Silexan does not cause withdrawal symptoms even when abruptly discontinued.

OBJECTIVE: Subsequent to a randomised, double-blind, double dummy clinical trial assessing the efficacy of silexan compared to placebo and paroxetine in patients suffering from generalised anxiety disorder (GAD), a 1week follow-up phase was added in order to assess possible withdrawal symptoms of silexan after abrupt discontinuation. METHODS: Participants received silexan 80 mg/d, silexan 160 mg/d, paroxetine 20 mg/d, or placebo at a ratio of 1:1:1:1. Study medication was discontinued after the 10 week active treatment phase of the original trial. Whereas paroxetine was tapered as indicated, silexan administration was discontinued abruptly. Assessment of possible withdrawal effects was done using the Physician Withdrawal Checklist questionnaire (PWC-20). RESULTS: During the 1 week down-titration phase, mean total PWC-20 scores had reduced by 0.19 in placebo, 0.23 in silexan 80, 0.65 in silexan 160, and 0.51 in paroxetine. The median change in all four groups was 0.00. In none of the treatment groups withdrawal effects occurred after discontinuation. CONCLUSIONS: Values assessed for the silexan groups indicate the absence of a dependency potential of this preparation.

[Cognitive disorders in schizophrenic patients]. / Kognitive Störungen bei schizophrenen Patienten.

Cognitive disorders have become a major topic not only in the scientific community but also among clinicians. Cognitive disorders are of special importance in schizophrenic patients. The present paper gives a survey over the basic definitions and the extent of these disturbances in schizophrenic patients, the main etiopathogenetic hypotheses and the development over time as well as treatment options with special regard to psychopharmacological treatment options.

[Therapeutic effects of venlafaxine extended release for patients with depressive and anxiety disorders in the German outpatient setting - results of 2 observational studies including 8500 patients]. / Klinische Effekte von retardiertem Venlafaxin (Trevilor retard) bei Patienten mit Depression und Angsterkrankungen in der ambulanten Behandlungspraxis in Deutschland - Ergebnisse von zwei Anwendungsbeobachtungen mit 8500 Patienten.

The therapeutic effects of venlafaxine extended release have been investigated by two prospective observational studies including 8506 patients in the outpatient setting of office based general practitioners and specialists. The efficacy has been documented by the Clinical Global Impression (CGI) scale and by the Hamilton depression (HAMD-21) scale. The tolerability has been assessed by the documentation of adverse events. About (2/3) of the patients were treated because of depression and about (1/3) mainly because of anxiety disorder. The patients of specialists did receive higher dosages and were more severely affected. The response rate on the CGI scale was 87.4 for the patients of general practitioners and 74.2 % for the patients of specialists. The results of the HAMD-21 scale, which has been used by specialists, showed a response rate of 71.8 and a remission rate of 56.3 %. These positive effects could be demonstrated even for the more severely and chronically affected patients. The incidence of adverse events was low in both studies and comparable to the tolerability profile of randomized studies. Importantly, the good tolerability profile was similar even for patients with concomitant cardiovascular disease. In conclusion, these results confirm the efficacy and good tolerability of venlafaxine extended release in the outpatient setting in Germany.

[Antidepressive pharmacotherapy. In slight and severe disease, young and old]. / Antidepressive Pharmakotherapie. Bei leichter und schwerer Erkrankung, bei jung und alt.

During the past decade a variety of promising new compounds launched onto the market not only enhancing serotonergic and noradrenergic neurotransmission, but also influencing the dopamine and the melatonergic receptor system. In spite of misleading discussions both in the specialized and in the lay press the clinical effectiveness of antidepressants still is indisputable. The main advantages of the newer drugs are the broadening of the spectrum treatments and a far better tolerability profile in comparison to older compounds. Predominantly depression of medium to high severity should be treated pharmacologically. Especially severe depression seems to respond better to dually acting antidepressants. In children effectiveness of Omega3-fatty acids has been shown, in adolescents SSRI treatment was efficacious. Older patients respond to all antidepressant mechanisms, but more selective substances should be preferred due to a better tolerability. The study of new treatment options is of major importance to provide better strategies for the clinical management of depression in the future, and is thus also of great socio-economic importance.

Continuation and long-term maintenance treatment with Hypericum extract WS 5570 after recovery from an acute episode of moderate depression--a double-blind, randomized, placebo controlled long-term trial.

The efficacy and safety of Hypericum extract WS 5570 in preventing relapse during 6 months' continuation treatment and 12 months' long-term maintenance treatment after recovery from an episode of recurrent depression were investigated in a double-blind, placebo controlled multicenter trial. Adult out-patients with a recurrent episode of moderate major depression, a 17-item Hamilton Depression Rating Scale (HAMD) total score > or =20 and > or =3 previous episodes in 5 years participated. After 6 weeks of single-blind treatment with 3 x 300 mg/day WS 5570 patients with score < or =2 on item 'Improvement' of the Clinical Global Impressions (CGI) scale and a HAMD total score decrease > or =50% versus baseline were randomized to 3 x 300 mg/day WS 5570 or placebo for 26 weeks. 426 patients were evaluated for efficacy. Relapse rates during continuation treatment were 51/282 (18.1%) for WS 5570 and 37/144 (25.7%) for placebo. Average time to relapse was 177+/-2.8 and 163+/-4.4 days for WS 5570 and placebo, respectively (time-to-event analysis; p=0.034; alpha=0.025 one-sided). Patients treated with WS 5570 showed more favorable HAMD and Beck Depression Inventory time courses and greater over-all improvement (CGI) than those randomized to placebo. In long-term maintenance treatment a pronounced prophylactic effect of WS 5570 was observed in patients with an early onset of depression as well as in those with a high degree of chronicity. Adverse event rates under WS 5570 were comparable to placebo. WS 5570 showed a beneficial effect in preventing relapse after recovery from acute depression. Tolerability in continuation and long-term maintenance treatment was on the placebo level.

Reboxetine and cytochrome P450--comparison with paroxetine treatment in humans.

OBJECTIVES: The noradrenaline-selective antidepressant reboxetine in vitro is a weak inhibitor of both cytochrome P450 (CYP) 2D6 and CYP3A4. Thus, in this study the pharmacokinetics of reboxetine in relation to pharmacogenetics and the effects of reboxetine compared to paroxetine treatment on the CYP2D6 and CYP3A4 phenotype were analyzed in healthy control subjects. METHODS: Healthy male volunteers were treated with either 6 mg reboxetine (n = 26) or 30 mg paroxetine (n = 25). On Days 10/11 of treatment, serum concentrations of the antidepressants were measured and pharmacokinetic parameters calculated. Volunteers were phenotyped at the end of treatment and after at least 3 weeks washout (true phenotype) using 30 mg dextromethorphan (DM) hydrobromide given orally and measuring DM and metabolites in serum 2 h after intake. CYP2D6 and CYP2C19 genotypes were determined in parallel. RESULTS AND CONCLUSION: Reboxetine serum concentrations showed no correlation with the CYP2D6 genotype and the CYP2D6 phenotype, whereas paroxetine concentrations showed some dependence on CYP2D6. In contrast to in vitro investigations, indicating a major role of CYP3A4 in reboxetine metabolism, reboxetine concentrations in serum showed no correlation with the respective DM metabolic ratios. There was also no correlation between paroxetine concentrations and the CYP3A4 phenotype data. The CYP2C19 genotype (only heterozygosity) had no influence on reboxetine and paroxetine pharmacokinetics. There were only minor changes in the DM metabolite pattern on treatment with reboxetine and no evidence of enzyme inhibition was obtained. In contrast and as expected, paroxetine strongly inhibited CYP2D6. Thus, reboxetine treatment has no effect on the CYP2D6 genotype and no clinically relevant drug interactions involving CYP2D6 are anticipated.

Increased blink rate in drug-naive acute schizophrenic patients.

Eye blinks were investigated during a standardized visuomotor task in 15 drug-naive schizophrenic inpatients (8 men and 7 women) and 15 age- and gender-matched healthy volunteers. Whereas the schizophrenics demonstrated the same precision as normal controls in executing the visuomotor task, their mean blink rate was markedly increased (16.2 +/- 10.8 versus 9.3 +/- 6.4, p less than 0.05). Following neuroleptic treatment, the blink rate decreased, and was no longer statistically distinct from controls. The changes in blink rate correlated significantly with changes in several Brief Psychiatric Rating Scale (BPRS) items: "anxiety" (tau = 0.75; p less than 0.02), "hostility" (tau = 0.78; p less than 0.02), and "unusual thought content" (tau = 0.59, p less than or equal to 0.05), but not with the neuroleptic dose given between the first and second testing. These results underscore the influence of psychopathology on blink rates in schizophrenics.

Phototherapy in nonseasonal depression.

Previous reports have shown that bright light exposure may benefit patients with seasonal depression. In the present study, the possible therapeutic effect of bright light in nonseasonal major depressive disorder was examined. Forty-two depressed patients not receiving additional antidepressant medication were exposed to bright white light of 2500 lux or dim red light of 50 lux over one week for two hr daily in the morning. The change in depressive symptoms was assessed by rating scales (Hamilton Depression Rating Scale, CGI) and by self-rating scales (Depression Scale, Complaint List, Visual Analogue Scale). Consistent for all ratings, the decrease in depressive symptoms after bright white light was only slight and not different from dim red-light exposure. Contrary to the findings in seasonal affective disorder, phototherapy administered over one week for two hr daily is not effective in nonseasonal major depressive disorder.

Serum concentrations of thyroid hormones in patients with nonseasonal affective disorders during treatment with bright and dim light.

Serum concentrations of thyroxine (T4), triiodothyronine (T3), and thyrotropine were measured in 34 patients with nonseasonal affective disorders before and after 1 week of light treatment. Nineteen of these patients received bright white light (2500 lx) and 15 dim red light (50 lx) for 2 hours daily in the mornings over a 1-week period. Slight but significant reductions in the rating scores for the depressive symptomatology were found for both the bright-and dim-light groups, but there were no significant differences between the two groups. The improvement is thus most likely a placebo effect. Surprisingly, the small changes in the severity of the depressive symptoms in the group as a whole were significantly correlated to the changes in the serum levels of T4 during the weeks of bright- and dim-light treatment, respectively. The more a patient improved, the further his or her T4 level fell and vice versa. The fluctuations in the concentrations of T4 during light treatment were significantly greater in the depressed patients than in a group of 12 healthy controls who also received bright or dim light, whereas the changes in T3 were significantly smaller than those of the healthy controls. The pronounced fluctuations in T4 levels were probably not secondary to changes in mood. Rather, they are likely to reflect changes in tissue (intracellular) metabolism of T4, which may be involved in the mechanisms underlying the fluctuations in mood in these patients.

Abnormalities of auditory evoked magnetic fields and structural changes in the left hemisphere of male schizophrenics--a magnetoencephalographic-magnetic resonance imaging study.

Functional and structural changes in 10 DSM-III-R male schizophrenics and 10 healthy volunteers were investigated using magnetoencephalographically (MEG) detected long-latency (N100 m) auditory evoked fields (AEFs) and magnetic resonance imaging (MRI). The AEFs were characterized by single moving equivalent dipoles, which were superimposed on MRIs. There were significant differences in dipole orientations and in AEF latencies in the left hemisphere of schizophrenics, when compared to the controls. The MEG-detected alterations were found to be associated with a bilateral volume reduction of the posterior superior temporal gyrus (pSTG), which was more pronounced in the left hemisphere. Separate analysis of white and gray matter has shown that the pSTG volume reduction resulted from decreased gray matter volumes without white matter changes. Both the functional and the morphological data indicate a left-hemispheric disturbance in our patients.

31P magnetic resonance spectroscopy in the dorsolateral prefrontal cortex of schizophrenics with a volume selective technique--preliminary findings.

Pettegrew et al (Arch Gen Psychiatry 48:563-568, 1991) were the first to determine abnormalities concerning phospholipids and high energy metabolites in the dorsolateral prefrontal cortex of drug-naive schizophrenics with 31P magnetic resonance spectroscopy (MRS). Other investigations could not replicate these findings. We included in our study 13 schizophrenic inpatients and 14 age-matched controls. Whereas Pettegrew et al found increased levels of phosphodiesters and decreased levels of phosphomonoesters we measured decreased levels of phosphodiesters in the schizophrenics as compared to controls. One possible explanation for the contradictory findings of the both trials might be the different localization techniques used.

31Phosphorus magnetic resonance spectroscopy of the dorsolateral prefrontal region in schizophrenics--a study including 50 patients and 36 controls.

BACKGROUND: In a preliminary study we found decreased phosphodiester (PDE)% values and an increased phosphomonoester (PME)/phosphodiester ratio in the dorsolateral prefrontal region (DLPFR) of 13 chronic schizophrenics vs. 14 controls using 31phosphorus magnetic resonance spectroscopy (31P-MRS). Since these results are in contrast to the findings of other groups, we increased our study group to a total of 50 chronic schizophrenics on stable neuroleptic medication and 36 controls to minimize the possibility of a chance result due to small sample size. METHODS: An image-selected in vivo 31P-MRS method on a Philips Gyroscan ACS II scanner working at 1.5 T was used. RESULTS: We could confirm our earlier findings of decreased PDE% levels in schizophrenics. Additionally, we found phosphocreatine (PCr)% and PCr/adenosine triphosphate (ATP) to be increased in the schizophrenics. While no association between PME% and PDE% with neuroleptic medication was found, ATP% correlated positively and PCr/ATP negatively with the chlorpromazine equivalent dose. CONCLUSIONS: The decreased PDE% levels might be characteristic only for chronic, neuroleptic-treated patients. The finding of altered high-energy phosphate levels can be interpreted as an indication of decreased energy-demanding processes in the DLPFR of the investigated patients compared to controls.

Increase of phosphodiesters during neuroleptic treatment of schizophrenics: a longitudinal 31P-magnetic resonance spectroscopic study.

BACKGROUND: Increased levels of phosphodiesters (PDE%) and reduced relative concentrations of phosphomonoesters (PME%) have been reported in unmedicated schizophrenics, whereas findings in brain of medicated patients were not consistent. METHODS: We determined in vivo the metabolism of phospholipids and high-energy phosphates in the left and right frontal lobes of 8 patients with schizophrenia using 31P-magnetic resonance spectroscopy (31P-MRS). Serial investigations were performed first after a neuroleptic-free period (mean 7.5 +/- 1.9 days) and second, after neuroleptic treatment (mean 20.6 +/- 11.1 days). RESULTS: PDE% increased significantly in the left frontal lobe (32.0 +/- 5.9% versus 36.9 +/- 5.6%, p = .009) after medication. All other parameters showed no significant differences. CONCLUSIONS: Our study suggests that neuroleptics do not decrease phospholipase A2 activity in schizophrenia. Individual neuroleptics may have different effects on phospholipase A2 activity as indicated by animal studies. An influence of neuroleptics on high-energy phosphates cannot be confirmed by our data.

Cerebral phosphate metabolism in first-degree relatives of patients with schizophrenia.

OBJECTIVE: Most phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) studies have described measures of lower membrane anabolism or greater catabolism in the frontal lobes of patients with schizophrenia. The purpose of the present study was to evaluate whether these findings can also be detected in young subjects at genetic risk for schizophrenia. METHOD: Fourteen children and siblings of patients with schizophrenia (mean age=16.7 years) and 14 comparison subjects (mean age=16.9 years) were included in a (31)P-MRS study of the frontal lobe. RESULTS: The high-risk subjects had significantly lower mean ratios of phosphomonoesters to phosphodiesters (0.25 versus 0.31) and higher mean phosphodiester values (37.59% versus 34.87%) than comparison subjects. CONCLUSIONS: These findings suggest greater phospholipid breakdown even in young first-degree relatives of patients with schizophrenia. This suggestion is discussed with respect to the membrane phospholipid hypothesis of schizophrenia.

Drug treatment of depression in the 1990s. An overview of achievements and future possibilities.

This article looks at the most important developments of antidepressants in the 1990s. The major properties of selective serotonin reuptake inhibitors, reversible and selective inhibitors of monoamine oxidase type A, selective serotonin and noradrenaline reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants are discussed. On the basis of the specific advantages and disadvantages of these compounds, unmet medical needs in the psychopharmacological treatment of depression are considered and the profile of an ideal antidepressant is outlined, followed by some closing remarks on potential new mechanisms of action. The most important progress in the past 10 years has been the development of compounds which possess markedly reduced binding capacities at receptor sites not linked to their antidepressive actions. This development has improved tolerability, both in therapeutic use and in overdose. Three main therapeutic needs have still to be met: (i) superior efficacy to tricyclic antidepressants; (ii) a faster onset of action; and (iii) reliable effectiveness in the treatment of therapy-resistant depression.

Abnormalities of auditory evoked magnetic fields in the right hemisphere of schizophrenic females.

Eight DSM-III-R female schizophrenics were investigated by magneto-encephalographically (MEG) detected long latency (N100m) auditory evoked fields (AEFs). In contrast to controls, in schizophrenics a lack of interhemispheric asymmetry was present, which was found to be due to alterations of the right hemisphere.

Impaired sensory processing in male patients with schizophrenia: a magnetoencephalographic study of auditory mismatch detection.

The generation of mismatch negativity (MMN) as a component of auditory evoked event-related brain potentials has been reported previously to be severely disturbed in patients with schizophrenia. In the present study, we extended these findings to magnetoencephalography and investigated the neuromagnetic mismatch field (MMNm) in 15 male schizophrenic inpatients as compared to 16 healthy male volunteers. A standard tone of 1000 Hz and three different types of mismatch (1050-Hz tone, 5000-Hz tone, tone omission) were employed within the same paradigm, each mismatch occurring with a 10% pseudorandom probability. After correction for eye artifacts, the mean global field power of the mismatch reaction was calculated. Mismatch generation in patients with schizophrenia proved to be significantly impaired for all three conditions. This result confirms the theory of impaired auditory information processing in patients with schizophrenia at the level of the primary auditory cortex. Deficient generation of MMNm probably represents an impaired generation and/or faster decay of the sensory memory trace on the basis of disturbed sensory processing in male patients with schizophrenia.

High-energy phosphates in the frontal lobe correlate with Wisconsin Card Sort Test performance in controls, not in schizophrenics: a 31phosphorus magnetic resonance spectroscopic and neuropsychological investigation.

In recent years, a number of 31phosphorus magnetic resonance spectroscopy (P-MRS) studies on the frontal lobe of schizophrenics have been performed, reporting alterations of phospholipids and high-energy phosphates. Deicken et al. (1994b) recently found positive correlations between left frontal phosphomonoester% (PME%) levels and the performance of a specific frontal lobe task, the Wisconsin Card Sorting Test (WCST), in schizophrenics. In the present paper, the correlations between phospholipids and high-energy phosphates in the frontal lobe of 26 schizophrenics and 23 controls measured with a volume-selective P-MRS method were investigated. Overall, we could not find any correlations between WCST results and phospholipid levels, but in controls phosphocreatine% (PCr%) and PCr/adenenosine triphosphate (ATP) ratios were negatively correlated with test performance. Since PCr behaves as a buffer of ATP, in the sense that when ATP is consumed by neuronal activity PCr is catalysed rapidly to ATP, increased PCr% values and, moreover, increased PCr/ATP ratios point to a decreased ATP consumption. Thus, the correlations found between PCr% and PCr/ATP and test performance in controls point to an association between reduced performance in a specific frontal lobe task and decreased energy demanding processes at rest. This association was not found in schizophrenics, possibly due to the influence of neuroleptic medication or the disease process per se.

Time estimation in schizophrenia: an fMRI study at adjusted levels of difficulty.

fMRI was performed in nine male schizophrenia patients and 15 healthy male controls during an auditory time estimation (timing), a frequency (i.e. pitch) discrimination task, and rest. An adaptive psychophysical approach, the weighted up-down method, was used to adjust individual performance to a level of 75% probability for correct answers. Although performing on the same level of individual difficulty, schizophrenia patients revealed less activations in prefrontal cortex and caudate nucleus, comparing time vs rest. Timing specific differences (i.e. timing vs pitch) between patients and controls were found in the posterior putamen, anterior thalamus, and right medial prefrontal cortex, with patients showing relative hypoactivity. Impairment in time estimation in schizophrenia might be mediated by specific fronto-thalamo-striatal dysfunction.