Effects of tryptophan depletion in drug-free depressed patients who responded to total sleep deprivation.

BACKGROUND: There is some evidence that sleep deprivation (SD) might exert its antidepressant properties by involving serotonergic mechanisms. We investigated the effects of short-term tryptophan depletion (TD) on depressed patients who responded to a single night of total SD. METHODS: Drug-free depressed inpatients (n = 30) were randomly assigned to either TD or sham depletion. Tryptophan depletion was induced by a 24-hour low-tryptophan diet (day 1) followed the next morning by ingestion of a tryptophan-free amino acid mixture (day 2). During sham depletion, the diet and the amino acid beverage were supplemented with tryptophan. Sleep deprivation was performed from day 1 until day 2. Only SD responders received the amino acid beverage the morning after SD. Behavioral ratings and total and free plasma tryptophan levels were obtained before and after the test sessions. RESULTS: Twenty-two of 30 patients showed a favorable outcome after SD. As predicted, TD significantly lowered total and free plasma tryptophan levels, whereas both levels increased during sham depletion. No acute effects on mood were observed during the day after SD in either treatment group. Unexpectedly, TD, but not control testing, prevented the depressive relapse after the recovery night in most of the patients. CONCLUSIONS: Tryptophan depletion did not reverse the antidepressant effects of SD, but it prevented the relapse beyond a night of recovery sleep. These findings suggest that SD does not act via a single monoamine-related mechanism, but they allow the assumption that TD may induce neurochemical alterations that transiently improve depression.

Rapid tryptophan depletion in drug-free depressed patients with seasonal affective disorder.

OBJECTIVE: Brain serotonin systems might be involved in the pathophysiology of seasonal affective disorder. The authors tested whether tryptophan depletion alters the mood of depressed patients with seasonal affective disorder. METHOD: Eleven drug-free depressed patients with seasonal affective disorder underwent tryptophan depletion in a placebo-controlled, double-blind crossover study. Tryptophan depletion was induced by a 24-hour low-tryptophan diet and by ingestion of a tryptophan-free amino acid beverage. During control testing the diet and the beverage were supplemented with tryptophan. Behavioral ratings and plasma total and free tryptophan levels were obtained before the diet started and several times after administration of the beverages. RESULTS: The diet and the tryptophan-free amino acid drink reduced plasma total and free tryptophan levels by 79.0% and 87.5%, respectively. Both levels increased during control testing. No significant behavioral changes were induced by tryptophan depletion or control testing. CONCLUSIONS: The failure of tryptophan depletion to exacerbate the depressive syndrome suggests that dysfunctional serotonergic activity does not play a primary, direct role in the pathogenesis of winter depression.

Suicidal tendencies as a complication of light therapy for seasonal affective disorder: a report of three cases.

BACKGROUND: Suicidality in seasonal affective disorder (SAD) subjects treated with bright light therapy seems to be a rare phenomenon. We report on three SAD patients with predominant atypical symptoms who presented for treatment in our clinic for SAD. Two suffered from bipolar disorder, one from recurrent major depressive disorder. METHOD: All subjects were drug-free and treated with bright light therapy as a monotherapy for the first time. Treatment response was assessed weekly by standardized rating instruments, using the Hamilton Rating Scale for Depression (HAM-D) and the HAM-D-SAD addendum for assessment of atypical symptoms. RESULTS: Within the first week after beginning bright light therapy, two subjects attempted suicide. The third patient developed suicidal thoughts that were so acute and overwhelming that we had to discontinue bright light therapy and start with psychopharmacologic treatment in an inpatient setting. CONCLUSION: It is suggested that bright light-induced amelioration of drive and mood can be dissociated as can be the case in the "critical time" of antidepressant therapy. The authors believe the collection of prevalence data on suicide and SAD would be worthwhile.

Sertindole and dopamine D2 receptor occupancy in comparison to risperidone, clozapine and haloperidol - a 123I-IBZM SPECT study.

The striatal D2 dopamine binding was studied in schizophrenic patients treated with the novel atypical antipsychotic drug sertindole (n=10). Comparisons were obtained with haloperidol (n=8), clozapine (n=6), risperidone (n=11) and untreated healthy controls (n=8) of a dataset which has partly been reported previously. 123I-Iodobenzamide (IBZM) single photon emission computerized tomography (SPECT) was used for estimation of striatal dopamine D2 receptor binding. Sertindole-treated patients exhibited significantly (P < 0.001) lower levels of striatal D2 binding (BG/FC ratio:1.28) compared with those treated with haloperidol (BG/FC ratio:1.09) and risperidone (8 mg:1.18) but significantly (P < 0.005) higher levels compared with clozapine (BG/FC ratio: 1.49). However, if patients were pretreated with a depot neuroleptic, significantly (P < 0.05) higher striatal D2 binding (BG/FC ratio:1.12) has been obtained. Since sertindole has been shown to exert distinct clinical efficacy for treatment of positive and negative symptoms, our data are indicative that antipsychotic efficacy is not associated with a high degree of striatal D2 receptor occupancy in schizophrenic patients.

The citalopram challenge test in patients with major depression and in healthy controls.

Neuroendocrine challenge tests in depressed patients have revealed a blunted hormonal reaction to serotonergic stimuli. In the present study, citalopram was chosen as the serotonergic agent for neuroendocrine stimulation. Compared to earlier challenge agents, citalopram has the advantage of serotonergic selectivity, its application is well tolerated and the possibility of intravenous application reduces pharmacokinetic interference. Sixteen patients suffering from an acute episode of major depression and 16 healthy controls underwent the stimulation procedure with 20 mg of citalopram and placebo. Whereas significant differences in the secretion of prolactin and cortisol between citalopram and placebo challenge were observed in the control group, no differences were found in the group of depressed patients. Comparison of depressed patients and controls showed a significantly blunted prolactin secretion in patients. Differences in cortisol secretion following serotonergic stimulation with citalopram did not become significant. The stimulation procedure was well tolerated in all subjects, although a higher number of side effects was observed in the control group. The amount of side effects did not correlate with the hormone responses. These results are in line with the hypothesis of serotonergic hypofunction in depressed patients. In conclusion, the 20-mg citalopram challenge test is thought to be a promising tool for further investigation of serotonergic function in psychiatric illness.

IBZM-SPECT imaging of dopamine D(2) receptors with typical and atypical antipsychotics.

Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. Since psychopharmacological treatment is thought to act on the underlying biological basis of the disease, brain imaging techniques enable us to understand the mechanism of action of such compounds. One important tool used to determine patterns of brain dysfunction and how psychopharmacological agents such as antipsychotic compounds work is single-photon emission computerised tomography (SPECT). This technique allows determination of striatal D(2) receptor occupancy rates, which are associated with the extrapyramidal side effects (EPS) of antipsychotic drugs. Studies have confirmed that atypical antipsychotic agents have lower occupancy rates than typical agents. No association has been found between D(2) receptor occupancy rates in the striatum and antipsychotic efficacy, and it therefore appears that striatal D(2) receptor occupancy rates are not necessary for the antipsychotic effect of such agents in schizophrenia. The availability of more refined radioligands will help us not only to understand the action of antipsychotics but also the pathophysiology of schizophrenia.

IBZM-SPECT imaging of dopamine D(2) receptors with typical and atypical antipsychotics.

Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. Since psychopharmacological treatment is thought tc act on the underlying biological basis of the disease, brain imaging techniques enable us to understand the mechanism of action of such compounds. One important tool used to determine patterns of brain dysfunction and how psychopharmacological agents such as antipsychotic compounds work is single-photon emission computerised tomography (SPECT). This technique allows determination of striatal D(2) receptor occupancy rates, which are associated with the extrapyramidal side effects (EPS) of antipsychotic drugs. Studies have confirmed that atypical antipsychotic agents have lower occupancy rates than typical agents. No association has been found between D(2) receptor occupancy rates n the striatum and antipsychotic efficacy, and it therefore appears that striatal D(2) receptor occupancy rates are not necessary for the antipsychotic effect of such agents in schizophrenia. The availability of more refined radioligands will help us not only to understand the action of antipsychotics but also the pathophysiology of schizophrenia.

[Maintenance therapy with 20 mg fluoxetine. Results of an administration study of 1,737 depressed patients]. / Erhaltungstherapie mit 20 mg Fluoxetin. Ergebnis einer Anwendungsbeobachtung an 1737 depressiven Patienten/innen.

An application study was carried out in 1993/94 on the use of fluoxetine for the continuation therapy of depression. 1737 patients received fluoxetine at a dosage of 20 mg per day over a period of 6 months. Diagnosis was made by clinical evaluation of phenomenology and ICD-10 classification. Over the observation period physicians rated the course of illness according to severity of the depression, somatic complaints and therapeutic efficacy on a scale graded 1-4. Side effects and concomitant medication were also noted. Coincidentally, patients recorded subjective satisfaction with therapy, as well as side effects. In a subsample of 423 patients the physicians additionally used a modified version of the Hamilton Depression Rating Scale (HRDS) for behavioural ratings. Standard assessment was performed after the 2nd and 6th weeks of treatment and again after the 3rd and 6th months. The rating scale showed a decrease in depressive symptomatology and somatic complaints at the end of treatment in 53% and 44% of patients, respectively. Treatment efficacy was rated as excellent in 82% of cases, as evaluated by the physicians; patients were satisfied in 89% of cases. These results are strengthened by the reduction from 22.4 +/- 7.0 to 9.2 +/- 6.4 in the subsample of 423 patients according to the HRDS, equivalent to a decrease in depression symptomatology of 59%. This study is the first open phase IV trial in Austria investigating continuation therapy with 20 mg fluoxetine per day and confirms results obtained in international multicentre placebo-controlled studies involving considerably smaller numbers of patients.

[The tryptophan depletion test. Basic principles and clinical relevance]. / Der Tryptophandepletionstest. Grundlagen und klinische Relevanz.

The application of a tryptophan-free amino acid mixture (tryptophan depletion test) induces a rapid and substantial lowering of both total and free plasma tryptophan. Consequently, the brain serotonin content and also cerebral serotonin function are decreased. This method provides a paradigm to study the role of serotonin in the pathobiology of depressive disorders and their treatment modalities. Untreated depressed patients show few behavioral effects during tryptophan depletion. In depressed patients during an antidepressant or light-therapy-induced stable remission, a transient depressive relapse was induced by tryptophan depletion. Healthy subjects with a genetic risk for affective disorder show worsening of their condition induced by tryptophan depletion. These findings indicate the relevance of altered brain serotonin function in the pathophysiology of affective disorders and strengthen the importance of serotonin in the mechanism of action of antidepressants. Since recently published studies revealed some evidence that the serotonergic system is directly involved in the pathophysiology of various psychiatric syndromes besides depression, it seems to be reasonable to evaluate the validity of the tryptophan depletion test also in non-depressed patients.

Effects of tryptophan depletion in fully remitted patients with seasonal affective disorder during summer.

BACKGROUND: Deficiencies in brain serotonin function are believed to play an important role in the pathophysiology of seasonal affective disorder/winter type (SAD). However, no direct evidence has been reported so far that lowered brain serotonin activity causes the symptoms of SAD. METHODS: We studied 11 SAD patients who had suffered recurrent winter depressive episodes of SAD and were fully recovered and off treatment during the summer. In a randomized, balanced, double-blind crossover design patients received two amino acid beverages, one containing tryptophan and the other containing no tryptophan but otherwise identical. Behavioural ratings and plasma total and free tryptophan concentrations were assessed at baseline before administration of the amino acid beverages and at several time points afterwards. RESULTS: The tryptophan-free amino acid beverage induced significant decreases of plasma total and free tryptophan levels and both levels increased during sham depletion (condition x time interaction: P < 0.001). Tryptophan depletion, but not sham depletion caused a transient return of depressive symptoms (condition x time interaction: P < 0.001). CONCLUSIONS: The present study demonstrates that SAD patients in remission during the summer are vulnerable to a return of depression when depleted of tryptophan. This finding supports the importance of serotonergic mechanisms in the pathophysiology of SAD.