Antipsychotic drug-induced neutropenia: results from the AMSP drug surveillance program between 1993 and 2016.

Neutropenia and agranulocytosis (N&A) are relatively rare, but potentially fatal adverse drug reactions (ADR). This study presents cases of N&A related to one or more antipsychotic drugs (APDs) in psychiatric inpatients. Data on APD utilization and reports of N&A caused by APDs were analyzed by using data from an observational pharmacovigilance program in German-speaking countries-Arzneimittelsicherheit in der Psychiatrie (AMSP)-from 1993 to 2016. 333,175 psychiatric inpatients were treated with APDs for schizophrenia and other indications during the observation period. A total of 124 cases of APD-induced N&A were documented, 48 of which fulfilled the criteria for agranulocytosis, corresponding to a rate of 0.37, respectively, 0.14 in 1000 inpatients treated with APDs. Neutropenia was more often detected in women, whereas there was no difference regarding sex in cases of agranulocytosis. Clozapine had the highest relative risk for inducing N&A and was imputed alone as a probable cause of N&A in 60 cases (1.57‰ of all patients exposed). Perazine showed the second highest relative risk with 8 cases and an incidence 0.52‰, followed by quetiapine (15 cases resp. 0.23‰ of all patients exposed) and olanzapine (7 cases; 0.13‰ of all patients exposed). N&A most often occurred during the first 3 months of treatment. Overall N&A are severe and potentially fatal complications that can occur during treatment with APDs. The results from this study largely agree with the currently available literature, highlighting the positive effects of alertness and established appropriate monitoring.

Galactorrhea during antipsychotic treatment: results from AMSP, a drug surveillance program, between 1993 and 2015.

Galactorrhea is a well-known adverse drug reaction (ADR) of numerous antipsychotic drugs (APD) and is often distressing for those affected. Methodological problems in the existing literature make it difficult to determine the prevalence of symptomatic hyperprolactinemia in persons treated with APDs. Consequently, a large sample of patients exposed to APDs is needed for more extensive evaluation. Data on APD utilization and reports of galactorrhea caused by APDs were analyzed using data from an observational pharmacovigilance program in German-speaking countries-Arzneimittelsicherheit in der Psychiatrie (AMSP)-from 1993 to 2015. 320,383 patients (175,884 female inpatients) under surveillance were treated with APDs for schizophrenia and other indications. A total of 170 events of galactorrhea caused by APDs were identified (0.97 cases in 1000 female inpatient admissions). Most cases occurred during the reproductive age with the highest incidence among patients between 16 and 30 years (3.81 cases in 1000 inpatients). The APDs that were most frequently imputed alone for inducing galactorrhea were risperidone (52 cases and 0.19% of all exposed inpatients), amisulpride (30 resp. 0.48%), and olanzapine (13 resp. 0.05%). In three cases, quetiapine had a prominent role as a probable cause for galactorrhea. High dosages of the imputed APDs correlated with higher rates of galactorrhea. Galactorrhea is a severe and underestimated condition in psychopharmacology. While some APDs are more likely to cause galactorrhea, we identified a few unusual cases. This highlights the importance of alertness in clinical practice and of taking a patient's individual situation into consideration.

Screening for delirium after surgery: validation of the 4 A's test (4AT) in the post-anaesthesia care unit.

Postoperative delirium is common and has multiple adverse consequences. Guidelines recommend routine screening for postoperative delirium beginning in the post-anaesthesia care unit. The 4 A's test (4AT) is a widely used assessment tool for delirium but there are no studies evaluating its use in the post-anaesthesia care unit. We evaluated the performance of the 4AT in the post-anaesthesia care unit in a tertiary German medical centre. Adults who were able to provide informed consent, were not scheduled for postoperative intensive care, and who did not have dementia or severe neuropsychiatric disorders underwent screening by trained research staff with the Nurse Delirium Screening Scale and a new German translation of the 4AT in a random order at the point of discharge from the post-anaesthesia care unit. Reference standard assessment of delirium was psychiatric evaluation by experienced clinicians. Five hundred and forty-three patients (mean age (SD) 52 (18) years) were analysed; 22 (4.1%) patients developed delirium. The sensitivity and specificity of the 4AT were 95.5% (95%CI 77.2-99.9) and 99.2% (95%CI 98.1-99.8), respectively. The area under the receiver operator characteristic curve was 0.998 (95%CI 0.995-1.000). The Nursing Delirium Screening Scale had a sensitivity of 27.3% (95%CI 10.7-50.2) and specificity of 99.4% (95%CI 98.3-99.9), with an area under the curve of 0.761 (95%CI 0.629-0.894). These findings suggest that the 4AT is an effective and robust instrument for delirium detection in the post-anaesthesia care unit.

Suicide and assisted dying in dementia: what we know and what we need to know. A narrative literature review.

BACKGROUND: Evidence-based data on prevalence and risk factors of suicidal intentions and behavior in dementia are as scarce as the data on assisted dying. The present literature review aimed on summarizing the current knowledge and provides a critical discussion of the results. METHODS: A systematic narrative literature review was performed using Medline, Cochrane Library, EMBASE, PSYNDEX, PSYCINFO, Sowiport, and Social Sciences Citation Index literature. RESULTS: Dementia as a whole does not appear to be a risk factor for suicide completion. Nonetheless some subgroups of patients with dementia apparently have an increased risk for suicidal behavior, such as patients with psychiatric comorbidities (particularly depression) and of younger age. Furthermore, a recent diagnosis of dementia, semantic dementia, and previous suicide attempts most probably elevate the risk for suicidal intentions and behavior. The impact of other potential risk factors, such as patient's cognitive impairment profile, behavioral disturbances, social isolation, or a biomarker based presymptomatic diagnosis has not yet been investigated. Assisted dying in dementia is rare but numbers seem to increase in regions where it is legally permitted. CONCLUSION: Most studies that had investigated the prevalence and risk factors for suicide in dementia had significant methodological limitations. Large prospective studies need to be conducted in order to evaluate risk factors for suicide and assisted suicide in patients with dementia and persons with very early or presymptomatic diagnoses of dementia. In clinical practice, known risk factors for suicide should be assessed in a standardized way so that appropriate action can be taken when necessary.

Reduced gray matter brain volumes are associated with variants of the serotonin transporter gene in major depression.

The serotonergic system is involved in the pathophysiology of major depression as well as in the early central nervous system development and adult neuroplasticity. The aim of the study was to examine in 77 patients with major depression and 77 healthy controls the association between the triallelic polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and gray matter (GM) brain volumes measured with 1.5 T magnetic resonance imaging. Voxel-based morphometry were estimated on magnetic resonance images and genotyping was performed. We found that healthy controls have a strong association between the 5-HTTLPR and GM volumes of the dorsolateral prefrontal cortex, left anterior gyrus cinguli, left amygdala as well as right hippocampus, whereas there is no such association in patients with major depression. Healthy subjects carrying the S- or L(G)-allele have smaller GM volumes than those with the L(A)-allele, indicating that 5-HTTLPR contributes to the development of brain structures. Patients with depression show reduced GM volumes, particularly when they are homozygous for the L(A)-allele, suggesting that these patients are more vulnerable for morphological changes during depressive episodes.

[Core symptoms of depression. Effectiveness of antidepressant therapy]. / Depressive Kernsymptome. Wirksamkeit medikamentöser antidepressiver Therapieverfahren.

Core symptoms of depression are a combination of psychological and somatic symptoms, often associated with psychomotor and cognitive disturbances. The diagnostic classifications of depression include the concepts of melancholic, endogenous, or severe depression. All subgroups describe severely depressed patients suffering from most of the core symptoms of depression. In addition these patients exhibit the clinical characteristics of a recurrent unipolar or bipolar course, lower placebo response rates, or higher response rates to ECT, to antidepressant treatments with dually or mixed modes of action, or to lithium augmentation. Higher rates of HPA axis hyperactivity and specific EEG patterns may also occur in this patient group. This suggests a broad overlap of patient subgroups within the diagnostic classification of depression. Because the positive diagnosis of the core symptoms of depression may include clinical consequences, it would be useful to integrate all these concepts into the upcoming new versions of the diagnostic systems DSM-V and ICD-11.

Impact of gene-gender effects of adrenergic polymorphisms on hypothalamic-pituitary-adrenal axis activity in depressed patients.

OBJECTIVE: There is overwhelming evidence that activation of the hypothalamic-pituitary-adrenal (HPA) system plays a major role in depression and cardiovascular disease in genetically susceptible individuals. We hypothesized that due to the multiple interactions between the sympathetic and the HPA systems via adrenoceptors, polymorphisms in these genes could have an impact on HPA axis activity in major depression. METHODS: Using the dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test, we investigated the association of alpha(2)-adrenoceptor (ADRA2A -1291C-->G) and the beta(2)-adrenoceptor gene (ADRB2 Arg16Gly) in 189 patients with major depression during the acute state of the disease and after remission. RESULTS: Male ADRA2A -1291G allele homozygotes showed significant pretreatment HPA axis hyperactivity, with increased adrenocorticotropin (ACTH; F = 4.9, d.f. = 2, p = 0.009) and cortisol responses (F = 6.4, d.f. = 2, p = 0.003). In contrast, female ADRB2 Arg/Arg homozygotes had increased pretreatment ACTH (F = 7.17, d.f. = 2, p = 0.001) and cortisol (F = 8.95, d.f. = 2, p = 0.000) levels. Interestingly, in the respective genotypes, the stress hormones remained elevated in the second DEX/CRH test, despite a reduction in depressive symptoms. CONCLUSIONS: This study provides evidence that, depending on gender and polymorphisms, there is continuous HPA axis overdrive in a proportion of patients irrespective of the status of depression. Considering the importance of stress hormones for cardiovascular disorders, our data might suggest that these patients are at high risk of comorbidity between depression and cardiovascular disorders.

Neuroendocrinological mechanisms of actions of antidepressant drugs.

Noradrenaline or serotonin (5-HT) reuptake-inhibiting antidepressants such as reboxetine or citalopram acutely stimulate cortisol and adrenocorticotrophic hormone (ACTH) secretion in healthy volunteers, whereas mirtazapine acutely inhibits the ACTH and cortisol release, probably due to its antagonism at central 5-HT(2) and/or H(1) receptors. These differential effects of antidepressants on cortisol and ACTH secretion in healthy subjects after single administration are also reflected by their different time course in the down-regulation of hypothalamic-pituitary-adrenocortical (HPA) axis hyperactivity in depressed patients as assessed by serial dexamethasone (DEX)/corticotrophin-releasing hormone (CRH) tests: Reuptake-inhibiting antidepressants such as reboxetine gradually normalise HPA axis hyperactivity in depressed patients during several weeks of treatment via up-regulation of mineralocorticoid and glucocorticoid receptor function and by step-by-step restoration of the disturbed feedback control. By contrast, mirtazapine markedly reduces HPA axis activity in depressed patients within 1 week, but there is a partial re-enhancement of HPA hormone secretion after several weeks of therapy. In all studies performed to date, the short-term effects of daily treatment with antidepressants on the DEX/CRH test results are comparable in responders and nonresponders. Moreover, a reduction in HPA axis activity is not necessarily followed by a favourable clinical response and some depressed patients keep on showing nonsuppression in the DEX/CRH test despite clinical improvement. Therefore, the importance of HPA axis dysregulation for the short-term efficacy of antidepressants continues to be a matter of debate. However, there are convincing data suggesting that persisting nonsuppression in the DEX/CRH test despite clinical remission predicts an enhanced risk for relapse of depressive symptomatology with respect to the medium- and long-term outcome.

Neuroactive steroids as modulators of depression and anxiety.

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3alpha-reduced pregnane steroids are potent positive allosteric modulators of the GABA type A-receptor. During major depression there is a dysequilibrium of 3alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment we studied the impact of non-pharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroids observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder changes in neuroactive steroid composition have been observed opposite of those seen in depression. These changes may represent counterregulatory mechanisms against the occurrence of spontaneous panic attacks. However, during experimental panic induction with either cholecystokinin-tetrapeptide or sodium lactate there was a pronounced decline in the concentrations of 3alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3alpha, 5alpha-tetrahydrodeoxycorticosterone, allotetrahydrodeoxycorticosterone. The modulation of GABA type A-receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds.

Neuroactive steroids and affective disorders.

Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABA(A)) receptors. Preclinical studies suggested that neuroactive steroids may modulate anxiety and depression-related behaviour and may contribute to the therapeutical effects of antidepressant drugs. Attenuations of such neuroactive steroids have been observed during major depression and in several anxiety disorders, suggesting a pathophysiological role in such psychiatric conditions. In panic disorder patients a dysequilibrium of neuroactive steroid composition has been observed, which may represent a counterregulatory mechanism against the occurrence of spontaneous panic attacks. Furthermore, alterations of 3alpha-reduced pregnane steroids during major depression were corrected by successful treatment with antidepressant drugs. However in contrast, non-pharmacological antidepressant treatment strategies did not affect neuroactive steroid composition. In addition, changes in neuroactive steroid concentrations after mirtazapine therapy occurred independently from the clinical response, thereby suggesting that changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of antidepressants rather than clinical improvement in general. Nevertheless, the effects of antidepressant pharmacotherapy on the composition of neuroactive steroids may contribute to the alleviation of certain depressive symptoms, such as amelioration of anxiety, inner tension or sleep disturbances. Moreover, first studies investigating the therapeutical effects of dehydroepiandrosterone revealed promising results in the treatment of major depression. In conclusion, neuroactive steroids are important endogenous modulators of depression and anxiety and may provide a basis for development of novel therapeutic agents in the treatment of affective disorders.

Effects of alprazolam on cholecystokinin-tetrapeptide-induced panic and hypothalamic-pituitary-adrenal-axis activity: a placebo-controlled study.

Cholecystokinin-tetrapeptide (CCK-4) induces panic attacks both in patients with panic disorder (PD) and healthy volunteers. It has been shown that panic elicited by CCK-4 is improved after treatment with antidepressants. Moreover, a reduction of CCK-4-induced panic has also been demonstrated after treatment with lorazepam in single subjects and after selective GABAergic treatment with vigabatrin. Although benzodiazepines are widely used as anxiolytics, no controlled study on the effects of benzodiazepines on CCK-4-induced panic symptoms is available so far. Therefore, we investigated the effects of alprazolam and placebo on CCK-4-induced panic symptoms in a double-blind, placebo-controlled study. A total of 30 healthy subjects were challenged with 50 microg CCK-4. Out of these 30 subjects, 26 showed a marked panic response to CCK-4. Subjects were rechallenged after a 7-day interval and treated with 1 mg alprazolam or placebo 1 h prior to the second CCK-4 challenge. Panic was assessed using the acute panic inventory (API) and a DSM-IV-derived panic symptom scale (PSS). Moreover, the number of reported symptoms and self-rated anxiety and arousal were recorded. We found a significant reduction of the API and PSS scores and of the number of reported symptoms compared to placebo. Moreover, compared to placebo the CCK-4-induced ACTH and cortisol release were significantly attenuated during the CCK-4 challenge after alprazolam treatment. However, also placebo treatment reduced CCK-4-induced anxiety and HPA-axis activation to a certain extent. In conclusion, our data show that alprazolam reduces CCK-4-induced panic, which supports the hypothesis of a possible interaction between the GABA and the CCK system.

Lack of association of serotonin-2A receptor gene polymorphism (T102C) with suicidal ideation and suicide.

Serotonergic dysfunction has been implicated in the pathophysiology of affective disorders and suicidality. Especially the density of the 5-HT2A receptor was claimed as being increased in suicidality, proposed as an adaptive upregulation due to reduced serotonergic transmission. Recent studies have shown an association of allele C of the 5-HT2A-T102C polymorphism with suicidal ideation in patients with major depression. The purpose of this study was to test whether this proposed marker indicates susceptibility not only to suicidal ideation in depressed patients but also to suicidality as a syndrome. We investigated the 5-HT2A-T102C polymorphism in 131 suicide victims with unknown underlying psychiatric diagnoses, 84 patients with major depression with or without suicidal ideation, and 125 healthy controls. We were unable to find any association of genotype or allele frequencies to major depression, suicidal ideation, or suicide as a syndrome. Thus, our results suggest that this polymorphism may not commonly be involved in the susceptibility to suicidality. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:831-835, 2000.

C-type natriuretic peptide exerts stimulatory effects on the corticotropin-releasing hormone-induced secretion of hormones in normal man.

C-type natriuretic peptide and atrial natriuretic peptide have been reported to bind to distinct receptors and to exert opposing effects on different systems. Although it is known that atrial natriuretic peptide inhibits the corticotropin-releasing hormone-stimulated hormone release in man, the corresponding action of C-type natriuretic peptide has so far not been characterized. We investigated the effects of 30-min infusions of 150 and 300 micrograms C-type natriuretic peptide on adrenocorticotropin, cortisol, and prolactin release stimulated by 100 micrograms corticotropin-releasing hormone and on cardiovascular parameters in 8 healthy male volunteers. Compared with placebo, 300 micrograms C-type natriuretic peptide significantly (P < 0.05) enhanced the stimulation of cortisol (area under curve (arbitrary units): 520 +/- 35 vs 651 +/- 55) and prolactin (area under curve: 29 +/- 3 vs 37 +/- 5). Adrenocorticotropin levels were increased, but the differences did not reach statistical significance (maximum increment: 27 +/- 4 vs 36 +/- 2 pg/ml). C-type natriuretic peptide at a dose of 150 micrograms had no clear effect on these hormones and C-type natriuretic peptide also produced no cardiovascular or subjective effects. Our data suggest stimulatory effects of C-type natriuretic peptide on corticotropin-releasing hormone-induced hormone release and offer further evidence for a complex role of different natriuretic peptides in endocrine regulation.

Effects of mirtazapine on growth hormone, prolactin, and cortisol secretion in healthy male subjects.

In the present study the effects of acute PO-administration of 15 mg mirtazapine on the growth hormone (GH), prolactin (PRL), and cortisol (COR) secretion were examined in eight physically and mentally healthy male subjects, compared to placebo. Mirtazapine is a new antidepressant agent which does not inhibit the reuptake of norepinephrine or serotonin but is an antagonist of presynaptic and, presumably, postsynaptic alpha 2-receptors as well as an antagonist of postsynaptic 5-HT2 and 5-HT3-receptors. After insertion of an i.v. catheter, blood samples were drawn 1 h prior to the administration of mirtazapine or placebo, at time of application, and during the time of 4 h after application in periods of 30 min. Plasma concentrations of GH, PRL, and COR were determined in each blood sample by double antibody RIA methods. The area under the curve (AUC) value was used as parameter for the GH, PRL, and COR response. With respect to GH and PRL secretion, mirtazapine did not show any effects in comparison with placebo. However, in all subjects, the COR concentrations were remarkably lower after mirtazapine compared to placebo, the difference being obvious in the mean value graphs 60 min after the application up to the end of the measurement period. The t-test for paired samples revealed a highly significant difference (P < 0.01) in COR-AUC-values between the mirtazapine group (mean COR-AUC: 1558.07 micrograms/100 ml x 240 min) and the placebo group (mean COR-AUC: 2698.86 micrograms/100 ml x 240 min). Further studies have to elucidate the question whether the demonstrated inhibition of COR secretion after application of 15 mg mirtazapine is caused by central or peripheral effects of this substance.

The combined dexamethasone-CRH test before and after repetitive transcranial magnetic stimulation (rTMS) in major depression.

BACKGROUND: Hypothalamic-pituitary-adrenocortical (HPA) dysregulation assessed by the combined dexamethasone corticotropin releasing hormone test (DEX/CRH test) has been demonstrated to normalize after successful antidepressant pharmacotherapy. Here, we investigated whether repetitive transcranial magnetic stimulation (rTMS) also leads to a normalization of HPA system activity in depressed patients. METHODS: Thirty-seven medication free patients suffering from a major depressive episode (DSM-IV) underwent a DEX/CRH test before and after 13 daily sessions of left prefrontal rTMS in an open trial. RESULTS: There was an overshoot of CRH-induced cortisol release that was not affected by rTMS treatment. Postdexamethasone cortisol levels prior to CRH challenge decreased in responders after rTMS treatment, whereas no change of CRH-induced adrenocorticotropic hormone (ACTH) and cortisol release in responders or nonresponders was observed. CONCLUSIONS: The persisting HPA system hyperactivity after rTMS suggests a high risk for relapse and therefore argues for an immediate maintenance therapy in patients responding to this treatment.

Buspirone and lorazepam in the treatment of generalized anxiety disorder in outpatients.

In this double-blind, placebo-controlled 10-week trial, the anxiolytic properties of the nonbenzodiazepine buspirone were compared with the benzodiazepine lorazepam and placebo in 125 outpatients with generalized anxiety disorder according to DSM-III. After a 3- to 7-day wash-out period, patients were allocated at random to receive orally 3 x 5 mg buspirone (n=58), 3 x 1 mg lorazepam (n=57), or placebo (n=10) over a 4-week period. The study also comprised a 2-week taper period and a 4-week placebo-control period to assess the stability of clinical improvement. The patient's clinical state was estimated on entry and at weekly intervals by general practitioners using the Hamilton Rating Scale for Anxiety (HAM-A) and Clinical Global Impression (CGI) assessment and by a self-rating scale (State Trait Anxiety Inventory X2=STAI-X2). Lorazepam treatment resulted in descriptively, but not significantly, greater improvement on the Hamilton Rating Scale for Anxiety during the whole treatment (week 0-4) and taper period (week 5, 6) than did buspirone. After treatment with active drugs had been discontinued, the 4-week placebo control period showed buspirone-treated patients to display a stability of clinical improvement, while the symptoms of lorazepam-treated patients worsened at week 7-10. Both buspirone and lorazepam were more efficacious in reducing anxiety symptoms than placebo during the treatment and taper period; however, in contrast to the active drugs (buspirone, lorazepam), patients of the placebo group showed further clinical improvement during the control period, especially in the HAM-A score, so differences between placebo and active drugs became smaller at the end of the study.

Evidence for an association between a G-protein beta3-gene variant with depression and response to antidepressant treatment.

Abnormal signal transduction pathways have been implicated in the pathogenesis of bipolar disorder and major depression. G-proteins are key elements of these pathways in the regulation of cellular responses by transmission of signals from receptors to effector proteins. In recent years several studies have reported altered levels and activities of G-protein alpha subunits in depressive patients. A recently identified polymorphism of a G-protein beta3 subunit (C825T) has been shown to be associated with increased signal transduction and ion transport activity. Therefore, we investigated whether this Gbeta3 polymorphism is associated with affective disorders or with the response to antidepressant treatment in 88 depressive patients (10 bipolar disorder, 78 major depression) compared with 68 schizophrenic patients and 111 healthy controls. We found a significantly higher frequency of the T allele in depressive patients than in healthy controls (genotype: chi2 = 9.571, df = 2, p = 0.008; alleles: p = 0.004, OR = 1.87, 95% CI 1.23-2.84; Fisher's exact test, two sided) and schizophrenic patients (genotype: chi2 = 8.037, df = 2, p = 0.018; alleles: p = 0.009, OR = 1.94, 95% CI 1.99-3.14; Fisher's exact test, two sided). We also found a statistical significant association between TT homozygosity and response to antidepressant treatment after four weeks (p = 0.01). The results of this study suggest that the investigated G-protein beta3 subunit seems to be a susceptibility factor for major depression and maybe even for bipolar disorder, but not for schizophrenia. Further, the presence of the T allele could be an indicator for treatment response.

Sleep deprivation and hypothalamic-pituitary-adrenal (HPA) axis activity in depressed patients.

In the present study we investigated HPA axis activity in depressed patients treated with partial sleep deprivation (PSD) in order to identify endocrinological characteristics related to PSD responsiveness. Thirty-three drug-free patients (14 men, 19 women) suffering from major depression according to DSM-IV criteria were treated with PSD. Response to PSD was defined as a reduction of at least 30% according to the 6-item version of the Hamilton Depression Scale (6-HAMD). Subsequently, the combined dexamethasone-suppression/CRH-stimulation test (DEX/CRH test) was performed. Patients were pretreated with 1.5 mg dexamethasone (DEX) at 23:00 h and challenged with 100 microg corticotropin-releasing hormone (CRH) the following day. Postdexamethasone cortisol concentrations (before CRH administration) served as parameters for the DST status (dexamethasone suppression test). The cortisol stimulation after CRH was used as measurement for the DEX/CRH test status. Of the depressive patients, 54.5% (18 out of 33) responded to PSD. DST suppressors (postdexamethasone cortisol levels < 15 ng/ml) showed a significantly greater reduction in 6-HAMD scores after PSD than DST nonsuppressors. Furthermore, a significant negative correlation between postdexamethasone cortisol levels and reduction in 6-HAMD scores after PSD could be established. However, there was no relationship between the cortisol stimulation following CRH challenge and response to PSD. Although the combined DEX/CRH challenge test is a more sensitive marker for HPA axis dysregulation in depression than the standard DST, the negative feedback of the HPA system reflected by the DST status is apparently more closely associated with response to partial sleep deprivation in major depressive disorder.