Clinical research centers in Aarhus, Berlin, Hamilton and Vienna collected mortality data for 827 manic-depressive and schizoaffective patients given lithium treatment for more than 6 months. The ...average duration of the treatment was 81 months and the total time on lithium 5600 patient-years. For each patient, the mortality risk was calculated by entering the appropriate national life tables for the general population. The number of observed deaths was 44; the number of expected deaths was 49.7. The standardized mortality ratio, 0.89, did not differ significantly from 1.0. The mortality of manic-depressive patients is 2-3 times that of the general population. Our data show that the mortality of manic-depressive and schizoaffective patients given long-term lithium treatment does not differ significantly from that of the general population.
Antidepressants and suicidal risk Müller-Oerlinghausen, B; Berghöfer, A
The journal of clinical psychiatry,
1999, Letnik:
60 Suppl 2
Journal Article
Recenzirano
Only 5% of suicidal patients on the average use their prescribed antidepressant to commit suicide. Underprescription of antidepressants and failure of antidepressant therapy appear to be of greater ...practical importance than the toxicity of individual compounds. Prescribing less toxic agents, therefore, will not be of great advantage, especially if they are less efficacious. Several antidepressants including the selective serotonin reuptake inhibitors (SSRIs) may increase suicidal behavior by energizing depressed patients to act along preexisting suicidal thoughts or by inducing akathisia with associated self-destructive impulses. For acutely suicidal patients, the use of more sedating antidepressants is recommended. Clinical trials could not confirm a superiority of SSRIs over tricyclics in reducing the number of suicide attempts. There is evidence from large international data sources and a large multicenter controlled trial that lithium prophylaxis decreases the suicide risk and overall mortality in affective disorders. A suicide-preventing effect has not been demonstrated conclusively for antidepressants or non-lithium mood stabilizers.
Antipsychotics, when used to treat neuropsychological symptoms associated with dementia, are associated with low effectiveness but a high risk of side effects. Some of these unwanted effects are ...severe and include an increased rate of cerebrovascular events and increased mortality. Although neuropsychiatric symptoms are frequently associated with dementia, it appears that antipsychotics are often used without clear indications and for too long time periods. Antipsychotics should be used only when all non-pharmacological strategies have failed. A clear definition of the treatment target in advance and a continuous monitoring of the therapy are mandatory.
Einleitung:
Bei der Verordnung von Neuroleptika (Antipsychotika) und besonders Antidepressiva lassen sich zunehmend häufiger Irrationalitäten, unbegründete Indikationsausweitungen, off-label use etc. ...beobachten. Zum Beispiel nehmen in den USA fast 5% der Mädchen im Alter von 12 bis 17 Jahren ein Antidepressivum ein. In dem Vortrag geht es um die Frage, was für ein ärztliches Konzept hinter diesen Entwicklungen steht und welche Rolle dabei pharmazeutisches Marketing spielt.
Methoden:
Wesentliche Grundlage sind u.a. die detaillierten Analysen der kassenärztlichen Verordnungen im jährlich erscheinenden „Arzneiverordnungsreport“. Gemeinsam mit anderen Quellen und pharmakologischen Bewertungsstandards lassen sich daraus das tatsächliche Nutzen-Risiko-Verhältnis, besonders bei der Langzeitmedikation, und Probleme des Absetzens einer solchen langfristigen Behandlung abschätzen.
Diskussion:
Aktuelle Befunde und historische Vergleiche geben Anlass zum kritischen Nachdenken: bei den Antipsychotika ist es z.B. die zunehmende Verordnung bei Kindern, Jugendlichen und betagten wie hochbetagten Menschen, z.B. in Pflegeheimen. Gerade diese Befunde erhalten ihre Brisanz auf dem Hintergrund der in verschiedenen Studien gezeigten erhöhten Mortalität neuroleptisch behandelter Senioren.
TDM of psychotropic drugs is widely used, but there is little consensus regarding its optimal use in the clinical context. This prompted a multidisciplinary group comprised of clinical biochemists, ...clinical pharmacologists, and psychiatrists of the AGNP (Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie) to provide a consensus guideline. This will allow clinical psychiatrists, practitioners, and laboratory directors involved in psychopharmacotherapy to optimize TDM of antidepressants, antipsychotics, and opioid substituents. Recommendations are also given on the combined use of TDM and pharmacogenetic tests.
The dopamine D4 receptor (DRD4) may play a role in the pathogenesis of neuropsychiatric disease and in the action of dopaminergic drugs. The 48-bp repeat polymorphism (48-bp VNTR) coding for a ...16-amino acid segment in the third cytoplasmatic loop of the DRD4 was studied as a predictor of the therapeutic response to antipsychotics and as susceptibility factor for schizophrenia. We included 638 in-patients with acute schizophrenic, schizoaffective (mainly schizophrenic), and other nonaffective psychoses, as well as two reference groups: one with 278 in-patients with non-psychiatric diseases, and one with 474 healthy volunteers. Catatonic patients (DSM-IV 295.2) more frequently carried the DRD4 D4.2 and D4.3 allele than did all other schizophrenic cases (P < 0.001; OR: 2.7; CI: 1.5-4.9) and controls (P < 0.004; OR: 2.3; CI: 1.3-4.2). We found no significant difference in the DRD4 allele or in genotype frequencies in our comparison of all schizophrenic patients and controls. The subgroups with affected family members, and the subgroups with early or late onset of disease, also did not differ from the controls in DRD4 allele frequencies. The 48-bp VNTR was not a predictor for therapeutic outcome measured by the positive and negative symptoms scale. A total of 1390 subjects showed between 1 and 10 repeats (D4. 1 and D4.10), with 25 different genotypes. These data exclude a major role of DRD4 48-bp VNTR in response to antipsychotic therapy and as susceptibility factor for schizophrenia, but catatonic schizophrenia may be associated with the D4.2 and D4.3 alleles.
The dependence of platelet-5HT content on apparent kinetic parameters of 5HT uptake was analyzed in 56 healthy subjects and 47 depressed patients, who had not been taking psychotropic medication for ...several months. There were no significant relationships between apparent V
max or K
m and platelet-5HT content in both groups. However, the ratio of V
max to K
m, as a measure of apparent 5HT uptake efficiency, significantly correlated with the platelet-5HT concentration in healthy subjects (r=0.627 p<0.001). Female controls showed a higher correlation coefficient (r=0.723) than male controls (r=0.457). A marked deviation from the linear relationship between 5HT content and the ratio V
max/K
m was observed in female depressed patients (r=0.250 n.s.). In male depressed patients the correlation coefficient (r=0.485 p<0.05) was similar to male healthy subjects, but the regression equations differed significantly in slope and intercept. Dividing controls and patients in subgroups with low, median and high net uptake rates, it was found that the frequencies of these uptake rate classes were 24.6%, 33.3%, 42.1% in controls and 38.3%, 44.7%, 17.0% in patients respectively. Patients and controls with low net uptake rate showed very similar uptake kinetics and uptake efficiencies, but the lack of a significant correlation between 5HT content and the ratio V
max/K
m differentiated patients from controls. The status of the serotonergic system, expressed as relationship between 5HT content and uptake efficiency, was very similar in patients and controls in the range of medium net uptake rate. A trend toward higher values of uptake efficiency was apparent in patients with high net uptake rate but the platelet-5HT content was similar to corresponding controls. Mean scores on the HAMD scale (total score and psychic anxiety item) were significantly higher in the low net uptake rate group of patients than in those with a high net uptake rate.
Zusammenfassung
Das Absetzen von Antidepressiva kann Absetzsymptome, die Wiederkehr der ursprünglichen Erkrankung und einen Rebound bewirken. Bei Letzterem kehrt die Erkrankung stärker, rascher oder ...mit größerer Wahrscheinlichkeit zurück, als wenn keine medikamentöse Behandlung erfolgt wäre. Absetzsymptome sind vielgestaltig; vorherrschend sind unspezifische körperliche Symptome. Ihre Abgrenzung von der Wiederkehr depressiver Symptome kann schwierig sein. Die Evidenz zu Ausmaß und Häufigkeit von Rebound-Depressionen ist unzureichend. Aufgrund des Rebound-Risikos muss bei der Indikationsstellung der kurzfristige Nutzen gegen die mögliche langfristige Gefahr einer Chronifizierung der Depression und gegen das eventuelle Erfordernis einer Dauermedikation abgewogen werden. Patienten sollten schon bei der gemeinsamen Entscheidung über eine Pharmakotherapie sowie regelmäßig im Behandlungsverlauf über die Absetzrisiken aufgeklärt werden. Ein Absetzen sollte außer in Notfallsituationen ausschleichend erfolgen, wobei insbesondere im Niedrigdosisbereich kleinschrittig reduziert werden sollte.
Zusammenfassung
Klinisch besteht der Bedarf, in der Antidepressivabehandlung das Präparat und die individuell adäquate Dosierung gezielter auswählen zu können. Die Untersuchung pharmakokinetisch ...relevanter Gene ist hierfür ein vielversprechender Ansatz. In den vergangenen zwei Jahren wurden insbesondere ein Test der Firma Stada, der Varianten der Zytochrom-P450-Isoenzyme CYP2D6 und CYP2C19 untersucht, und ein Test der HMNC Brain Health GmbH, der Varianten des
ABCB1
-Gens untersucht, bei Ärzten beworben. Beide Tests werden nicht von den gesetzlichen Krankenversicherungen vergütet und dahingehend beworben, sie in Form von IGeL-Leistungen den Patienten selbst in Rechnung zu stellen. Die Anbieter äußern für beide Tests, dass hierdurch auf erfolglose Antidepressivabehandlungen verzichtet werden könne und dass es zu einem schnelleren Ansprechen auf die Behandlung komme. Diese Aussagen sind durch geeignete klinische Studien nicht gedeckt, da solche Studien fehlen bzw. widersprüchliche Ergebnisse liefern. Es wird daher vom routinemäßigen Einsatz dieser Tests abgeraten. In Übereinstimmung mit der S3-Leitlinie Unipolare Depression wird empfohlen, bei Nonresponse auf eine in Dauer und Dosis adäquat durchgeführte Antidepressivamedikation eine Serumspiegelbestimmung durchzuführen. Diese wird in der Regel von den gesetzlichen Krankenkassen übernommen. Nur bei außerhalb des Erwartungsbereichs liegenden Serumspiegeln und Ausschluss anderer Ursachen ist eine Zytochrom-P450-Genotypisierung sinnvoll. Diese kann in vielen Laboren durchgeführt werden, wofür in Einzelfällen die Kosten von den gesetzlichen Krankenkassen übernommen werden. Die weitere Beforschung der Bedeutung des
ABCB1
-Gens für die Behandlung mit Antidepressiva ist sinnvoll.
Therapeutic drug monitoring (TDM) of psychopharmaceuticals, i.e., the assay of plasma concentrations, is a practical therapeutic application of pharmacokinetic principles in psychiatry. The ...prescription information (summary of product characteristics, SPC) is provided by pharmaceutical companies according to the requirements of regulatory authorities. The present study investigated the degree of agreement of German SPCs for 48 psychopharmaceuticals with the existing medico-scientific evidence in the area of TDM. For this aim, an empirical summary score of SPC content related to TDM (SPCC (TDM)) was calculated and compared with the level of recommendation of TDM (LOR) of the AGNP-TDM expert group consensus guidelines. Considerable disagreement was found between the information on TDM in SPCs and existing medico-scientific evidence, e.g., in the case of antidepressant and antipsychotic drugs. Even for well studied compounds, such as amitriptyline and clozapine, insufficient information on TDM is included in German SPCs. Small differences existed in the TDM-related information in SPCs of generic drugs with, however, much variance between Germany, Austria and Switzerland. Generally, it must be concluded that deficits exist in the preparation of German SPCs for psychopharmaceutical drugs with respect to empirical pharmacokinetic data, i.e., TDM-relevant information. It is recommended that SPCs of psychopharmaceuticals should be improved in terms of TDM-related information and that target plasma concentrations be adjusted according to the guidelines of the AGNP-TDM expert group. A higher level of good pharmacokinetic practice may be thus achieved.
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