Reply to Dr. Schmidt's remarks on the paper of H.M. van Praag "Can stress cause depression?".
Explore the source record for details and available documents.
Depression↗
Biomedical subjects
H M van Praag
Publications and source records attributed to H M van Praag.
The cognitive paradox in posttraumatic stress disorder: a hypothesis.
Posttraumatic stress disorder (PTSD) is characterized by a peculiar cognitive state. The traumatic event(s) are partly hypermemorized, partly blurred, whereas the ability to store and retrieve new information is impaired. The question is raised as to what the biological systems might be that 'carry' this cognitive paradox. Four possible candidate systems are discussed. It is concluded that understimulation of the corticosteroid receptors, particularly the glucocorticoid receptors (GRs), overactivity of the noradrenaline (NA) and vasopressin (VA) systems, and deficits in the 5-Hydroxytryptamine (5-HT) system, particularly the 5-HT(1A) system, could generate a cognitive syndrome similar to the one observed in PTSD. A dual hypothesis is launched holding that (a) in PTSD, downregulation of the 5-HT(1A) receptor system is the primary lesion, while the other dysfunctions mentioned are subsidiaries and that (b) underdevelopment of or damage to the 5-HT(1A) receptor system will make a person PTSD-prone.
Animals↗
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-hydroxytryptamine (5-HT) and the stress hormones, this question was answered in the affirmative, based on the following two considerations: 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. 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.
Animals↗
Stress and suicide are we well-equipped to study this issue?
Stress almost always precedes suicidality. Stress also is a harbinger of a variety of psychiatric disorders, most notably depression. Depression is a major precursor of suicidal behavior. Consequently, the question of whether stress is an epiphenomenon or a decisive factor in the causation of suicidality and (certain forms of) mood disorders is crucial. Certainty about this question can only be obtained when it can be demonstrated that stress phenomena may induce changes in brain functioning similar to the ones supposedly associated with suicidality and with (certain forms of) depression. Since the phenomenology of stress syndromes, as well as their emotional intensity, are highly variable, careful definition of the stress syndrome to be studied is a first requirement. In studies into the significance of stress in the occurrence of suicidality and depression, this degree of finesse has not been achieved. The major shortcomings have been discussed. These should be systematically addressed to provide research into the relation between stress and psychopathology with the necessary acuity.
Humans↗
Dissociable hormonal, cognitive and mood responses to neuroendocrine challenge: evidence for receptor-specific serotonergic dysregulation in depressed mood.
Fifteen patients with major depression, dysthymia, or anxiety disorder with depressed mood (DSM-IV diagnoses) and 16 controls received single oral doses of 0.5mg/kg metachlorophenylpiperazine (m-CPP), a 5-HT(2C) agonist, and 10 mg ipsapirone, a 5-HT(1A) agonist, according to double-blind, placebo-controlled, cross-over design. The groups' levels of cortisol, adrenocorticotrophic hormone (ACTH) and prolactin did not differ at baseline. Both 5-HT agonists significantly elevated cortisol, ACTH, and prolactin. The cortisol response to ipsapirone was significantly blunted in major depression and dysthymia patients. Neuroendocrine responses to m-CPP did not differ between groups, but m-CPP selectively increased profile of mood states (POMS) depression and tenseness scores in patients. No effects of ipsapirone on mood were found. However, ipsapirone impaired memory performance in controls, but tended to improve memory performance in patients. The results support the evidence for both hypothalamic and possibly hippocampal 5-HT(1A) receptor desensitisation and non-hypothalamic, 5-HT(2C) receptor sensitisation, probably fronto-cortical, in patients with major depression and dysthymia.
Adrenocorticotropic Hormone↗
Why has the antidepressant era not shown a significant drop in suicide rates?
Over the past decades the rate of completed suicide has remained quite stable, whereas that of suicide attempts 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 and since antidepressants have been increasingly used over the years 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. This paper discusses a number of possible explanations that not only deserve, but are definitely in need of systematic investigation.
Antidepressive Agents↗
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 criteria 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.
Adult↗
Serotonin disturbances and suicide risk: is aggression or anxiety the interjacent link?
Explore the source record for details and available documents.
Aggression↗
Nosologomania: a disorder of psychiatry.
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.
Brain↗
A controlled study of temporal lobe structure volumes and P300 responses in schizophrenic patients with persistent auditory hallucinations.
Recent studies of cerebral pathology in patients with schizophrenia have focused on symptomatological and electrophysiological correlates of reduced temporal lobe structure volumes. Volume deficits of the left superior temporal gyrus have been correlated with auditory hallucinations as well as to left-sided P300 amplitude reduction. However, caution is needed to interpret correlational data as evidence of a specific relationship. Therefore, a controlled study was undertaken on schizophrenic patients with and without auditory hallucinations. MRI-defined volumes of the left superior temporal gyrus and other temporal lobe structures were quantified from 3-mm coronal slices in 15 schizophrenic patients with chronic auditory hallucinations (hallucinators), 15 schizophrenic patients without auditory hallucinations (nonhallucinators) and 17 healthy controls. In all subjects a simple oddball paradigm was used to elicit P300 responses at temporal and centro-parietal electrode sites. No evidence was found for volume reductions of temporal lobe structures in the combined patient group compared with controls, or in the hallucinators compared with the nonhallucinators. The patients did show left P300 amplitude reduction compared with controls, particularly in the hallucinator group. Correlations between volumes of left temporal lobe structures and left P300 amplitudes were low and not significant. The results of the present study do not indicate that auditory hallucinations and associated abnormal electrophysiological activity are the consequence of atrophy of localized temporal lobe structures. However, replication in a larger sample of subjects is needed before firm conclusions can be drawn.
Adult↗
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.
Adolescent↗
Specificity of the tryptophan depletion method.
Thirteen healthy subjects were subjected to tryptophan (TRP) depletion, lysine (LYS) depletion, and a placebo condition in a double blind cross-over study. The aim of the study was to test the specificity of psychological effects induced by TRP depletion. Subjects ingested a 100 g amino acid mixture with or without TRP or LYS. Six hours later, plasma TRP levels had decreased by 77% in the TRP depletion test and LYS levels by 51% in the LYS depletion condition. After 6 h of TRP depletion, subjects reported significantly more tiredness and lowering of mood, compared to subjects in the placebo group, and memory performance declined. After 6 h of LYS depletion, no significant differences in mood and memory compared to placebo were found. We conclude that the effects of TRP depletion on mood and memory are specific for the depletion of TRP and are not caused by the depletion of an amino acid per se. This supports the hypothesis that TRP depletion affects brain serotonin metabolism and not only brain protein metabolism in general.
Adolescent↗
Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation.
Serotonin (5-hydroxytryptamine; 5-HT) circuits may play a role in cognitive performance, particularly in learning and memory. Cognitive impairment is often seen in depressed patients, in whom 5-HT turnover in the brain is thought to be lowered. A possible human pharmacological model to study the involvement of the serotonergic system in cognitive impairment is to reduce central 5-HT synthesis through L-tryptophan depletion in healthy subjects. In this study, the cognitive effects of tryptophan depletion were assessed and whether genetically or developmentally determined vulnerability factors were predictive of the cognitive impairment induced by tryptophan depletion. Sixteen healthy volunteers with a positive family history of depression and 11 without were given 100 g of an amino acid mixture with or without tryptophan, according to a double-blind, cross-over design. Tryptophan depletion specifically impaired long-term memory performance in all subjects: delayed recall performance, recognition sensitivity, and recognition reaction times were significantly impaired after tryptophan depletion relative to placebo. Short-term memory and perceptual and psychomotor functions were unchanged. There were no differences between groups with a positive and a negative family history for depression. On the basis of these results, it is concluded that tryptophan depletion specifically impairs long-term memory formation, presumably as a result of an acute decrease in 5-HT turnover in the brain.
Adolescent↗
On what evidence should education concerning depression be based?
Disease depresses. As a consequence depressed mood is almost ubiquitous in medicine. This is as true for physical disorders as it is for mental disorders. Depressed mood, moreover, seldom comes alone but is generally accompanied by other troublesome phenomena. In other words, the transition from distress towards depression is a gradual one, at least from the clinical point of view. One could therefore rightfully assume, that most physicians will be well versed in diagnosing and treating depression. Regrettably that is not the case. Depression is an under-diagnosed and under-treated disorder. Hence sophisticated educational programs to enhance the diagnostic and therapeutic skills of those frequently encountering depressive and depressed patients are much in need. The Dep Relief program is a CD-ROM program well suited for this purpose. It is wide-ranging, evidence-based, easily adaptable to various audiences and scrutinized by a panel of international experts. In short, it is an important tool to disseminate up-to-date information about mood disorders.
Depressive Disorder↗
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.
Adult↗
Effects of tryptophan depletion on anxiety and on panic provoked by carbon dioxide challenge.
Results of several studies suggest that anxiety is under serotonergic control. We studied the influence of tryptophan depletion on generalized anxiety and on the response to a 35% carbon dioxide (CO2) challenge. Fifteen healthy male volunteers received both a mixture of amino acids without tryptophan and a placebo mixture under double-blind conditions. The tryptophan-free mixture led to an 80% decrease in blood tryptophan levels compared to the placebo. There was a significant increase in anxiety on the Spielberger Anxiety Inventory and a trend towards more tension on the Profile of Mood States-'tension' items, both of which were interpreted as increased nervousness. Furthermore, a significant increase in neurovegetative panic symptoms occurred after the CO2 challenge. We conclude that the serotonergic system is causally involved in anxiety-related mechanisms and that it may be worth pursuing the role of tryptophan depletion on CO2-induced panic in patients with anxiety disorders.
Adult↗
Anxiety and increased aggression as pacemakers of depression.
The concept of a serotonin (5-HT)-related, anxiety and/or aggression-driven, stressor-precipitated depression is formulated and discussed. The serotonergic disturbances found in some depressed individuals, particularly those with lowered CSF 5-HIAA, are linked to the anxiety and aggression components of the depressive syndrome. In this type of depression, called 5-HT-related depression, dysregulation of anxiety and/or aggression is hypothesized to be primordial and mood-lowering is a derivative phenomenon. In other words, this is a group of anxiety/aggression-driven depressions. The author submits that the serotonergic impairment in certain types of depression is a trait phenomenon, i.e. it persists during remission. This disturbance makes the individual susceptible to perturbation of anxiety and aggression regulation. Anxiety and (overt or suppressed) anger are core constituents of the stress syndrome. Thus the serotonergic disturbance will induce a heightend sensitivity to stressful events, i.e. the latter will induce stress phenomena, including anxiety and anger, more readily than normal. The latter psychological features induce lowering of mood, and thus 'drive' the patient into a full-blown depression. Furthermore, it is predicted that anxiolytics and serenics (i.e. anti-aggressive drugs) that act via normalization of serotonergic circuits will exert an antidepressant effect in 5-HT related depression, in addition to their therapeutic actions in anxiety disorders and states of increased aggressiveness, respectively. The exact nature of the serotonergic impairment in 5-HT-related depression has yet to be elucidated.
Affect↗
Inflationary tendencies in judging the yield of depression research.
The mood around mood disorders is one of optimism. Progress in diagnosis and treatment is generally felt to be considerable. Zeitgeist rests on convictions. In this case the main supporting convictions are the following: depression is a very frequent disorder and its diagnosis has improved greatly; we dispose of more or less specific agents to control depression: biological psychiatric research made great strides, particularly in the field of affective disorders; new antidepressants are properly tested before being clinically introduced. Each of these convictions is critically analysed. It is concluded that each of these claims is either a half-truth or not true. Apparently reality awareness and reality testing are out of balance. This harms the prospects of research, particularly biological research. Ways to avoid the stalemate are discussed.
Antidepressive Agents↗