both scans indicating differences of dopaminergic neurotransmission in different subtypes of alcohol dependency.

Frontoorbital volume reductions in adult patients with attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in childhood and adolescence and in a considerable number of patients it persists into adulthood. A network of brain regions have been shown to be abnormal in ADHD. In the present study we used magnetic resonance volumetry to investigate a possible role of the orbitofrontal cortex (OFC). Eight never medicated male patients fulfilling diagnostic criteria for ADHD and 17 male healthy controls were investigated. There was a significant reduction of the volume of the left OFC in patients with ADHD. It remains unknown whether small volumes are a primary deficit or a result of dysfunctional activation during childhood in terms of a residual deficit or a specific type of adult outcome of the disease.

[Comorbidity of depressive disorders and cardiovascular diseases. Implications for diagnosis, pharmaco- and psychotherapy]. / Komorbidität von depressiven Störungen und kardiovaskulären Erkrankungen. Implikationen für Diagnostik, Pharmako- und Psychotherapie.

Controlled studies and meta-analyses show not only that depression and cardiovascular disease often occur together, but that depressive illnesses are an independent risk factor in the development and the progression of coronary heart disease. It can be difficult to distinguish between reactive mood disturbance after myocardial infarction and depressive episodes that may have preceded the infarction and which require treatment. Due to this difficulty, depressive disorders are rarely diagnosed, and only a minority of patients receive adequate treatment. However, owing to the introduction of new antidepressants in recent years, the number of treatment options has increased. Specifically, selective serotonin reuptake inhibitors (SSRI) offer a valuable alternative to tricyclic antidepressants, which are problematic in heart disease. The authors describe on the one hand controlled studies of SSRIs and discuss differential therapeutic consequences. On the other hand, studies of psychotherapeutic interventions in comorbid patients with depression and coronary heart disease are reported. Finally, the authors discuss which psychotherapeutic interventions may be suitable.

Depression and panic disorder after heart transplantation--treatment with sertraline.

This report focuses on a case of major depression and panic disorder after heart transplantation. Due to these disorders, the male patient's compliance with cardiological treatment became increasingly insufficient. There are no controlled studies on psychopharmacological opportunities in cases such as this one. The patient was treated with sertraline and the outcome was healthy, without cardiovascular adverse effects or drug-drug interactions.

Subtle prefrontal neuropathology in a pilot magnetic resonance spectroscopy study in patients with borderline personality disorder.

The authors examined the brains of patients with borderline personality disorder (BPD) by using short echo time single voxel spectroscopy and found a significant 19% reduction of absolute N-acetylaspartate concentrations in the dorsolateral prefrontal cortex in BPD (P=0.01) compared with control subjects.

Attention-deficit disorder in adults with or without hyperactivity: where is the difference? A study in humans using short echo (1)H-magnetic resonance spectroscopy.

The DSM-IV distinguishes three subtypes of attention deficit hyperactivity disorder: The predominantly inattentive subtype (ADD), the hyperactive-impulsive subtype (ADHD) and the combined subtype. We used short echo time (1)H-magnetic resonance spectroscopy (TE=30 ms, TR=3000 ms) for absolute quantification of neurometabolites using the LC model algorithm to investigate a possible metabolic neuropathology in adult patients with ADD and ADHD and compared their spectra with healthy controls (n=5 in each group). Spectra were acquired in the left dorsolateral prefrontal cortex and the left striatum. There was a significant group difference in N-acetylaspartate (NAA) concentration in the left dorsolateral prefrontal cortex distinguishing patients with the ADHD from patients with pure ADD and healthy controls. The absolute NAA concentration was significantly reduced only in the ADHD group. Since NAA-depletion reflects a state of neuronal dysfunction, this finding indicates evidence of subtle left prefrontal neuropathology in ADHD in adults.

Acute and long-term treatment of catatonia with risperidone.

Catatonia is a rare but difficult-to-treat disorder. Here, we report on the case of a schizophrenic patient who developed several episodes of severe catatonia after suffering from adequately treated Lyme disease with encephalitis. The catatonic stupor was not responsive to typical neuroleptics and benzodiazepines. After the medication was changed to risperidone, there was a dramatic and persistent improvement of the patient's condition. Two relapses during the follow-up period over five years were caused by dose reductions. Risperidone might be a promising drug in the treatment of acute catatonia and in preventing further episodes.

Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients.

The objective of this study was to compare the effects of carbamazepine (CBZ) and valproate (VPA) cotreatment on the plasma levels of haloperidol and on the psychopathologic outcome in schizophrenic disorders. In this controlled clinical trial, 27 patients with an ICD-10 diagnosis of schizophrenia (N = 24) or schizoaffective disorder (N = 3) were randomly assigned to receive 4 weeks of treatment with either haloperidol alone, haloperidol with CBZ, or haloperidol with VPA. Whereas the haloperidol dose remained stable, the antiepileptic drug doses were adjusted to achieve therapeutic plasma levels. Clinical state was rated by the Positive subscale of the Positive and Negative Syndrome Scale and the Inpatient Multidimensional Psychiatric Scale. The use of CBZ was associated with significantly lower haloperidol plasma levels and with a worse clinical outcome compared with antipsychotic monotherapy. VPA had no significant effect on either plasma levels or on psychopathology. Our results suggest that comedication with haloperidol and CBZ is associated with a high risk for treatment failure. This might be a result of a pharmacokinetic interaction on the hepatic level. The concomitant use of VPA with neuroleptic therapy is not impaired by clinically significant drug interactions, but it is not associated with a better outcome under our conditions.

[Significance of hepatic cytochrome P450 enzymes for psychopharmacology]. / Die Bedeutung des hepatischen Cytochrom-P450-Systems für die Psychopharmakologie.

Nearly all psychotropic drugs are metabolized by hepatic cytochrome P450-enzymes. In humans, there are 5 isoenzymes involved in this process. The activity of these enzymes can be modulated by a number of commonly used drugs, yielding potentially hazardous interactions. Most of the recently introduced selective serotonin reuptake inhibitors are potent inhibitors of cytochrome P450 enzymes. Thus, the plasma concentrations of tricyclic antidepressants or clozapine might be elevated into toxic levels. In contrast, carbamazepine induces most of the isoenzymes. This potentiates the elimination of tricyclics and antipsychotics and might cause a serious risk for the recurrence of depressive or psychotic symptoms. Moreover, 5-10% of the population are slow metabolizers of CYP2D6. This group is prone to increased adverse effects of moderately dosed medication. This review systematically points out the reported or predicted pharmacokinetic drug interactions in psychopharmacology focussing on clinical significance.

[Adjuvant treatment of schizophrenic illness with carbamazepine]. / Zur adjuvanten Behandlung schizophrener Störungen mit Carbamazepin.

Very few controlled clinical trials have been assessing the interaction of antipsychotics and antiepileptics. However, schizophrenic patients frequently receive a combination therapy consisting of haloperidol and carbamazepine. The data for this treatment strategy are contradictory and may depend on the initial plasma concentration of the antipsychotic. There is convincing evidence that after addition of carbamazepine the plasma concentration of neuroleptics drops due to hepatic enzyme induction. In this study, we treated 18 schizophrenic patients either with haloperidol alone or in combination with carbamazepine. The use of carbamazepine was associated with a dramatic fall in haloperidol plasma levels and a worse clinical outcome compared to the monotherapy group. These results, together with a review of the literature, lead us to the conclusion that there are no obvious advantages of carbamazepine co-medication in schizophrenia compared to an optimized neuroleptic monotherapy.

A calcium antagonistic effect of the new antiepileptic drug lamotrigine.

The new antiepileptic drug lamotrigine (LTG; 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) has been shown to be effective in the treatment of focal epilepsies with or without secondary generalization. Furthermore, some case reports indicate an efficacy in the treatment of bipolar affective disorders. It has been suggested that the main mechanism of action of LTG is the inhibition of glutamate release through blockade of voltage sensitive sodium channels and stabilisation of the neuronal membrane. Since some antidepressant drugs and the antiepileptic substance carbamazepine have calcium antagonistic properties, which may be of significance in the pathophysiology of epilepsies and affective disorders, the interaction of lamotrigine with carbamazepine and the organic calcium channel blocker verapamil was analyzed in the low Mg(2+)-induced model epilepsy which has been shown to be suppressed specifically by organic calcium antagonists. Lamotrigine reduced the frequency of occurrence of low-magnesium induced field potentials in CA1 and CA3 areas of the hippocampus slice preparation (guinea pigs) in a dose-dependent manner. The subthreshold concentrations which yielded no effect were 1 mumol/l for lamotrigine, 10 mumol/l for carbamazepine and 2 mumol/l for verapamil. Combinations of these subthreshold concentrations elicited a reduction in the repetition rate of field potentials. The results indicate that lamotrigine behaves additive with verapamil and carbamazepine what can be due to a common action on the same subtype of calcium channels. It can be assumed that lamotrigine may have besides its action on high-frequency sodium dependent action potentials also effects on calcium channels.