[Adverse effects of treatment with psychotropic drugs in the elderly - special risks, protective mechanisms, prognosis]. / Unerwünschte Wirkungen unter Therapie mit Psychopharmaka im Alter - Spezielle Risiken, Schutzmechanismen, Prognosen.

Due to their multimorbidity elderly patients take multiple medications, which increase the risks of adverse side effects. In this patient group, main aim of treatment is to achieve an optimal quality of live. Unwanted effects of drugs and of drug combinations (polypharmacy) have carefully to be checked.

Evaluation of drug interactions in a large sample of psychiatric inpatients: a data interface for mass analysis with clinical decision support software.

In order to improve medication safety, more epidemiological data on the prevalence and clinical relevance of drug interactions are required. We developed an interface for mass analysis using the Clinical Decision Support Software (CDSS) MediQ and a multidimensional classification (Zurich Interaction System (ZHIAS)) incorporating the Operational Classification of Drug Interactions (ORCA). These were applied to 359,207 cross-sectional prescriptions from 84,607 psychiatric inpatients collected through the international AMSP program. MediQ issued 2,308 "high" and 71,112 "average" danger interaction alerts. Among these, after ORCA reclassification, there were 151 contraindicated and 4,099 provisionally contraindicated prescriptions. The ZHIAS provided further detailed categorical information on recommended management and specific increased risks (QTc prolongation being the most frequent one) associated with interactions. We developed a highly efficient solution for the identification and classification of drug interactions in large prescription data sets; this solution may help to reduce the frequency of overalerting and improve acceptance of the efficacy of CDSS in reducing the occurrence of potentially harmful drug interactions.

[Blended learning in continuing medical education. Evaluation of an innovative curriculum "bipolar and bipolar spectrum disorders"]. / "Blended learning" in der ärztlichen Fortbildung. Evaluation eines innovativen Fortbildungszyklus "Bipolare Störungen und verwandte Erkrankungen".

BACKGROUND: In this article a blended learning concept in continuing medical education is evaluated over a broad range of ages, as there is little data on this topic so far. The aims of this study were to document the blended learning concept, to evaluate the subjective gain of knowledge, as well as didactic and virtual means. Finally the actual usage and accreditation are reported. MATERIAL AND METHODS: The curriculum referred to the topic of bipolar disorder, combined episodes of face-to-face instruction and individual web-based learning over a period of 3 months. RESULTS: The didactic concept was very well accepted by the participants (N=346) and was evaluated as very user-friendly. The most appreciated dimensions were "subjective gain of knowledge" and "support by media tutor". Nearly 80% participated in both face-to-face as well in both web-based episodes. The component of web-based learning was accredited by the responsible institution (State Medical Association) with increasing number of credits over a period of 3 years. CONCLUSION: Blended learning is a useful didactic concept in continuing medical education of psychiatrists independent of the age of the participants.

In search of optimal lithium levels and olanzapine doses in the long-term treatment of bipolar I disorder. A post-hoc analysis of the maintenance study by Tohen et al. 2005.

PURPOSE: The aim of this study was to investigate whether lower lithium levels (LoLi) or olanzapine doses (LoOL) are risk factors for future mood episodes in patients with bipolar I disorder. METHODS: A post-hoc analysis of the olanzapine-lithium-maintenance study [31] was performed using proportional hazards Cox regression models and marginal structural models (MSMs), adjusting for non-random assignments of dose during treatment. RESULTS: The LoLi group (<0.6 mmol/L) had a significantly increased risk of manic/mixed (hazard ratio [HR]=1.96, p=0.042), but not depressive (HR=2.11, p=0.272) episodes, compared to the combined medium (0.6-0.79 mmol/L) and high lithium level (≥0.8 mmol/L) groups. There was no significant difference in risk between the two higher lithium level groups (0.6-0.79 mmol/L; ≥0.8 mmol/L) for new manic/mixed (HR=0.96, p=0.893) or depressive (HR=0.95, p=0.922) episodes. The LoOL group (<10mg/day) showed a significantly increased risk of depressive (HR=2.24, p=0.025) episodes compared to the higher olanzapine (HiOL) dose group (HiOL: 10-20 mg/day), while there was no statistically significant difference in risk for manic/mixed episodes between the two groups (HR=0.94, p=0.895). CONCLUSION: Lithium levels≥0.6 mmol/L and olanzapine doses≥10mg/day may be necessary for optimal protection against manic/mixed or depressive episodes, respectively in patients with bipolar I disorder.

Is the polarity of relapse/recurrence in bipolar-I disorder patients related to serum lithium levels? Results from an empirical study.

BACKGROUND: Preliminary evidence suggests that the polarity of relapse/recurrence (depressive vs. hypomanic/manic/mixed) in bipolar patients on lithium might be related to serum lithium levels. METHODS: Polarity of episodes in 64 bipolar-I patients on lithium monotherapy during a prospective 18-month maintenance trial was predicted from (a) intra-individual oscillations of lithium levels over time and from (b) absolute lithium levels preceding relapse/recurrence. RESULTS: On an individual basis, depressive (vs. hypomanic/manic/mixed) episodes were mostly preceded by lithium levels above the individual means (p<0.001). Relapse/recurrence occurring at lithium levels above the overall mean serum level of 0.66 mmol/l was depressive (not hypomanic/manic/mixed) in most cases (odds-ratio=3.86, p=0.032). Lithium levels before depressive episodes were numerically higher than before hypomanic/manic/mixed episodes (0.769+/-0.242 vs. 0.675+/-0.262 mmol/l, p=0.13). Cox-regression including current lithium levels as time-dependent predictor essentially confirmed these results. LIMITATIONS: As patients were not randomized to specific lithium levels, potential confounders could not be completely ruled out. Furthermore, a closer than monthly assessment of both lithium levels and psychopathology would have been desirable to better understand the interplay between lithium levels and new mood episodes. CONCLUSIONS: The results indicate that within the currently accepted therapeutic range (0.4-1.1 mmol/l), the relative risk for depressive vs. hypomanic/manic/mixed relapses/recurrences may be associated with higher lithium levels. Therefore, lithium levels at the lower range of the therapeutic spectrum may be sufficient for the optimal prevention of depressive episodes whereas higher lithium levels within this range may be needed for optimal protection against manic/mixed episodes.

What is the optimal serum lithium level in the long-term treatment of bipolar disorder--a review?

OBJECTIVES: There is substantial uncertainty about the most efficacious serum lithium level for the long-term treatment of bipolar disorder (BD). This review focuses on the available evidence taking into consideration the effects of previous lithium history, changes in lithium level and polarity of relapse or recurrence. METHODS: We conducted a MEDLINE search, using the MeSH Terms 'bipolar disorder' and 'lithium' together with 'randomized controlled trial' or 'controlled clinical trial' covering the time span from 1966 to March 2006. We only included studies reporting on the long-term treatment of mood disorders where patients with BD were examined as a separate group and were assigned to precisely specified target ranges of lithium level. RESULTS: The minimum efficacious serum lithium level in the long-term treatment of bipolar disorder was 0.4 mmol/L with optimal response achieved at serum levels between 0.6-0.75 mmol/L. Lithium levels >0.75 mmol/L may not confer additional protection against overall morbidity but may further improve control of inter-episode manic symptoms. Abrupt reduction of serum levels of more than 0.2 mmol/L was associated with increased risk of relapse. CONCLUSIONS: In the long-term treatment of bipolar disorder clinicians should initially aim for serum lithium levels of 0.6-0.75 mmol/L, while higher levels may benefit patients with predominantly manic symptoms.

[Clinical standing of valproate treatment of bipolar disorders]. / Klinischer Stellenwert der Valproat-Therapie bei bipolaren Störungen.

During recent years valproate has been established as a cornerstone for the drug-treatment of bipolar disorder. In Germany, valproate was licensed both for the treatment of acute mania and for maintenance treatment in summer 2005. At this occasion, this review summarises the scientific evidence and clinical experience of well-known experts with valproate-treatment. It was concluded that valproate will continue to be of high clinical significance despite the recent increase of treatment alternatives, both in monotherapy and combination treatment of acute mania, mixed states and maintenance treatment.

Galactorrhea during treatment with trimipramine. A case report.

Trimipramine, a tricyclic antidepressant, faced renewed attention in the last decade for its well-established antidepressant as well as its sleep-promoting properties. While the antidepressant mode of action of trimipramine is still unclear, its antihistaminic and anticholinergic potency is far better known, leading to side effects such as somnolence or dry mouth. Elevated prolactin serum levels, caused by antidopaminergic action, have been repeatedly observed. However, to our knowledge no case of galactorrhea while under treatment with trimipramine had been previously reported. A 31-year-old female inpatient, admitted to our hospital after an attempted suicide, was treated initially with paroxetine 20 mg/d. Because of persisting insomnia, after 5 weeks we gave a supplementary medication, trimipramine, with a successive increase in dose up to 150 mg/d. After another 9 weeks the patient reported a strong tension in both breasts together with galactorrhea. The prolactin serum level was 21.8 ng/ml. After reduction of the trimipramine dose to 50 mg/d, the symptoms disappeared within a few days. We discuss our case with special regard to the combination of trimipramine with a selective serotonin reuptake inhibitor (SSRI). This commonly used comedication could have led to an aggravation of the problem because (1) most SSRIs stimulate prolactin secretion and (2) trimipramine is metabolized by the cytochrome P450 2D6, which in turn is inhibited by all SSRIs, thus potentially leading to elevated trimipramine plasma levels. The problem can probably be kept to a minimum by giving lower doses of trimipramine (up to 50 mg/d) if co-administered with an SSRI.

Psychosocial and demographic factors associated with response to prophylactic lithium: a systematic review for bipolar disorders.

BACKGROUND: The aim was to systematically integrate the available evidence on psychosocial and demographic factors associated with response prediction to prophylactic lithium. METHOD: Each psychosocial or demographic variable that was related to lithium response in at least one study was examined with respect to response prediction. If several studies were located for the same variable results were integrated using a meta-analytical approach. To account for heterogeneity of primary studies aggregation of results was based on a random-effects model. RESULTS: Out of 27 psychosocial and demographic variables investigated in this review, nine variables were identified as significantly related to outcome under to prophylactic lithium: (1) high social status, (2) social support, (3) good compliance, and (4) dominance may be protective against a recurrence under lithium. In contrast, (5) stress, (6) high expressed emotions, (7) neurotic personality traits, (8) unemployment, and (9) a high number of life events were identified as possible risk factors for poor response. CONCLUSIONS: This systematic review shows a surprisingly high number of psychosocial variables to be related to lithium response. Effect sizes were, however, small to moderate. Many variables should, therefore, be considered simultaneously to predict response.

Which clinical factors predict response to prophylactic lithium? A systematic review for bipolar disorders.

OBJECTIVES: The aim of this study was to systematically integrate the available evidence on response prediction to prophylactic lithium based on clinical factors. METHODS: Each clinical variable that was related to lithium response in at least one prior study was examined with respect to response prediction. If several studies were located for the same variable, results were integrated using the meta-analytic approach as suggested by DerSimonian and Laird which was developed for substantial heterogeneity in primary studies. RESULTS: Of 42 potential clinical predictors investigated, five variables were identified as possible response predictors of prophylactic lithium: [1] An episodic pattern of mania-depression-interval, and [2] a high age of illness onset were identified as potentially protective against a recurrence under lithium. [3] A high number of previous hospitalizations, [4] an episodic pattern of depression-mania-interval, and [5] continuous cycling were identified as potential risk factors. Six further variables were found to be significantly related to lithium response, though calculation of fail-safe numbers indicates that current evidence is not sufficient to hold these variables as reliable predictors of lithium response. All effect-sizes relating clinical predictors to response were small to moderate. CONCLUSIONS: Although a few variables are quite robustly supported as response-predictors in this review, a more in-depth analysis of each potential predictor is needed. As none of the potential predictors had a very strong impact on response, prediction of lithium response should be based on a multitude of variables.

Prescribing practices in German and Swiss psychiatric university and in non-university hospitals: national differences.

OBJECTIVE: There are great variations between hospitals in the way drugs are prescribed, and these variations may be due to multiple factors such as local prescribing traditions, pharmacoeconomic considerations, drug availability, regional differences of population, disease prevalence etc. Available studies on prescribing habits, apart from studies performed in a unique center, have until now been mainly restricted to single countries or regions and the comparisons across countries or regions have often been limited by the use of diverse methodologies and definitions. The aim of the present study was to compare drug prescriptions between German and Swiss psychiatric services with regard to their preference of newer psychotropics. MATERIAL AND METHODS: Five psychiatric hospitals, associated to the AMSP project, were chosen to represent Swiss and German clinics, university and non-university settings. Data were available from one index day on 572 patients and 1,745 prescriptions. The comparisons were adjusted for age and gender. RESULTS: There was a significant difference (p < 0.001) with regard to the prescription of newer antidepressants (NAD), Swiss clinicians giving proportionally more (65.2%) than the German psychiatrists (48.3%). No significant difference was, on the other hand, found as to the proportion of atypical antipsychotics, the lack of difference being due to the higher proportion of clozapine among the atypical antipsychotics in Germany. CONCLUSION: There seems, therefore, to be a higher propensity for Swiss hospital psychiatrists to prescribe newer antidepressants. This seems to be due to national or regional prescribing traditions. Further studies are needed to investigate the economical influences on antidepressant prescribing in Swiss and German clinics.

Is polarity of recurrence related to serum lithium level in patients with bipolar disorder?

BACKGROUND: Recently published data might indicate that the polarity of recurrence is related to lithium serum levels. To systematically test this hypothesis all published maintenance trials in bipolar disorders were examined with regard to this issue. METHOD: Maintenance studies were subdivided in trials with low (i. e. below 0.6 mEq/l),medium (i. e. 0.6 to 0.8 mEq/l) and high (i. e. above 0.8 mEq/l) lithium serum levels. Percentage of depressive vs. (hypo-)manic or mixed recurrences were compared for these three groups. RESULTS: The percentage of depressive recurrences in the groups with low, medium and high lithium levels differed in a clinically and statistically significant manner (12% vs. 38% vs. 64%, p < 0.0001). CONCLUSION: The results might indicate that low lithium levels are effective in preventing depression whereas higher blood levels are needed to prevent (hypo-)manic or mixed states.

Concepts in the treatment of bipolar disorder.

OBJECTIVE: Concepts in the treatment of bipolar disorder are discussed considering clinical practice. METHOD: Results of the Multicenter Study of Long-term Treatment of Affective and Schizoaffective Psychoses (MAP) study, a controlled maintenance trial, are interpreted with respect to treatment concepts. RESULTS: The spectrum of patients diagnosed as bipolar has become more heterogeneous. It now comprises subtypes requiring differentiated treatment. The MAP study confirms that prophylactic efficacy of lithium seems to be specific to classic manic-depressive illness, whereas carbamazepine might be more efficacious in non-classic bipolar patients. With respect to clinical practice, treatment evaluation should also consider anti suicidal effects, inter-episodic morbidity and compliance. In these respects, results are in favour of lithium. Furthermore, data indicate that adherence to lithium clearly depends on illness concepts. This encourages efforts to supplement pharmacotherapy by psychoeducation and psychotherapy. CONCLUSION: With the broadening of diagnostic criteria, the treatment of bipolar disorder has become more complex. Patients need an integrated approach, including differentiated mood-stabilizing pharmacotherapy and psychotherapeutic measures.

Lithium in the long-term treatment of bipolar disorders.

Usefulness of lithium in the prophylaxis of bipolar disorders has been challenged for five major reasons. The authors review the empirical basis of these criticisms and come to the following conclusions. 1. Lithium efficacy is high and beyond reasonable doubt in classic manic-depressive illness. Bipolar patients presenting atypical features show a much poorer response rate to lithium. 2. There is no empirical evidence for a loss of lithium efficacy over time. 3. There is little evidence for discontinuation-induced refractoriness to lithium. 4. Lithium withdrawal phenomena are well established but seem to be rather specific to certain subgroups. Withdrawal phenomena seem to be common in atypical bipolar disorder but rare in fully stabilized classic manic-depressive illness. 5. Other factors limiting lithium efficacy in clinical practice (e. g., non-compliance) are not specific to lithium. In conclusion, prophylactic lithium does have major drawbacks and there is a clear need for more efficacious alternatives in non-classic bipolars. Compared to existing alternatives, lithium currently is to be considered the golden standard. This status might, however, be challenged by major alternative mood-stabilizers that are presently under clinical investigation.

[Confrontation instead of avoidance. Why anxiety patients should face the causes]. / Konfrontieren statt vermeiden. Warum Angstpatienten sich ihren Auslösern stellen müssen.

Psychiatric management forms the basis of any integrated psychiatric treatment. It serves to maximize the patient's level of performance, safety and quality of life. It also involves the patient's family members--who are usually indirectly affected by the disorder and may provide support during the course of treatment--in the therapeutic strategy. The psychiatric management of anxiety disorders can be effectively carried out, also by the family doctor familiar with mental disorders, since the GP is usually the first primary care instance to be approached by the patient, who assumes an underlying organic cause rather than a mental problem. Within the framework of psychiatric management, the family doctor should be kept fully informed of the individual steps in the treatment strategy, and coordinate the necessary interventions by other care providers. By taking psychoeducative measures he can already initiate effective treatment, and may create a positive atmosphere in which treatment-requiring anxiety can be openly discussed and perhaps partly resolved. Talking to the patient about early symptoms may help to avoid severe relapses. Psychiatric management as part of the general practitioner's activities helps achieve the goal of integrating the treatment of patients with anxiety disorders in the doctor's office.

Inter-episodic morbidity and drop-out under carbamazepine and lithium in the maintenance treatment of bipolar disorder.

BACKGROUND: Evaluation of mood-stabilizing treatment strategies usually focuses on their efficacy in preventing recurrences. The aim of this study is to supplement evaluation by two important aspects: inter-episodic morbidity and drop-out. METHODS: Using a global outcome measure, response to prophylactic lithium and carbamazepine was evaluated in N = 171 bipolar patients (DSM-IV) participating in a randomized controlled trial with an observation period of 2 1/2 years (MAP study). RESULTS: The rates of re-hospitalization were similar for both treatments. However, the percentage of good clinical response (i.e. patients with a low score of inter-episodic morbidity and without both re-hospitalization and drop-out during the observation period) was significantly higher in patients randomized to lithium (40% v. 24%). This superiority of lithium resulted essentially from a lower drop-out rate in patients without re-hospitalization (17% v. 42%). Regarding severity of inter-episodic morbidity, no clear difference between the drugs was found. For both medications the predominant symptomatology was minor depressive (but not manic, mixed or schizoaffective) symptoms. In the lithium group, inter-episodic morbidity in patients without re-hospitalization significantly decreased during the first 10 months and remained on the lower level for the rest of the observation period. For carbamazepine, reduction of inter-episodic morbidity over time did not reach statistical significance. Inter-episodic morbidity was significantly related to drop-out and to re-hospitalization for both medications. CONCLUSION: Taking inter-episodic morbidity, drop-out and re-hospitalization into consideration, the response rate in bipolar patients (DSM-IV) was higher for prophylactic lithium than for carbamazepine. The global outcome parameter used appears to be a valuable measure of clinical response to mood stabilizing drugs.

[Psychopharmacotherapy of bipolar affective diseases]. / Psychopharmakotherapie bipolarer affektiver Erkrankungen.

The broadening of the classification systems for manic-depressive illness towards a spectrum of bipolar disorders implicates a more differentiated use of pharmacotherapies. However, many questions still remain open. This implies that all consensus guidelines and recommendations have to be considered as preliminary. On the other hand, research in the last decade has developed many new treatment alternatives, both for mood stabilizers and antidepressants as well as antipsychotics. These recommendations, which have been developed in the process of two consensus meetings, try to consider the broadening of the concept of bipolar disorder by differentiating between subgroups according to acute symptomatology and characteristics of the long-term course, e.g., rapid cycling. In particular, the emerging role and new indications of mood stabilizing antiepileptic drugs, atypical antipsychotics, and new antidepressants will be discussed.

Disinhibition of libido: an adverse effect of SSRI?

BACKGROUND: The article focuses on adverse drug reactions (ADR) to selective serotonin reuptake inhibitors (SSRI) concerning libido and sexual behaviour: cases of disinhibition of libido observed at the Psychiatric Hospital of Kilchberg near Zurich are described. METHOD: Within the scope of a drug safety program, the physicians of the hospital are regularly asked about severe and unexpected events under drug treatment. RESULTS: During remission of depression, five outpatients noticed an increase of libido experienced as strange to them, i.e. preoccupation with sexual thoughts, first appearance of promiscuity, of unsafe sexual intercourse, and of excessive pursuit of pornography, respectively, during administration, change in dose or discontinuation of SSRI. DISCUSSION: The case studies suggest that SSRI treatment might be associated with increase and disinhibition of libido. The phenomena are discussed as a "selective switch" into partly manic symptomatology or an induction of mixed states with prevailing sexual symptoms.

Maintenance therapies for classic and other forms of bipolar disorder.

The progressive, episodic and chronic nature of bipolar disorder dictates the need for lifelong pharmacological maintenance treatment in the majority of patients. Prophylaxis should be considered after a single episode of severe mania or after more than one episode of hypomania in bipolar II disorder, although some clinicians now consider an episode of either sufficient to warrant maintenance therapy. Lithium is efficacious as maintenance therapy, but is not as highly effective as early studies initially suggested (abrupt discontinuation of lithium probably increased placebo relapse figures). Rates of premature discontinuation of lithium are high. Divalproex sodium is used frequently in the USA and Canada for long-term treatment for bipolar disorder but an insufficient number of controlled trials have been published to assess adequately its role. Carbamazepine is also employed in maintenance treatment. Randomized studies indicate it is superior to placebo but somewhat less effective than lithium. Augmentation of any of these drugs with another mood stabilizer, an antipsychotic, or electroconvulsive therapy appears to be effective, although there are few controlled studies. Design issues that need consideration in order to achieve meaningful data are discussed. A severe manifestation of bipolar disorder is rapid cycling. It is often induced by antidepressants, although this association frequently goes unrecognized. Patients with a rapid cycling course of illness are difficult to treat effectively. Although rapid cycling is often associated with poor response to lithium, there have been no randomized, controlled treatment studies. Based on open studies and expert panel recommendations, the International Exchange on Bipolar Disorder (IEBD) recommended initial treatment with divalproex sodium, with subsequent addition of other mood stabilizers, antipsychotics or thyroid supplementation as necessary. Combination treatments are frequently required for optimal response in these patients.

Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study.

In a randomized clinical trial with an observation period of 2.5 years, the differential efficacy of lithium versus carbamazepine was compared in 171 bipolar patients (DSM-IV). In order to investigate the efficacy of the two drugs in clearly defined subsamples, a series of subgroup analyses was carried out. First, patients with a bipolar I disorder (n = 114) were analyzed separately. In these patients, lithium was superior to carbamazepine. In contrast, carbamazepine was at least equally as efficacious as lithium in the subsample of patients with bipolar II disorder or bipolar disorder not otherwise specified (n = 57). In a second analysis on differential efficacy, the whole sample was subdivided into a classical subgroup (bipolar I patients without mood-incongruent delusions and without comorbidity; n = 67) and a nonclassical subgroup including all other patients (n = 104). Classical bipolar patients had a significantly lower hospitalization rate under lithium than under carbamazepine prophylaxis (26 vs. 62%, p = 0.012). For the nonclassical group, a tendency in favor of carbamazepine was found. In a third step, we analyzed the impact of episode sequence on differential efficacy. In a global view, the episode sequence prior to the index episode was not correlated to differential efficacy. Our results might, however, indicate that patients with an episode sequence of mania-depression-free interval responded better to lithium. Besides differential efficacy, suicidal behavior and patients' satisfaction with treatment were investigated. Regarding suicidal behavior, a trend in favor of lithium was found. The data on patients' satisfaction were significantly in favor of carbamazepine. In conclusion, lithium appears to be superior to carbamazepine in classical bipolar cases and might have additional impact on proneness to suicide. The distinctly larger group of patients with nonclassical features might profit more from carbamazepine which seems to be well accepted by the patients. Hence, treatment alternatives to lithium are desirable for the majority of bipolar patients.