Intravenous anti-obsessive agents: a review.

Oral antidepressants are currently the first-line pharmacotherapy for obsessive-compulsive disorder (OCD), but response rates can often be low and with delayed onset of therapeutic action. Some reports have suggested that intravenous (i.v.) anti-obsessive agents may have faster onset of action and greater efficacy. A Medline search was conducted for all reports pertaining to the use of i.v. antidepressants for OCD. Search terms included: 'intravenous', 'clomipramine', 'selective serotonin reuptake inhibitor', 'tricyclic', 'citalopram', 'sertraline', 'paroxetine', 'fluvoxamine', 'SSRIs' and 'intravenous antidepressants'. Relevant articles mainly investigated clomipramine (CMI) with one open trial examining citalopram. Intravenous agents appear to be well-tolerated, particularly in those who have failed oral agents, and may act more rapidly to produce initial clinical response, although this advantage is often lost over time. Preliminary evidence suggests subgroups of patients with severe treatment-refractory OCD may benefit from i.v. anti-obsessive agents, CMI and citalopram. Larger, controlled trials are needed for more definitive conclusions.

Symptom-onset dosing with citalopram in the treatment of premenstrual dysphoric disorder (PMDD): a case series.

The efficacy and tolerability of symptom-onset dosing with citalopram in the treatment of premenstrual dysphoric disorder (PMDD) was evaluated in an open trial. Eight outpatients, aged 18-45 years and diagnosed with PMDD, were treated with 10-20 mg of citalopram from the start of premenstrual symptoms until the onset of menses. Primary efficacy variables were the premenstrual tension scale (PMTS-O) and the clinical global impression of improvement (CGI). Treatment was associated with significant improvement in PMDD symptoms (p < 0.001).

Posttraumatic stress symptoms and salivary cortisol levels.

OBJECTIVE: This study assessed the relationship between posttraumatic stress symptoms and salivary cortisol levels after a severe ice storm. METHOD: Posttraumatic stress symptoms (Impact of Event Scale scores) and salivary cortisol levels were determined in 115 victims of an ice storm and in 27 healthy comparison subjects 1 month and approximately 1 year after the ice storm. RESULTS: One month after the storm, Impact of Event Scale scores for the victims (mean=20.31, SD=15.23) exceeded those of the comparison subjects (mean=5.30, SD=9.78) but were reduced approximately 1 year later (mean=14.01, SD=13.68). A quadratic relation was found to exist between Impact of Event Scale scores and cortisol levels. CONCLUSIONS: One month after the storm, cortisol levels were found to be elevated among the victims but were diminished among those with the highest Impact of Event Scale scores. This relationship was found not to exist approximately 1 year later.

Clinical guidelines for the treatment of depressive disorders. IV. Medications and other biological treatments.

BACKGROUND: The Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments partnered to produce clinical guidelines for psychiatrists for the treatment of depressive disorders. METHODS: A standard guidelines development process was followed. Relevant literature was identified using a computerized Medline search supplemented by review of bibliographies. Operational criteria were used to rate the quality of scientific evidence, and the line of treatment recommendations included consensus clinical opinion. This section, "Medications and Other Biological Treatments," is 1 of 7 articles that were drafted and reviewed by clinicians. Revised drafts underwent national and international expert peer review. RESULTS: Evidence-based recommendations are presented for 1) choosing an antidepressant, based on efficacy, tolerability, and safety; 2) the optimal use of antidepressants, including augmentation, combination, and switching strategies; 3) maintenance treatment; and 4) electroconvulsive therapy (ECT), light therapy, and additional somatic treatments. Evidence from metaanalyses is presented first, followed by conclusions from randomized controlled trials (RCTs) and, if appropriate, open-label data. CONCLUSIONS: There is significant evidence to support the role of selective serotonin reuptake inhibitors (SSRIs), novel agents, and classic agents in the treatment of major depressive disorder (MDD). There is also evidence to support the use of somatic treatments, including ECT and light therapy, for some patients with MDD. There is limited evidence for the use of specific medications to treat subtypes of MDD. There is emerging evidence to support augmentation and combination strategies for patients previously nonresponsive to medication.

Treatment of dysthymia with sertraline: a double-blind, placebo-controlled trial in dysthymic patients without major depression.

BACKGROUND: The selective serotonin reuptake inhibitor sertraline has been shown to be efficacious and well tolerated for the treatment of major depressive disorder. Relatively few trials, however, have examined the role of pharmacotherapy in dysthymia without concurrent major depression. The current investigation focuses on the use of sertraline for the treatment of dysthymia. METHOD: In this 12-week, multicenter, double-blind study, 310 patients with a DSM-III-R diagnosis of dysthymic disorder without concurrent major depression were randomly assigned to receive either sertraline (N = 158) or placebo (N = 152). Sertraline was initiated at a dose of 50 mg daily, with titration permitted to a maximum of 200 mg daily. The primary evaluation criteria were the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales. RESULTS: Mean percentage reductions for the intent-to-treat population in SIGH-SAD scores were 44.6% for the sertraline-treated group and 33.2% for the placebo-treated group (p = .03); MADRS scores, 43.6% and 33.0% (p = .02); and CGI-S scores, 32.8% and 22.8% (p = .02). A significantly greater proportion of the sertraline-treated group was classified as responders (defined for HAM-D and MADRS scores as a 50% score reduction and for CGI-I as a score of 1 or 2 by the final visit) and remitters (SIGH-SAD score < or = 8) relative to the placebo-treated group by the final visit. In addition, sertraline-treated patients experienced greater improvements in all 9 domains of the Battelle Quality of Life Questionnaire than placebo-treated patients did, with a significant difference observed in favor of sertraline in 8 of the 9 domains. The life satisfaction and social interaction quality of life domains showed significantly greater response in sertraline responders compared with placebo SIGH-SAD responders. Sertraline was well tolerated. Thirteen percent of the sertraline-treated group versus 8% of the placebo-treated group withdrew from therapy owing to adverse events (p = .14). CONCLUSION: Sertraline is efficacious and well tolerated in the short-term treatment of dysthymia without concurrent major depression.

Dysthymia: a review of pharmacological and behavioral factors.

Although dysthymia, a chronic, low-grade form of depression, has a morbidity rate as high as that of major depression, and increases the risk for major depressive disorder, limited information is available concerning the etiology of this illness. In the present report we review literature concerning the biological and characterological features of dysthymia, the effectiveness of antidepressant treatments, the influence of stressors in the precipitation and maintenance of the disorder, and both quality of life and psychosocial correlates of the illness. We also provisionally suggest that dysthymia may stem from disturbances of neuroendocrine and neurotransmitter functioning (eg, corticotropin releasing hormone and arginine vasopressin within the hypothalamus, or alternatively monoamine variations within several extrahypothalamic sites), and may also involve cytokine activation. The central disturbances may reflect phenotypic variations of neuroendocrine processes or sensitization of such mechanisms. It is suggested that chronic stressor experiences or stressors encountered early in life lead to the phenotypic neurochemical alterations, which then favor the development of the dysthymic state. Owing to the persistence of the neurochemical disturbances, vulnerability to double depression is increased, and in this instance treatment with antidepressants may attenuate the symptoms of major depression but not those of the basal dysthymic state. Moreover, the residual features of depression following treatment may be indicative of underlying neurochemical disturbances, and may also serve to increase the probability of illness recurrence or relapse.

Lymphocyte proliferation among major depressive and dysthymic patients with typical or atypical features.

BACKGROUND: Depressive illness may be associated with immune and cytokine alterations. However, data are unavailable concerning functional immune changes associated with chronic, low-grade depression (dysthymia). Moreover, the contribution of the neurovegetative features of depression (e.g., altered sleep, eating) to the immune alterations remains to be determined. METHODS: Mitogen-stimulated cell proliferation was assessed in major depressive and dysthymic patients exhibiting either typical or atypical features. In a subset of patients, lymphocyte proliferation was also assessed before and after pharmacotherapy to determine whether alleviation of symptoms would be accompanied by normalization of immune functioning. RESULTS: Lymphocyte proliferation was reduced to a greater extent among dysthymic than among major depressive patients. Among dysthymic patients reduced cell proliferation was evident irrespective of symptom typicality; however, among major depressive patients the contribution of neurovegetative features varied with the specific mitogen used. Symptom alleviation following antidepressant treatment was not accompanied by normalization of cell proliferation. LIMITATIONS: Patients received 12 weeks of antidepressant treatment, and more sustained therapy may be required for normalization of immune activity. As well, conclusions concerning normalization of immune functioning in drug-treated major depressive patients requires that a greater number of patients be assessed. CONCLUSIONS: As the immune variations were more pronounced in dysthymia than in major depression, chronicity of illness may be a pertinent factor in promoting immune disturbances. This does not exclude the possibility that depression is associated with immune activation, which then provokes suppression of other aspects of immunity. As well, it is conceivable that immune alterations indirectly contribute to the symptoms accompanying depressive state, although it does not appear that variations of lymphocyte proliferation are associated with neurovegetative status.

A prospective study of neuroendocrine and immune alterations associated with the stress of an oral academic examination among graduate students.

Stressful experiences may influence neuroendocrine, immune and cytokine functioning, as well as physical and psychological well being. The present prospective investigation assessed physiological and behavioral variations in anticipation of a critical oral academic examination among graduate students (i.e. related to a dissertation or comprehensive defense). Relative to matched control subjects, plasma cortisol levels were elevated among graduate students, especially females, 1 h prior to the oral examination, but not 6-8 weeks earlier (at about the time of the submission of the written document). In contrast, mitogen-stimulated (Con-A) lymphocyte proliferation was only reduced 6-8 weeks before the examination. Neither adrenocorticotrophic hormone (ACTH), prolactin, serum interleukin-1beta (IL-1beta) nor mitogen stimulated IL-1beta production was influenced at any time. Although, graduate students did not differ from controls with respect to perceived stress and feelings of mastery, they reported more frequent malaise (e.g. headaches, sore throat, fatigue) than did controls. The present findings suggest that during the course of lengthy anticipatory periods preceding a scheduled stressor, different stress-sensitive, situation-dependent biological processes may be engendered. It is further suggested that cortisol release is most closely aligned with immediate threats, while the immune alterations are sensitive to more distal events, or are subject to adaptation in response to a protracted stressor.

Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder.

There is evidence indicating that density of 5-HT2A receptors is altered in brain regions of depressed suicide victims and in platelets of suicidal subjects with major depression or schizophrenia. Recent studies have also shown an association between the allele C of 102T/C polymorphism in the 5-HT2A receptor gene and schizophrenia. The present investigation tested the hypothesis that the observed changes in 5-HT2A receptor density in platelets of patients with major depression are a trait rather than state phenomenon and are associated with the 102 C allele in 5-HT2A receptor gene in a sample of 120 patients with major depression and a group of 131 control subjects comparable with respect to age, sex, and ethnic background. The allele and genotype frequencies of 102T/C polymorphism in 5-HT2A receptor gene were compared between patients and control subjects and between suicidal and non-suicidal patient groups. The major finding of this study was a significant association between the 102 C allele in 5-HT2A receptor gene and major depression, chi(2) = 4.5, df = 1, P = 0.03, particularly in patients with suicidal ideation, chi(2) = 8.5, df = 1, P < 0.005. Furthermore, we found that patients with a 102 C/C genotype had a significantly higher mean HAMD item 3 score (indication of suicidal ideation) than T/C or T/T genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:56-60, 2000.

Obsessive-compulsive spectrum disorders: effective treatment with paroxetine.

OBJECTIVE: To examine whether, like pure obsessive-compulsive disorder, obsessive-compulsive spectrum disorders are treatable with a selective serotonin reuptake inhibitor (SSRI). METHOD: Case histories of patients prescribed paroxetine for compulsive collecting, skin-picking, and trichotillomania were reviewed. RESULTS: All patients were successfully treated with paroxetine. CONCLUSIONS: Obsessive-compulsive spectrum disorders may share a serotonin-related dysfunction, and SSRIs may prove effective in their treatment.

Treatment of primary dysthymia with group cognitive therapy and pharmacotherapy: clinical symptoms and functional impairments.

OBJECTIVE: This study assessed the efficacy of antidepressant treatment (sertraline) and group cognitive behavior therapy, alone or in combination, in primary dysthymia. The clinical features of dysthymia, as well as the functional impairments associated with the illness (e.g., quality of life, stress perception, coping styles), were evaluated. METHOD: Patients (N = 97) diagnosed with primary dysthymia, but no other current comorbid disorder, received either sertraline or placebo in a double-blind design over 12 weeks. In addition, a subgroup of the patients (N = 49) received a structured, weekly group cognitive behavior therapy intervention. RESULTS: Treatment with sertraline, with or without group cognitive behavior therapy, reduced the functional impairment of depression. The reductions were similar in the drug-cognitive therapy group and in subjects who received the drug alone. Furthermore, while group cognitive behavior therapy alone reduced the depression scores, this effect was not significantly greater than the effect of the placebo. The drug treatment also induced pronounced improvement in the functional measures, and in some respects these effects were augmented by group cognitive behavior therapy. Among patients who responded favorably to cognitive behavior therapy, the improvements in the functional measures were similar to those who responded to drug treatment, whereas such functional changes were not seen among patients who responded to placebo. CONCLUSIONS: Sertraline treatment effectively reduces the clinical symptoms and functional impairments associated with dysthymia. Although the group cognitive behavior therapy intervention was less effective in alleviating clinical symptoms, it augmented the effects of sertraline with respect to some functional changes, and in a subgroup of patients it attenuated the functional impairments characteristic of dysthymia.

The effect of acute tryptophan depletion and fenfluramine on quantitative EEG and mood in healthy male subjects.

BACKGROUND: Efforts to model putative serotonergic deficits associated with affective disorders have frequently involved acute tryptophan depletion (ATD) as a manipulation strategy aimed at lowering brain serotonin synthesis. In an attempt to widen the scope of the measurement probes used in these investigations, the central actions of ATD and a subsequent dose of fenfluramine were examined via utilization of quantitative electroencephalography (EEG) and mood ratings. METHODS: Electroencephalograms (EEG) and subjective mood ratings were assessed in 28 healthy men before and after double-blind ingestion of a tryptophan-depleting (T-) amino acid mixture, or a nutritionally balanced (B) amino acid mixture containing tryptophan, and again after a single-blind oral dose of D,L-fenfluramine hydrochloride (60 mg). RESULTS: Compared to the B mixture, the T- mixture reduced total plasma tryptophan by more than 75% 5 hours after ingestion. Tryptophan depletion was associated with a modest lowering of mood and a slowing of EEG as indicated by increases in delta amplitude. Fenfluramine caused no change in mood but increased fast wave (beta) activity in anterior recordings when administered after the T-, but not after the B mixture. CONCLUSIONS: Quantitative EEG measurements may be a promising method for studying the central mechanisms underlying serotonin-mediated changes in mood and behavior.

Circulating lymphocyte subsets in obsessive compulsive disorder, major depression and normal controls.

BACKGROUND: Obsessive compulsive disorder (OCD) shares several features with depressive illness (e.g., comorbidity, early escape from dexamethasone suppression, effectiveness of serotonergic pharmacotherapy). It was of interest to establish whether OCD, like major depression, was also associated with immune alterations, notably elevations of circulating natural killer (NK) cells. METHOD: Circulating lymphocytes were determined from morning blood samples taken from OCD and major depressive patients, as well as from age- and sex-matched controls. Stress perception and coping styles were evaluated in order to assess whether such variables accompanied the NK alterations. Finally, in a subset of patients, symptoms of the illness, stress/coping, and circulating lymphocytes, were also evaluated following 12 weeks of antidepressant medication (serotonergic reuptake inhibitor). RESULTS: The major depressive and OCD patients reported increased perception of day-to-day stresses, coupled with reliance on emotion focused coping styles. Moreover, circulating NK cells were elevated among male OCD and major depressive patients, whereas only a modest increase of NK cells was seen in female major depressives. Twelve weeks of medication alleviated depressive and OCD symptoms, and resulted in normalization of NK cells in the major depressives. However, in OCD patients the reduction of symptoms was not accompanied by significant variations of circulating NK cells. CONCLUSIONS: Although major depression and OCD are both accompanied by elevated circulating NK cells, at least in males, normalization of NK cells following treatment was only evident in depression. The persistent elevations of NK cells among male OCD patients may reflect either a trait characteristic of the illness, or symptom reduction and not true remission. LIMITATIONS: Although elevations of lymphocyte subsets in major depressive and OCD patients were observed, conclusions concerning immune status in OCD ought to be held in abeyance pending assessment of other indices of immune and cytokine functioning.

Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features.

Depression has been associated with both suppression and enhancement of various aspects of immune functioning. It was of interest to determine whether cytokine alterations associated with depression, including interleukin-1 (IL-1beta) and interleukin-2 (IL-2), were related to the neurovegetative symptom profile or to the chronicity of the illness. Circulating ACTH, cortisol, norepinephrine (NE) and epinephrine levels, and production of IL-1beta and IL-2 from mitogen-stimulated lymphocytes were assessed in classical major depression, atypical depression (ie, with reversed neurovegetative features), and dysthymia (chronic depression without comorbid major depression) with either typical or atypical profiles, as well as nondepressed control subjects. Among atypical depressives, plasma ACTH levels were elevated while cortisol was reduced relative to controls. Irrespective of neurovegetative profile, IL-1beta production was increased in dysthymic patients, and was highly correlated with age-of-onset and duration of illness. In contrast, IL-2 production was reduced in each of the groups, although less so among atypical major depressives. Moreover, IL-2 production in the depressive groups was directly related to plasma NE levels. While neither depressed mood per se nor neurovegetative features accounted for this effect, it seemed likely that chronicity of illness or age-of-onset were associated with cytokine alterations. Given that circulating cytokines influence neuroendocrine functioning, and may affect neurovegetative features, a role for interleukins may exist with respect to the pathophysiology of certain subtypes of depression.

Paraphrenia redefined.

BACKGROUND: Paraphrenia is a disorder similar to paranoid schizophrenia but with better-preserved affect and rapport and much less personality deterioration. It is now diagnosed relatively infrequently and is not listed in the current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) or International Classification of Diseases (ICD-10). However, it appears that some psychiatrists recognize the illness but label it "atypical psychosis," "schizoaffective disorder," or "delusional disorder" for lack of a better diagnostic category. Virtually no systematic research on paraphrenia has been conducted in the past 60 years. METHOD: The authors distinguish paraphrenia from "late paraphrenia," a diagnosis used mainly in the United Kingdom, and provide a neo-Kraepelinian description of paraphrenia that would be compatible with the formats of DSM-IV and ICD-10. Using a questionnaire adapted from this description, intake cases in 2 Canadian psychiatric centres (Ottawa [Ontario] and Dartmouth [Nova Scotia]) were surveyed. Cases of paraphrenia were distinguished from those of schizophrenia and delusional disorder and were examined at the time of intake and immediately prior to discharge. RESULTS: For logistical reasons, collecting a totally consecutive series was not possible. However, during an 18-month period, investigators in both centres identified 33 cases closely fitting paraphrenia. The outstanding features of these cases are enumerated, and an outline description of paraphrenia is derived. CONCLUSION: It is possible to define and recognize paraphrenia; it is a viable diagnostic entity. Further research would benefit paraphrenia and schizophrenia patients. Cases in this study have been coded to permit follow-up investigations.

Influence of acute tryptophan depletion on mood and immune measures in healthy males.

Depressive illness has been associated with variations of several aspects of immune functioning, as well as alterations of cytokine production in stimulated lymphocytes. In the present investigation we sought to determine whether pharmacologically-induced reductions of mood in healthy, male subjects would be associated with alterations in the levels of circulating IL-1 beta or IL-6 or to in vitro lymphocyte proliferation in response to T cell mitogens, PHA and Con A. Lowering tryptophan levels by means of a tryptophan-deficient amino acid mixture, which reduced plasma tryptophan and serotonin (5-HT) levels, produced a lowering of mood in a subset of male subjects (that had no personal or family history of depression) relative to subjects that received a balanced amino acid mixture. Correlational analyses revealed that the change of mood (particularly depression and anger) in subjects that received the tryptophan-free mixture was related to the extent of the tryptophan or 5-HT reductions. However, while fenfluramine administration resulted in recovery of tryptophan and 5-HT levels, this was not accompanied by recovery of mood. Furthermore, it was observed that the lowering of tryptophan levels and the reduced mood were not accompanied by variations of the cytokine levels or cell proliferation. Evidently, transient and modest alterations of 5-HT or mood induced by a tryptophan-free amino acid mixture were insufficient to promote variations of immune activity or circulating IL-1 beta or IL-6 levels. Even if depression were related to immune disturbances, the mood and 5-HT alterations associated with this type of manipulation may be too brief to promote immune changes comparable with those ordinarily associated with severe or chronic depressive illness.

Interleukin-1 beta production in dysthymia before and after pharmacotherapy.

BACKGROUND: Like major depression, dysthymia has been associated with elevated production of interleukin-1 (IL-1 beta) in mitogen-stimulated lymphocytes. In the present investigation, we assessed whether the elevated IL-1 beta production in dysthymic patients would normalize following treatment with sertraline. METHODS: The production of IL-1 beta was determined in dysthymic patients and in nondepressed control subjects. Patients then received 12 weeks of doses of either sertraline or placebo in a double-blind trial, after which cytokine production was again determined. RESULTS: Basal IL-1 beta was elevated in dysthymic patients relative to control subjects. Cytokine production was modestly correlated with the severity of symptoms and with the age of illness onset. Relative to placebo treatment, sertraline attenuated the symptoms of depression; however, this was not accompanied by normalization of IL-1 beta production. CONCLUSIONS: While dysthymia is associated with elevated IL-1 beta production, the failure for the cytokine to normalize following symptom alleviation suggests that either the IL-1 beta may be a trait marker of the illness, or that more sustained treatment is necessary to reduce cytokine production. Given the neuroendocrine and central neurochemical consequences of exogenously administered IL-1 beta, the possibility ought to be explored that increased IL-1 beta production may play a role in the pathophysiology of dysthymia.

A 12-week study comparing moclobemide and sertraline in the treatment of outpatients with atypical depression.

One hundred and ninety-seven outpatients with atypical depression [Atypical Depression Diagnostic Scale (ADDS) score=4] were randomized to 12 weeks of double-blind treatment with sertraline or moclobemide in a multicentre, parallel-group clinical trial. Patients were started on either 50 mg/day sertraline or 300 mg/day moclobemide. If the therapeutic response was not satisfactory after 4 weeks, the dose could be increased to either 100 mg/day sertraline or 450 mg/day moclobemide. Primary efficacy evaluations were the 29-item Hamilton Psychiatric Rating Scale for Depression (HAM-D) and the Clinical Global Impression of Improvement (CGI-I) response rate (much or very much improved) at study endpoint. Secondary efficacy evaluations included the ADDS, the Hamilton Anxiety Scale (HAMA), the Leeds Sleep Scale, and the Battelle Quality of Life Battery (BQOLB). In the analysis of the 172 patient efficacy-evaluable population, there was significant baseline to endpoint improvement in all primary and secondary efficacy assessments after treatment with either sertraline or moclobemide. At the endpoint, the proportion of responders on CGI-I, was 77.5% in the sertraline group and 67.5% in the moclobemide group (p=0.052). The baseline to endpoint mean 29-item HAM-D score decreased from 35.9 to 14.5 in the sertraline group and from 36.3 to 16.1 in the moclobemide group. Sertraline also resulted in a significantly (p < 0.05) greater degree of improvement at the endpoint, compared with moclobemide, in the proportion of remitters on the HAMA (total score < or = 7), ADDS Category IID (Rejection Sensitivity), Leeds Sleep Factor 4 (Integrity of Behaviour Following Awakening), and on three dimensions of the BQOLB (Energy/Vitality, Social Interaction and Life Satisfaction). There were no other significant differences between treatment groups. Overall, both medications were well tolerated. In this study, both sertraline and moclobemide improved the symptoms of atypical depression.

Influence of psychosocial, psychogenic and neurogenic stressors on several aspects of immune functioning in mice.

Analysis of stressor effects on immune functioning is complicated by the fact that the nature of the changes observed may be influenced by organismic factors (e.g., species, strain, age), the nature, severity and chronicity of the stressor, as well as the specific immune parameters being examined. It is demonstrated in the present investigation that in the highly reactive inbred BALB/cByJ mouse, the relatively hardy C57BL/6ByJ strain, as well as in the noninbred CD-1 strain, acute psychogenic (predator exposure) and neurogenic (footshock) stressors reduced splenic macrophage activity, and this effect was less marked after a chronic stressor. With protracted, but not transient, psychosocial disturbances (isolated housing) similar effects were seen, suggesting that the effect was not simply due to a change of the social mileau. The psychogenic and neurogenic stressors also enhanced LPS-stimulated lymphocyte proliferation in CD-1, but not in the inbred strains. However, isolated housing reduced both B and T cell proliferation, indicating that social isolation likely affects processes distinct from those of other stressors. Interestingly, when the aversiveness of the psychogenic stressor was increased (by decreasing the distance between the rat and the mouse) LPS-stimulated lymphocyte proliferation was reduced in the reactive BALB/cByJ strain, but increased in the hardy C57BL/6ByJ mice. This stressor, however, enhanced T cell proliferation in both strains of mice. It is suggested that analysis of stressor effects need to consider in greater detail the characteristics of the organism being stressed, as well as the characteristics of the stressor itself.