Amitriptyline N-oxide (AMINO) was given to male Wistar rats orally in single and multiple doses, and the levels of the drug and its main metabolite amitriptyline (AMI) were assayed in blood and brain by HPLC. After the single dose of AMINO (20 mg/kg), the levels of the parent compound and of AMI in the brain were higher than in blood. In the brain Cmax of AMINO and AMI were similar, whereas in the blood Cmax of AMI was considerably lower than that of the parent compound. After chronic treatment with AMINO (10 mg/kg twice daily, at 12 h intervals, for 14 days) the brain level of AMI reached the value of approx. 4 micrograms/g of tissue and remained nearly stable for 12 h after the last dose. Brain Cmax of AMINO was approx. 2 micrograms/g; the drug was eliminated more rapidly than AMI and 24 h after the last dose it was not detectable. The blood level of AMINO exceeded the level of AMI, but the difference was less marked than that observed after a single dose. The brain and blood levels of both drugs were considerably higher than those observed in the acute experiment. When AMI was given to rats chronically (dosage and schedule as above) its blood and brain levels were 2-5 times higher than the corresponding levels of AMI after treatment with AMINO, and its elimination was more rapid. Our results indicate that after oral administration of AMINO to rats AMI is formed in significant amounts, its brain level is high and becomes more stable after chronic treatment.
There is some evidence that the early response of schizophrenic patients to neuroleptic treatment is of prognostic value for the subsequent course of treatment. This hypothesis was confirmed in a prospective study. It was demonstrated that already the therapeutic effect on the first day of treatment is of prognostic value, especially with a standardized drug regimen.
A nation-wide survey on the abuse of benzodiazepines in Switzerland showed an average morbidity (incidence) of 0.0006 per year for isolated abuse of benzodiazepines. The exposure risk was, independently of the benzodiazepine compound used. 0.00002 per prescription. The afflicted population differed demographically in no way from the population of "normal" benzodiazepine consumers, legitimate therapeutic use of a benzodiazepine being the only visible risk factor for development of an abuse. The motivation for abuse, too, was in about 90% of the case self-medication of anxiety and/or insomnia and related symptomatology. Main source of the drug was new prescriptions by the treating physician. The majority of patients were medically in a good state of health and socially well adjusted; 52 out of 180 patients, however, showed negative consequences. Withdrawal syndromes were reported in about one quarter of the detected cases, but detection was mostly due to the increased frequency of prescriptions of confession of the patient. Because of the low frequency of severe negative consequences and the mostly unobtrusive behaviour of the patients, differing in many ways from the accustomed picture of an "abuser of (illicit) drugs", the physician's attitude towards abuse of benzodiazepines was in many cases ambivalent, resulting in a tacit acquiescence and continued prescription. From the data presented it is concluded that the most appropriate measure against abuse of benzodiazepines would be, rather than international control, education of medical professionals and the public, according to internationally accepted medical knowledge and to national law and prescription regulations.
A brief review is presented of the use of lithium salts in medical practice before 1949. The present-day indications for lithium, in the treatment of affective disorders, are seen to have been anticipated in the second half of the nineteenth century, although the rationale for its use was subsequently found to be erroneous.
Recent studies report the occurrence of withdrawal reactions in a significant number of patients after long-term use of benzodiazepines, i.e. daily use for one year or more. The abstinence syndrome is partially characterized by anxiety, dysphoria, sleep disturbances and other unspecific symptoms. In addition, some patients experience symptoms, which, so far, have not been described as typical part of a withdrawal syndrome, especially disturbances of sensory perception. The withdrawal syndrome is less acutely distressing than a classical withdrawal syndrome of the barbiturate type, but occasionally it can show a protracted course.
In an open study of schizophrenic patients treated with perazine (Taxilan), a multidimensional approach comprising the following three areas was chosen: 1. psychopathology (AMDP, BPRS); 2. psychophysiology (habituation of skin resistance reaction, pulse rate); 3. pharmacokinetics (perazine-desmethylperazine plasma levels). Looking beyond the known global effect of the neuroleptic drug, interactions between these three areas were studied. Furthermore, methodological questions concerning possible predictor variables for treatment outcome were examined. Finally, an improved method for analyzing psychopathological data was employed. The methodological framework of the study, the examination techniques, and patient population are presented.
Nine patients with endogenous depression have been treated with infusions of the synthetic methionine enkephaline analogue FK 33-824 for two days. Only on the first day acute effects on depressive symptoms could be observed. It cannot be decided if the observed mood alterations on the first treatment day are placebo effects. Depressive patients showed fewer adverse reactions than healthy volunteers. This might be explained by the previously described greater pain tolerance in depressives.
The present survey highlights the rationale for the use of state-dependent biological markers as predictors of clinical course in depression. Cortisol plasma levels after dexamethasone provide such a tool to monitor clinical progress. Since dexamethasone-resistant cortisol gradually returns to normalcy before a complete clinical remission is seen this measure has a possible predictive potential. Moreover, reversion to abnormal dexamethasone responses is prognostically infaust. Though the dexamethasone test has some merits, technical factors (e.g. exclusion criteria, dexamethasone-kinetics) which invalidate test results deserve careful consideration in future studies. Cortisol hypersecretion is considered as a physiological readout of a central disinhibition. This hypothesis is tested applying corticotropin-releasing factor and corticotropin in normal and abnormal DST responders. The data support the validity of the concept which assumes an intact but overactive pituitary-adrenal axis in a depressed subpopulation. A thesis is submitted which places the variety of biological disturbances in depression between two extreme viewpoints. One view considers all biological disturbances as sequelae to one particular dysfunction, e.g. disinhibition of corticosteroid secretion. The opposite view considers the myriad of biological disturbances as a sign of general loss of order, i.e. increased entropy, the precipitating mechanism of which is unknown.
6 schizophrenic patients were treated in a cross-over design for 4 days each with 20 mg naloxone or placebo. No patient showed a significant change of his or her psychotic behaviour. This result is not in agreement with an antipsychotic action of the opiate antagonist.
Concentrations of Fraction I and II endorphins in CSF and serum and CSF haloperidol levels were determined in 12 patients with therapy-resistant chronic schizophrenia during highdose haloperidol medication. After increasing the haloperidol dose from 60 mg to 120 mg daily a tendency for an increase of CSF Fraction I endorphin level was observed (t = 1.65 p > 0.05). In addition, there was a trend for a parallel increase of CSF Fraction I endorphin and serum and CSF heloperidol levels although the correlations did not reach statistical significance.
Using a double-blind experimental design, two dosage regimens of haloperidol were compared in acutely decompensated, newly admitted schizophrenic patients. Patients in group A (n = 21) received 5 mg haloperidol tablets, patients in group B (n = 20) 15 mg haloperidol tablets. The number of tablets did not exceed six a day but could be varied according to the condition of each patient. On the average patients of group A were prescribed 4.0 tablets, corresponding to 20.0 mg haloperidol a day, and patients of group B 3.9 tablets, corresponding to 58.0 mg haloperidol a day. A significant amelioration of the psychopathology as measured by BPRS were observed in both groups. Between both groups investigated, no differences were found neither with regard to therapeutic efficacy nor to the tolerance of the treatment. Administration of higher oral haloperidol doses cannot be recommended as a standard procedure.
The authors describe two female patients with bipolar I depression who did not respond to tricyclic antidepressants in their previous depressive episodes and were prophylactic lithium nonresponders. Both patients showed a high pretreatment platelet MAO activity and responded well and rapidly to monoamine oxidase inhibition (MAOI) treatment. These findings suggest that although bipolar depressed patients show a low platelet MAO activity, there may be a subgroup with high enzyme activity. These patients revealed a low tendency to respond to tricyclic antidepressants and showed rapid improvement on MAOI therapy.
Siberian chipmunks (Eutamias sibiricus) were kept individually in small cages attached to a running wheel. Under continuous illumination of two different light intensities (0.4-0.9 lux and 400-1200 lux) the influence of Rolipram, a putative new antidepressant, on the period length tau was tested. Under both conditions Rolipram caused a lengthening of tau, a decrease of activity time alpha and an increase of rest time delta, resulting in a decrease of the alpha/delta ratio. These effects of Rolipram could be due to a slowing down of the circadian oscillatory system or an influence on the sensitivity towards light.
In vivo turnover of NA in the brain is considerably high, but in vitro only a low activity of the enzyme DBH is detectable. It is supposed that this effect is brought about by endogenous enzyme inhibitors. It was demonstrated that the addition of rat brain homogenate, as well as different subcellular fractions from rat brain, inhibit the human serum DBH. Inhibitory activity is resistant to heat and acid but does not seem to be uniformly distributed within the cell. Pretreatment of brain homogenate with pronase reduced its inhibitory activity. In conclusion, pronase sensitive peptides are partially responsible for the inhibitory potency of tissue homogenates.
Twenty-eight patients with acute schizophrenic illness received an oral daily dose of 200-800 mg perazine (Taxilan) for 4 weeks. Weekly plasma level determinations showed a constant perazine concentration from day 7 to day 28, whereas the equilibrium level of its metabolite desmethyl perazine was only achieved at day 14; on an average it amounted to twice the level of perazine. Additional measurements were carried out 2 and 4 h after administration of the morning dose on day 14. The maximal increase of the perazine concentration was usually reached after 2 h; though it varied between 7 and 240% of the morning level, a close correlation existed between minimal and maximal levels. The perazine fraction not bound to plasma proteins was found to be 3.1-5.5% on day 21. The percent improvement in target syndromes during 4 weeks of neuroleptic therapy, as documented with the AMDP system, was most marked in those patients who had perazine levels in the 100-230 ng/ml range at day 28; patients with lower or higher levels improved significantly less. Curvilinear relationships also appeared to exist between improvement and free perazine concentration as well as maximal level on day 14. With regard to total scores on the Brief Psychiatric Rating Scale or scores of higher-order factors, no significant relationship between improvement and perazine level was found. The desmethyl perazine concentration did not exhibit a significant relationship to the therapeutic result. The pharmacokinetic parameters investigated seem to have a limited influence on the clinical outcome.(ABSTRACT TRUNCATED AT 250 WORDS)
Clinical and biological variables were investigated for their predictive value with respect to an antidepressant drug treatment. Thirty patients received clomipramine and thirty patients maprotiline. Characteristic features of the biography, the family anamnesis and the previous course of illness (apart from intermittent course) have no predictive value. The psychopathological symptoms before the start of treatment are also not suitable for prediction (except vegetative syndrome). The activity of the enzymes MAO, COMT and DBH before the start of treatment have no predictive value. The serum level of maprotiline on the seventh day of treatment does not correlate with the outcome of treatment. It is possible that patients, who have relatives with suicidal tendencies, are more likely to be clomipramine non-responders; patients with relatives who have a psychiatric history but without suicidal tendencies, are more likely to be maprotiline responders; i.a., relatives of the first degree manifesting psychiatric problems speak against a response to clomipramine and indicate a response to maprotiline. Patients with diurnal variations before the start of treatment are possibly more likely to respond to maprotiline than to clomipramine. There are statistically established findings for only the following variables: Diurnal variations during treatment speak in favour of an antidepressant response. A positive SD reaction indicates clomipramine response. A serum level of more than 75 ng clomipramine and more than 30 ng desmethyl-clomipramine/ml serum on the 7th day of treatment clearly predict a response to clomipramine.
The effect of L-deprenyl on neuroleptic-induced parkinsonism was evaluated in eleven patients. No significant improvement was observed during the treatment with L-deprenyl in the overall assessment. Four patients, however, were considered responders as their total scores on the modified version of Neurological Rating Scale decreased by at least 50%. No somatic or mental complications were observed during the study. The pretreatment platelet monoamine oxidase activity of the responders was slightly but not significantly higher than that of the non-responders. The plasma prolactin (PRL) levels of the patients with high pretreatment levels decreased significantly during the administration of L-deprenyl.
As lithium has a wide range of biological effects, it is not surprising that the benefit from lithium treatment has been observed in several types of psychiatric disorders. Mood stabilization has been seen in episodic disorders; antiaggressive effect has been reported in mental retardation and other illnesses, and some endocrine and hematological effects have been utilized in internal medicine and neurology. To date, however, only the stabilizing effect on recurrent mood disorders appears to be reliably predictable. The prediction is based primarily on the diagnosis, quality of free interval and frequency of episodes; and several associated indicators can also be helpful. Results of the presented series of studies on the response to stabilizing lithium treatment suggest that such a response is predictable for most patients. The epitome of an excellent lithium responder is a patient with a good quality of remissions, a moderate frequency of recurrences, and a diagnosis of primary affective disorder. If the MMPI profile taken at the patient's optimum is abnormal, the chances of stabilization on lithium alone are greatly reduced. In addition, the responders more frequently have a family history of primary affective disorder and a positive M antigen. It appears that in the present practice the assessment of patients for stabilizing lithium treatment may frequently not be comprehensive enough. As a result, lithium is at present probably overprescribed in North America, and possibly elsewhere as well.
The prognosis of a clinical neuroleptic treatment was prospectively examined in 26 schizophrenic patients using a predetermined set of predictors and outcome criteria. Prognosis before treatment did not discriminate significantly between patients with good and poor outcome. Significant differences of outcome were observed between the prognostic groups, if prognosis was established after 5 days of treatment. Retrospective analysis of individual predictors indicated the following rank order: initial improvement, age, duration of symptoms before treatment, sex, subjective tolerance of the treatment. The relative weight of the individual predictor in forming the prognosis is still an open question.
