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BACKGROUND: In a recent publication we reported the existence of around 11 (to 15) 'elementary syndromes' that may combine in various ways, rather like 'building blocks', to explain the wide range of psychiatric symptoms. 'Bridge symptoms' seem to be responsible both for combining large sets of symptoms into elementary syndromes and for combining the various elementary syndromes to form one globally connected network structure. AIM: To discuss the implication of these findings for clinical practice. METHOD: We performed a network analysis of symptom scores. RESULTS: Elementary syndromes provide a massive simplification of the description of psychiatric disease. Instead of the more than 300 categories in DSM-5, we now need to consider only a handful of elementary syndromes and personality domains. This modular representation of psychiatric illnesses allows us to make a complete, systematic and efficient assessment of patients and a systematic review of treatment options. Clinicians, patients, managerial staff and insurance companies can verify whether symptom reduction is taking place in the most important domains of psychopathology. Unlike classic multidimensional methods of disease description, network models of psychopathology can be used to explain comorbidity patterns, predict the clinical course of psychopathology and to designate primary targets for therapeutic interventions. CONCLUSION: A network view on psychopathology could significantly improve everyday clinical practice.

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The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus-pituitary-adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.

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The neuropeptide vasopressin is centrally involved in the regulation of social behaviour and response to stress. We previously found support for a subcategory of depression defined by above-normal plasma vasopressin (AVP) concentration. This subcategory is validated by a positive family history of depression and correlating plasma AVP and cortisol concentrations. The data support the validity of above-normal plasma AVP concentration as a genetically determined biological marker for a subcategory of depression. The aim of the present study was to test whether above-normal plasma AVP concentration in depression is related to personality characteristics reflecting a specific social behaviour style. The data of 78 patients from a previously investigated sample were reanalysed. Fifty-eight patients were available after 2 years, 15 of whom with initially above-normal plasma AVP. The dimensions of the Temperament and Character Inventory (TCI) were scored, with particular focus on the dimensions of Cooperativeness (CO) and Reward-dependence (RD). Normative subjects and other depressed subjects were used as controls. After full remission, patients with initially above-normal AVP had low CO compared with normal and patient controls. During depression, these patients had both low CO and low RD compared with normal controls and low RD compared with patient controls. Low CO is a presumably premorbid trait and reduced RD a state-dependent characteristic in depression with above-normal plasma AVP. The low CO further supports the validity of above-normal plasma AVP concentration as a genetically determined biological marker for a subcategory of depression.

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BACKGROUND: It should be possible to improve the diagnosis of endogenous or melancholic depression by applying Jaspers' multidimensional model of clinical symptoms, by considering the role of vasopressinergic activity in dysregulated stress reactions and by referring to Cloninger's personality model. METHOD: The strategy of Robins and Guze is used to develop diagnostic concepts. Melancholic depression according to DSM-IV criteria is converted into a mixture of basic symptom dimensions and this mixture is investigated for its possible links with familial depression, time needed for complete recovery, plasma vasopressin-concentration, correlated plasma vasopressin- and cortisolconcentrations, and features of temperament and character. RESULTS: Two subtypes were found. One is a highly anxious-retarded subtype, with slow recovery, a correlation between vasopressin and cortisol, low pre-morbid self-directedness and a positive family history of depression; the other is a subtype with an above-normal plasma vasopressin concentration, an anxious-retarded phenotype without an intensity threshold, correlated vasopressin- and cortisol-concentration, low pre-morbid cooperativeness and a positive family history of depression. CONCLUSION: A multidimensional description of clinical symptoms and personality makes it possible to integrate pathophysiological aspects into new diagnostic concepts.

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BACKGROUND: Anxious-retarded depression is a two-dimensionally defined subcategory of depression derived from DSM-IV melancholia. It is related to increased plasma vasopressin, correlative plasma vasopressin and cortisol levels, and a positive family history. We now explored its relation with outcome. METHODS: Seventy depressed patients were included to follow-up for two years. Outcome was defined by time until full-remission. Cox regression analyses were used to compare anxious-retarded and non-anxious-retarded patients, as well as melancholic and non-melancholic patients. RESULTS: Anxious-retarded depression had poor outcome. LIMITATIONS: The number of patients was relatively small. CONCLUSION: The poor outcome of anxious-retarded depression further supports its validity.

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Earlier work has shown that plasma vasopressin levels of depressed patients were higher than those of healthy controls. The aim of the present study was to determine whether plasma vasopressin levels were correlated to parameters of the circadian rhythm. Forty-one patients with major depression and twenty-five controls participated in a case-control design under natural circumstances in a field study to investigate plasma vasopressin levels three times daily, circadian motor activity, and the 24-h periodicity of body temperature for five consecutive 24-h periods. Temperature measurements consisted of at least five, but mostly six or more measurements every 24 h. Twenty-two percent of the patients, but none of the controls lacked 24-h periodicity of body temperature. In melancholic patients increased vasopressin levels in plasma correlated with a weak 24-h periodicity of body temperature. The role of vasopressin is discussed in the light of the present findings.

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BACKGROUND: A Dutch cohort of predominantly out-patient DSM-III-R major depressive patients was followed for 3 to 5 years after start of treatment in a psycho-neuro-endocrinological prediction study. The study design permitted description of the course of remissions, relapses and recurrences. METHODS: Pharmacological treatment was standardized, psychotherapy was tailored to the needs of the patient, follow-ups were done monthly until 3 years or more after the initial recruitment. RESULTS: After 9 months 49% of the patients had reached full remission and 45% were in partial remission. During the following 3 to 5 years 82% of the patients had reached a period of full remission. Sixteen per cent of the patients needed 2 years or more before full remission. A relapse or recurrence rate of 41% within 5 years was found. Patients with residual symptoms relapsed particularly in the first 4 months after remission, while patients without residual symptoms recurred mainly after 12 months after remission. Previous depressive episodes and psychoticism predicted relapse. Psychomotor retardation at inception predicted a longer time to partial remission. CONCLUSION: In most cases, major depression is a seriously impairing episodic disease. This is also true for a sample of predominantly out-patients treated at a university clinic.

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BACKGROUND: The aim of the study was to search for the existence of, and define, a possible relationship between performance in neuropsychological tests and baseline concentrations of plasma cortisol, vasopressin and oxytocin in medication-free patients with a major depressive episode. METHODS: Measures of depression and anxiety were obtained and a neuropsychological battery was presented. Blood for neuropeptide analysis was drawn by venepuncture at 8.00, 16.00 and 23.00 h. RESULTS: The melancholic patients performed less well on the neuropsychological battery than did the non-melancholic patients, but these differences could be accounted for by the severity of the illness. Global intellectual functioning was negatively correlated with mean baseline plasma concentrations of cortisol. Patients with high mean plasma vasopressin concentrations remembered more auditory presented words in the delayed recall test and produced more intrusions in the visual word learning list than did patients with low or normal mean plasma vasopressin concentrations. No association was found between neuropsychological performance and plasma concentrations of oxytocin. CONCLUSIONS: Our findings support the hypothesis that elevated baseline plasma cortisol concentrations are related to cognitive impairment in depressed patients and the hypothesis that the neuropeptide vasopressin independently enhances memory, directly or indirectly through increasing arousal and attention.

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BACKGROUND: Previously, we found that mean plasma concentrations of arginine vasopressin (AVP), but not of oxytocin (OT), were higher in depressed patients than in healthy controls. Plasma AVP concentrations were positively correlated to clinically rated psychomotor retardation. To further explore this previously reported relation we studied psychomotor retardation by means of an activity monitor, which is a more fine-focused and more objective instrument to analyze motor retardation than a clinical rating scale. METHODS: Plasma AVP and OT concentrations, and day- and nighttime wrist activity were measured in 48 in- and outpatients with major depression and 30 healthy controls during a period of 5 consecutive days and nights. RESULTS: Principal components analysis revealed three components of motor activity: motor activity during wakefulness, motor activity during sleep, and the awake/sleep time ratio. In patients and controls an inverse relationship between plasma AVP concentrations and motor activity during wakefulness was found. Patients with elevated AVP plasma levels showed increased motor activity during sleep. CONCLUSIONS: These results suggest that high plasma AVP levels are related to the clinical picture of daytime psychomotor retardation and nighttime motor activity in major depression. Mean plasma OT concentrations were not related to measures of motor activity.

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Mentally healthy subjects show increased plasma concentrations of the neuropeptides, arginine vasopressin (AVP) and oxytocin (OT), under conditions of stress, but data are lacking about plasma concentrations of AVP and OT in patients with major depression. We thus assessed plasma concentrations of AVP and OT in patients with major depression (n = 52) and healthy controls (n = 37). Mean plasma AVP concentrations were higher in the group of depressed patients than in controls. A subgroup of 16 patients showed very high levels of plasma AVP, but no other feature differentiating this subgroup from the other patients was found. In-patients showed higher plasma AVP levels than out-patients, and melancholic patients had higher plasma AVP levels than did nonmelancholic patients. Plasma AVP levels were slightly related to psychomotor retardation and significantly inversely to neuroticism. Patients' plasma OT concentrations had a wider range than in controls. AVP and AVP-mediated functions may be a factor in the clinical picture of depression, possibly by influencing the activity of the hypothalamic-pituitary-adrenal axis.

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Hypertonic hemolysis was increased in patients with a manic episode (n = 6, mean NaCl concentration in mol/L at which 50% of the erythrocytes was hemolyzed (H50) 3.24 +/- 0.10), compared to healthy controls (n = 12, mean H50 3.43 +/- 0.13) (p < or = 0.02) and patients with a nonaffective psychotic disorder (n = 15, mean H50 3.42 +/- 0.18) (p < or = 0.02). Compared to these two control groups, hypertonic hemolysis was decreased in patients with a severe depressive episode (n = 8, mean H50 3.62 +/- 0.19) (p < or = 0.05 and p < or = 0.02, respectively). Within the total depressed patient group, the patients with an increased genetic vulnerability (n = 8, mean H50 3.68 +/- 0.16) showed a decreased hypertonic hemolysis compared to the other depressed patients (n = 14, mean H50 3.40 +/- 0.16) (p < or = 0.002).

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AIM: Translation of a specific instrument to measure psychomotor retardation, the "Widlöcher Retardation Rating Scale" and validation of this Dutch translation (Widlöcher remmingsschaal, WRS). METHOD: In three separate studies, we studied reliability (n = 26), concurrent and divergent validity (n = 25) and predictive validity (n = 28) of the WRS. In- and outpatients with a depressive disorder or schizophrenia participated, and scores on the WRS were compared with those on the Montgomery Asberg Depression Rating Scale (MADRS) and retardation items of the Comprehensive Psychopathological Rating Scale (CPRS). RESULTS: The internal consistency was good (Cronbach alpha = 0.86), interrater reliability was sufficient to good, the correlation between the sumscores of both raters was r = 0.84, n = 23, p <0.01 and the kappa's were between 0.23 and 0.80. Convergent and divergent validity showed in comparing the correlation between the sum scores on the WRS and the CPRS retardation items (r = 0.91, n = 25, p < 0.01 ) with the correlation between the sumscores on the WRS and the MADRS (r = 0.40, n = 25, p = 0.1). The decrease of the sum scores on the WRS after two weeks of treatment with antide-pressants predicted remission after six weeks. A subgroup of the patients who were not in remission after six weeks, showed a predominance of retardation signs over mood disturbances. The same clinical picture was seen in a group of patients with a chronic disorder. CONCLUSION: De Widlöcher Retardation Rating Scale in this Dutch translation is a usefull instrument to measure psychomotor retardation. The connection between remaining retardation symptoms and longterm prognosis deserves further investigation.

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Both the classification based on independent psychiatric categories as well as the concept of an underlying 1-dimensional hierarchy of syndromes are insufficiently valid. At symptom level we previously found 5 factor-analytical components representing 6 dimensions of psychopathology. Rasch analysis based on the prevalence of signs and symptoms now demonstrates the presence of hierarchic patterns in each of these dimensions. Manic, psychotic and rare neurotic symptoms, being the negative instances of the 1-dimensional hierarchy, contribute to high rates of hierarchic patterns in this multidimensional hierarchic model. Depending on the dimension tested, 5% to 13% of the patterns were nonhierarchic.

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