Herman M. Van Praag

Mood effects of 24-hour tryptophan depletion in healthy first-degree relatives of patients with affective disorders

BACKGROUND Acute tryptophan (TRP) depletion was evaluated in healthy volunteers with or without a family history of major affective disorder (FH+ versus FH-). METHODS Twenty-seven subjects (16 FH+, 11 FH-) received 100 g of an amino acid mixture with and without TRP according to a placebo-controlled, double-blind cross-over design and a diet devoid of TRP for the next 24 hours. RESULTS The ratio TRP/large neutral amino acids declined to 22% of baseline values after 6 hours, and increased during the night reaching 85% of baseline after 24 hours. Overall, after 6 hours, TRP depletion lead to a lowering of mood, but after 24 hours, these changes were no longer detected. Mood changes and gastrointestinal side effects were significantly more evident in FH+ subjects than in FH- subjects. CONCLUSIONS Our data support the hypothesis that subjects with a positive family history for depression are predisposed to increased vulnerability to the adverse consequences of serotonergic imbalance.

Can stress cause depression

The central issue raised in this paper is: can stress cause depression? Phrased more precisely: can stress cause brain disturbances thought to underlie (certain forms of) depression or particular components of the depressive syndrome. Focussing on 5-HT and the stress hormones, this question was answered in the affirmative, based on the following two considerations: (1) changes in the 5-HT and stress hormone systems produced by sustained stress, mimic to a substantial extent the disturbances in these systems that may be observed in depression; (2) substantial evidence indicates that the 5-HT and stress hormone disturbances in depression are of pathophysiological significance and not merely a consequence of the depressed state or a product of stress generated by the depressed state. Furthermore, the question was raised whether a depression type could be identified particularly stress-inducible. This question, too, was answered in the affirmative. The depression type in question was named anxiety/aggression-driven depression and characterized on three levels: psychopathologically, biologically and psychologically. Preferential treatment of this depression type was discussed. In studying stress-inducible depression biological depression research should shift focus from depression per se to the neurobiological sequelae of stress. Treatment of stress-inducible depressions and particularly its prevention should be geared towards reduction of stress and stress sensitiveness, utilising both biological and psychological means.The central issue raised in this paper is: can stress cause depression? Phrased more precisely: can stress cause brain disturbances thought to underlie (certain forms of) depression or particular components of the depressive syndrome. Focussing on 5-HT and the stress hormones, this question was answered in the affirmative, based on the following two considerations: (1) changes in the 5-HT and stress hormone systems produced by sustained stress, mimic to a substantial extent the disturbances in these systems that may be observed in depression; (2) substantial evidence indicates that the 5-HT and stress hormone disturbances in depression are of pathophysiological significance and not merely a consequence of the depressed state or a product of stress generated by the depressed state. Furthermore, the question was raised whether a depression type could be identified particularly stress-inducible. This question, too, was answered in the affirmative. The depression type in question was named anxiety/aggression-...

Nosologomania: A Disorder of Psychiatry

Summary: For many years, psychiatry has been devoted to nosology. This disease model conceives psychiatric conditions as discrete entities, with a particular pathophysiology and predictable relations between phenomenology, course and outcome. This model witnessed a true revival with the introduction of the DSM III. Its foundations, however, are weak. Many of the disorders, so delineated, are of doubtful validity. This is demonstrated, taking major depression as a paradigm. The nosological way of thought, moreover, carries with it harmful side effects, such as proliferation of new diagnoses, magnification of comorbidity, border problems and neglect of the factor psychogenesis. The question is raised of a possible alternative disease model and the reaction form model is considered to be just that. This model is defined and discussed and the conclusion is reached that it fits clinical practice and biological research better than the nosological disease model. A reconstruction of the diagnostic process in psychiatry is proposed, in such a way that it gains in sophistication and at the same time creates opportunities for comparative studies of the merits of the nosological and the reaction form model for psychiatric practice and research.Summary: For many years, psychiatry has been devoted to nosology. This disease model conceives psychiatric conditions as discrete entities, with a particular pathophysiology and predictable relations between phenomenology, course and outcome.This model witnessed a true revival with the introduction of the DSM III. Its foundations, however, are weak. Many of the disorders, so delineated, are of doubtful validity. This is demonstrated, taking major depression as a paradigm. The nosological way of thought, moreover, carries with it harmful side effects, such as proliferation of new diagnoses, magnification of comorbidity, border problems and neglect of the factor psychogenesis.The question is raised of a possible alternative disease model and the reaction form model is considered to be just that. This model is defined and discussed and the conclusion is reached that it fits clinical practice and biological research better than the nosological disease model.A reconstruction of the diagnostic process in psychi...

Anxiety/aggression - driven depression: A paradigm of functionalization and verticalization of psychiatric diagnosis

Abstract 1. A new subtype of depression is proposed, named: anxiety/aggression-driven depression. 2. The psychopathological, psychopharmacological and biochemical evidence on which this construct is based, is being discussed. 3. Selective postsynaptic 5-HT1A agonists together with CRH and/or cortisol antagonists are hypothesized to be a specific biological treatment for this depression type, in conjunction with psychological interventions to raise the stressor-threshold and to increase coping skills. 4. The development of this depression construct has been contingent on the introduction of two new diagnostic procedures, called functionalization and verticalization of psychiatric diagnosis. 5. These procedures are explained and it is stressed that they are essential to psychiatric diagnosing, in order to put this process on a scientific footing.

Serotonin syndrome after challenge with the 5-HT agonist meta-chlorophenylpiperazine

meta-Chlorophenylpiperazine (mCPP) is a non-selective 5-HT-receptor agonist/antagonist that is used extensively in psychiatry to assess central serotonergic function. We report on three patients who developed symptoms of the serotonin syndrome when they participated in an mCPP (0.5 mg/kg body weight p.o.) challenge test as part of a research protocol. They had relatively high plasma mCPP concentrations. The syndrome did not occur in normal volunteers who had comparable plasma concentrations of mCPP. Investigators should be aware of the possible occurrence of the serotonin syndrome after a single oral dose of mCPP.

Panic-associated suicidal and aggressive ideation and behavior

Some investigators have noted an increased incidence of suicidal ideation and attempts in individuals with panic attacks. The direct temporal relationship between the panic state and suicidal thoughts and behaviors has not been well elucidated however. Furthermore, although aggressive behavior is often manifested in individuals with suicidal behavior, the relationship between aggression and panic has received little attention. The aim of this study was to assess the frequency and type of reported suicidal and aggressive ideation and behaviors that occur during the panic state in patients with panic disorder. In order to evaluate the contribution of depression, individuals with pure (i.e. uncomplicated) panic disorder were compared with individuals who had comorbid panic and major depression. Nineteen patients with a diagnosis of pure panic disorder and 28 patients with comorbid panic plus major depression were included in the study. All patients were given the Panic, Suicide and Aggression Scale (PSAS), a questionnaire specifically designed to assess reported suicidal and aggressive thoughts and behaviors that occur during panic attacks. Other scales given to all patients included overall measures of impulsivity, suicide risk and violence risk. Patients with pure panic disorder reported high rates of suicidal and aggressive ideation and behavior during panic. The presence of comorbid depression resulted in a doubling of the rate of reported panic-associated suicidal ideation, property destruction and assaults, and a five-fold increase in the rate of homicidal ideation. The rate of reported suicide attempts was equal in the pure panic and comorbid group. There were also high correlations in all panic patients between measures of panic-associated suicide and aggression with the psychometric measures of impulsivity, suicide risk and violence risk.

Neuroendocrine response to meta-chlorophenylpiperazine and ipsapirone in relation to anxiety and aggression.

The aim of this study was to establish the association of trait anxiety and anger with hormonal responses to acute challenges with two different 5-HT agonists in a mixed group of patients with depressed mood. Fifteen patients and 16 normal controls received single oral doses of 0.5 mg/kg meta-chlorophenylpiperazine (MCPP), a 5-HT(2C) agonist, and 10 mg of ipsapirone, a 5-HT(1A) agonist, according to a double-blind, placebo-controlled, cross-over design. Dutch-adapted versions of the Spielberger Trait-Anxiety Inventory and the Spielberger Trait-Anger Scale administered assessed at study entry. Hormonal responses, expressed as drug-placebo differences, to MCPP and ipsapirone (changes in cortisol, ACTH and prolactin) were measured. Blood levels of MCPP and ipsapirone were also measured. MCPP and ipsapirone elevated cortisol, ACTH and prolactin. In the patient group, there was a significant correlation between trait anxiety and the cortisol response to MCPP. No significant correlations between the ACTH and prolactin responses to MCPP and levels of anxiety/anger were observed in the patients. No significant correlations could be established between levels of anxiety/anger and hormonal responses to ipsapirone. This study provided evidence for an association between measures of anxiety/aggression and the hormonal response to MCPP. Thus, in subjects with depressed mood, high levels of anxiety suggest a higher probability of 5-HT(2C) disturbances.

Avoiding and Managing Anticholinergic Effects of Antidepressants

SummaryThe anticholinergic actions of antidepressants can have undesirable effects that affect patient’ well-being. These effects can be peripheral or central in origin. The most frequently occurring anticholinergic effects are sedation, psychomotor and memory impairment, dry mouth and blurred vision.One of the most prominent central anticholinergic effects is that on cognitive function. Effects that occur after a single dose consist of sedation (lowering of activation and arousal), psychomotor impairment [slowed sensorimotor processes that can adversely affect operational manual control (e.g. car driving)] and memory disturbances (forgetfulness, inability to store and retrieve information and recall events). After long term administration, tolerance to sedation and psychomotor impairment is likely to develop, but not to memory disturbances.Elderly patients can be assumed to be particularly sensitive to central anticholinergic effects on cognitive functioning and also to peripheral anticholinergic effects such as dryness of the mouth and loss of accommodation in the eye. It is argued that for this reason, prescription of the classical tricyclic antidepressants should be avoided in elderly depressed patients. The second generation, or atypical antidepressants, and the newer selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) are considered to be useful alternatives to tricyclics in elderly patients. These drugs possess greatly diminished anticholinergic activity, although the atypical antidepressants are very sedative and the effects of long term administration of SSRIs on cognition have rarely been studied. Another approach to avoiding anticholinergic effects is to use reversible inhibitors of monoamine oxidase (MAO)-A (RIMAs), such as moclobemide. These agents can attenuate scopolamine-induced cognitive dysfunction.An important point in managing and avoiding anticholinergic effects of antidepressants is to realise that not all so-called ‘anticholinergic effects’ are actually cholinergically determined. Many other pharmacological effects of antidepressants, such as antihistaminergic and anti-α1-adrenergic effects, can induce sedation, cognitive and psychomotor impairment, blurred vision and dry mouth.

A stubborn behaviour: The failure of antidepressants to reduce suicide rates

SummaryOver the past decades the rate of completed suicide has remained quite stable, that of suicide attempts even seems to have increased (to the extent it has been studied in defined regions). These are puzzling observations, since depression is the major suicide precursor and since antidepressants over the years have been increasingly used in the treatment of depression. These observations have not attracted sufficient attention, possibly because they do not accord with consensus opinions about depression treatment in psychiatry today. In this paper a number of possible explanations are discussed. They not only deserve but are definitely in need of systematic investigation.Summary Over the past decades the rate of completed suicide has remained quite stable, that of suicide attempts even seems to have increased (to the extent it has been studied in defined regions). These are puzzling observations, since depression is the major suicide precursor and since antidepressants over the years have been increasingly used in the treatment of depression. These observations have not attracted sufficient attention, possibly because they do not accord with consensus opinions about depression treatment in psychiatry today. In this paper a number of possible explanations are discussed. They not only deserve but are definitely in need of systematic investigation.

Clinical correlates of depression following myocardial infarction.

Objective: Post-MI depression increases mortality, especially in the first 18 months after MI. Identifying patients at risk for post-MI depression is therefore important. In the present study we investigated possible correlates for post-MI depression on an a priori basis. Method: Based on the literature, four clinically easily attainable variables were selected as possible correlates for post-MI depression. These were prescription of benzodiazepines during acute hospitalization, cardiac complications during acute hospitalization, history of depression, and not being able to stop smoking within six months after MI. A consecutive cohort of 173 first-MI patients was screened with the SCL-90 depression scale and DSM-III-R citeria for major depression. Of this cohort 35 depressed patients were compared with 35 non-depressed post-MI patients, matched for gender, age, and severity of MI. Results: In univariate analyses, complications during hospitalisation (OR = 2.14; CI = 0.89–5.14), prescription of benzodiazepines (OR = 3.67; CI = 1.11–12.1), history of depression (OR = 3.0; CI = 0.87–10.4), and not being able to stop smoking (OR = 4.5; CI = 1.11–18.2) were clinical correlates for post-MI depression. Multivariate analyses showed that none of these variables were independent of the others in predicting depression. Conclusions: A number of easily measurable patient characteristics identify those MI-patients at risk of post-MI depression. Further investigations should focus on the predictive value of these factors in relation to post-MI depression.