Metabolic/inflammatory/vascular comorbidity in psychiatric disorders; soluble epoxide hydrolase (sEH) as a possible new target.

The common and severe psychiatric disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are associated with inflammation, oxidative stress and changes in peripheral and brain lipid metabolism. Those pathways are implicated in the premature development of vascular and metabolic comorbidities, which account for considerable morbidity and mortality, including increased dementia risk. During endoplasmic reticulum stress, the soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory fatty acid epoxides generated by cytochrome p450 enzymes into their corresponding and generally less anti-inflammatory, or even pro-inflammatory, diols, slowing the resolution of inflammation. The sEH enzyme and its oxylipin products are elevated post-mortem in MDD, BD and schizophrenia. Preliminary clinical data suggest that oxylipins increase with symptoms in seasonal MDD and anorexia nervosa, requiring confirmation in larger studies and other cohorts. In rats, a soluble sEH inhibitor mitigated the development of depressive-like behaviors. We discuss sEH inhibitors under development for cardiovascular diseases, post-ischemic brain injury, neuropathic pain and diabetes, suggesting new possibilities to address the mood and cognitive symptoms of psychiatric disorders, and their most common comorbidities.

Impact of chronically street homeless tenants in congregate supportive housing.

New initiatives to house chronically street homeless (CSH) adults have led to increasing proportions of this population living in congregate supportive housing, but little is known about the impact of this shift on supportive housing programs. The present multisite, mixed-methods study examined service utilization and lease compliance among 52 chronically street homeless and 46 long-term shelter stayer (LTSS) adults during their first 12 months in congregate supportive housing. Quantitative analysis of administrative data revealed that CSH tenants used significantly more service resources than LTSS tenants, including more advocacy, escorting, and psychiatric treatment and more assistance with financial, housing, and mental and physical health issues. The 2 groups did not differ significantly on measures of lease compliance. Qualitative focus groups with CSH tenants, service provider staff, and property management staff all indicated that existing supportive housing services are suitable for this population, although some adjustments, additional resources, or both, may be indicated.

Estimated prevalence of the seasonal subtype of major depression in a Canadian community sample.

OBJECTIVE: To examine estimates of lifetime prevalence of seasonal affective disorder (SAD) in Toronto, Ontario. METHOD: Random telephone numbers were generated for the city of Toronto, and 781 respondents completed a telephone interview. Trained nonphysician interviewers conducted all interviews, which involved structured questions for diagnosing major depression. Patterns of symptom change across seasons were evaluated to establish a diagnosis of SAD according to DSM-III-R criteria. RESULTS: Correcting for sex and age, the prevalence of SAD defined by DSM-III-R criteria was 2.9% (95% CI, 1.7% to 4.0%), and the overall lifetime prevalence of major depression in the sample was 26.4% (95% CI, 23.3% to 29.4%). Some subjects were contacted for a follow-up interview conducted in person; the positive predictive value for the diagnosis of major depression for the telephone interview was 100%, and the negative predictive value was 93%. CONCLUSIONS: The seasonal subtype of depression represents 11% of all subjects with major depression, suggesting that SAD is a significant public health concern. The telephone interview demonstrated adequate reliability, indicating that it is appropriate for epidemiological surveys of this nature.

Impaired distractor inhibition on a selective attention task in unmedicated, depressed subjects.

BACKGROUND: Impaired distractor inhibition may contribute to the selective attention deficits observed in depressed patients, but studies to date have not tested the distractor inhibition theory against the possibility that processes such as transient memory review processes may account for the observed deficits. A negative priming paradigm can dissociate inhibition from such a potentially confounding process called object review. The negative priming task also isolates features of the distractor such as colour and location for independent examination. METHOD: A computerized negative priming task was used in which colour, identification and location features of a stimulus and distractor were systematically manipulated across successive prime and probe trials. Thirty-two unmedicated subjects with DSM-IV diagnoses of non-psychotic unipolar depression were compared with 32 age, sex and IQ matched controls. RESULTS: Depressed subjects had reduced levels of negative priming for conditions where the colour feature of the stimulus was repeated across prime and probe trials but not when identity or location was the repeated feature. When both the colour and location feature were the repeated feature across trials, facilitation in response was apparent. CONCLUSIONS: The pattern of results supports studies that found reduced distractor inhibition in depressed subjects, and suggests that object review is intact in these subjects. Greater impairment in negative priming for colour versus location suggests that subjects may have greater impairment in the visual stream associated with processing colour features.

Is self-criticism unique for depression? A comparison with social phobia.

BACKGROUND: This study further examined the diagnostic specificity of the self-critical personality dimension, as measured by the Depressive Experiences Questionnaire (DEQ; Blatt et al., 1976. The Depressive Experiences Questionnaire. Yale University Press, New Haven). METHODS: Patients with major depression (n=26) were compared to social phobia patients (n=32). RESULTS: Depressed patients scored significantly higher on the DEQ Self-Criticism dimension. However, when current level of depressed mood was controlled for, self-criticism was not a significant predictor of diagnostic status. Further, the level of DEQ self-criticism reported by patients with social phobia was almost three times greater than the level reported in an earlier diagnostic specificity study with panic disorder patients [Bagby et al., 1992. Diagnostic specificity of the dependent and self-critical personality dimensions in major depression. J. Affect. Disord. 26, 59-64]. LIMITATIONS: Only one measure of self-criticism was used in this study, and the research design was cross-sectional rather than prospective. CONCLUSIONS: Self-criticism is not unique to major depression, and this personality dimension may be implicated in other forms of psychopathology [Blatt, 1991. A cognitive morphology of psychopathology. J. Nerv. Ment. Dis. 179, 449-458]. Some cognitive features believed to play an important role in depression may also be salient in persons with social phobia.

Mexiletine in treatment-resistant bipolar disorder.

BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of mexiletine, a medication with antiarrhythmic, anticonvulsant and analgesic properties, in treatment-resistant bipolar disorder patients. METHODS: Twenty subjects with rapid-cycling bipolar disorder who had failed to respond or were intolerant to lithium, valproic acid and carbamazepine were entered into the 6-week, open label study. Subjects were followed on a weekly basis for dosing of mexiletine, blood levels, and completion of the Hamilton Depression Rating Scale (HAM-D) and the Manic State Rating Scale (MSRS). "Burden of Mood Symptoms" (BMS) was calculated by combining scores for the HAM-D and MSRS. RESULTS: Thirteen subjects (10 female, 3 male), mean age 41 years (S.D.=7.6), and mean duration of illness 20 years (S.D.=7.7) completed the study. The dose range of mexiletine was 200-1200 mg/day. Full response (>/=50% reduction in BMS) was seen in 46% of the subjects, and a partial response (25-49% reduction in BMS) in 15%. Of note, 5/5 subjects with a mixed or manic state demonstrated a full or partial response. LIMITATIONS: This study has an open label design, and a small number of subjects. CONCLUSIONS: Mexiletine may be effective and safe in patients with highly treatment-resistant, chronic bipolar disorder. Randomized, controlled trials are required to confirm the current results.

Suicidal ideation in major depression: sex differences and impact of comorbid anxiety.

BACKGROUND: Being female and having comorbid anxiety are both thought to increase suicidality in patients with major depression. Whether these effects are independent or related to severity of depression is not known. METHOD: We conducted a retrospective review of 533 patients (190 men, 343 women) with major depression at the time of assessment. RESULTS: Suicidal ideation was present in 57.8% of all patients, and 43.2% of all patients had a lifetime anxiety disorder. Significantly more women than men experienced suicidal ideation, and both men and women with a lifetime anxiety disorder were more likely to be suicidal. Age and severity of depression did not account for these results. CONCLUSIONS: In patients with a current major depression, being female and having a lifetime anxiety disorder increase suicidality independently of one another and independently of severity of depression.

Do depressed subjects who have failed both fluoxetine and a tricyclic antidepressant respond to the combination?

BACKGROUND: Recent evidence suggests that the combination of fluoxetine and desipramine may provide a rapid and effective treatment for depression. METHOD: The current study evaluated 13 subjects with DSM-III-R nonpsychotic major depression who had previously failed either desipramine or imipramine and who were currently unsuccessfully treated with fluoxetine. Desipramine or imipramine was added to fluoxetine and Hamilton Rating Scale for Depression (HAM-D) scores, Beck Depression Inventory (BDI) scores, and plasma tricyclic levels were monitored for 3 weeks. RESULTS: Of the 13 subjects, 7 (54%) had a greater than 40% decline in HAM-D scores and 4 of these (31%) had 50% or greater decline in HAM-D. At week 3, responders (767 +/- 282 nmol/L) had a significantly higher mean tricyclic level as compared with nonresponders (515 +/- 95 nmol/L, F = 25.1, p < .0001), and change in BDI scores was significantly correlated with tricyclic level (r = -0.60, p < .05). CONCLUSION: These findings suggest that in some subjects the positive clinical effect of combining fluoxetine and a tricyclic antidepressant may be related to the plasma levels of the tricyclic compound.

Selective alteration of personality in response to noradrenergic and serotonergic antidepressant medication in depressed sample: evidence of non-specificity.

Recent investigations suggest that serotonergic mechanisms modulate dimensions of personality, in particular decreases in Anger-Hostility and increases in Affiliation. None of these studies, however, demonstrated a specific serotonergic effect on personality, as other neurotransmitter systems have not been assessed for their impact on these personality dimensions. In this study, 76 depressed outpatients were treated with either the noradrenergic antidepressant desipramine (n = 38) or a selective serotonin re-uptake inhibitor (paroxetine or sertraline) (n = 38) over a period of 8-14 weeks. Personality scores were measured pre- and post-treatment using the revised NEO Personality Inventory, which measures five basic dimensions of personality, with subscales assessing Anger-Hostility and Affiliation (Gregariousness). There was a significant decrease in Neuroticism and Anger-Hostility, and a significant increase in Extraversion and Gregariousness following antidepressant treatment. Although changes in neuroticism and extraversion were significantly correlated with change in depression severity, Anger-Hostility and Gregariousness personality scores were not. Therefore, changes in these personality traits were not attributable to a non-specific effect of medication on changes in depression severity. There were no significant differences in personality change scores between the antidepressant treatment groups. Thus, while antidepressants may have a direct effect on neurochemical pathways relevant to personality, independent of changes in depression severity, these effects cannot be directly or specifically attributed to a serotonergic mechanism.

Relationship between antidepressant partial and nonresponse and subsequent response to antidepressant augmentation.

OBJECTIVE: To evaluate the relationship between the degree of antidepressant nonresponse and subsequent response to lithium and triiodothyronine (T3) augmentation. METHOD: This is a retrospective analysis of data combined from two previous controlled studies of lithium and triiodothyronine augmentation of tricyclic antidepressants. RESULTS: There was no difference in the rate of augmentation response between partial and nonresponders to tricyclic antidepressant treatment. CONCLUSIONS: Augmentation response does not appear to be related to the degree of nonresponse to the preceding antidepressant trial.

Rumination and distraction in major depression: assessing response to pharmacological treatment.

BACKGROUND: Response style theory of depression (RST) predicts that individuals who ruminate in response to their depressed mood will suffer an amplification and prolongation of that mood, whereas individuals who engage in distraction responses will alleviate and attenuate their depressed mood. RST has been shown to predict prolonged depression in samples of non-clinical, untreated individuals with mild to moderate depression but has not been tested in samples of depressed patients undergoing treatment. OBJECTIVE: In this preliminary investigation we examined: (1) whether RST predicts non-response to pharmacotherapy with outpatients suffering from major depression, and (2) whether distractive and ruminative responses are associated with clinical variables hypothesized to be associated with them. METHODS: Eighty-nine depressed outpatients being treated with standard antidepressant pharmacotherapy were administered the Response Style Questionnaire, a scale designed to measure rumination and distraction, prior to treatment. RESULTS: Distraction, but not rumination, predicted change in depression severity over the course of treatment and overall treatment outcome. Neither rumination nor distraction was associated with previous number of depressive episodes or duration of current depressive episode. DISCUSSION: These results provide only partial support for RST as a predictor of treatment response. Future investigations are needed to determine if rumination and distraction are predictive of recurrent depressive episodes in recovered depressed patients. LIMITATIONS: As the data in this study was retrieved from a clinical database, the conclusions of this report must be viewed tentatively. Replication with other clinical samples is needed.

Impact of suppression of thyroxine on folate status during acute antidepressant therapy.

Antidepressant response is associated with a rise in red cell folate (RCF) and a reduction in thyroxine (T4). Since T4 levels may directly influence folate status, it is possible that the increase in folate with recovery results from the decline in T4. To examine the possible role of thyroid hormones in the observed change in folate status during antidepressant therapy, T4, tri-iodothyronine (T3) or placebo was given in a double-blind fashion to 25 depressed subjects at the initiation of standard antidepressant treatment. Folate levels and mood [using the Hamilton Rating Scale for Depression (HAMD), Montgomery-Asberg Depression Rating Scale (MADRS) and Beck Depression Inventory (BDI)] were measured at baseline and following 4 weeks of therapy. Using MANOVA for repeated measures, there was a significant interaction between response status and time for vitamin and hormone levels. Univariate analysis confirmed that response was associated with a significant change in red cell folate, but not a significant change in T4 or T3. The mean change in RCF across the 4-week trial was significantly greater in the 14 responders than the 11 non-responders. Change in RCF, and not change in T4 or T3, was significantly correlated with change in HAMD and contributed significantly to the variance in change in HAMD. These results suggest that change in RCF is closely tied to response to antidepressant treatment, and this effect is not inhibited by exogenous administration of thyroid hormones or the changes in T4 that the exogenous hormones produce. These findings support the possible role of folate, independent of thyroid function, in the modulation of mood.

Hormonal and subjective responses to intravenous m-chlorophenylpiperazine in women with seasonal affective disorder.

BACKGROUND: There is emerging evidence of serotonergic dysfunction in patients with seasonal affective disorder (SAD). We examined central serotonergic function in female patients with SAD (fall-winter pattern) by means of neuroendocrine and subjective responses to the postsynaptic serotonin receptor agonist m-chlorophenylpiperazine. METHODS: Using a double-blind, randomized, placebo-controlled design, we assessed neuroendocrine and subjective responses to m-chlorophenylpiperazine (0.1 mg/kg intravenously) and placebo in 14 unmedicated female patients with SAD in the depressed state and 15 female normal controls. All testing was done in the fall-winter months and during the follicular phase of the menstrual cycle. Plasma prolactin and cortisol levels were used as neuroendocrine measures, while subjective responses were assessed by means of visual analog scales of 10 mood states. RESULTS: On the basis of net responses to m-chlorophenylpiperazine (placebo effects subtracted from drug effects), patients with SAD exhibited blunted prolactin responses and less sadness than normal controls in response to the drug. When order of presentation of drug and placebo was taken into consideration, altered "calm" and "high" responses were also found in the patient group. CONCLUSION: Evidence of dysfunction at or downstream to central serotonergic receptors in female patients with SAD confirms and extends findings from previous research.

Does the chronological relationship between the onset of dysthymia and major depression influence subsequent response to antidepressants?

OBJECTIVE: To determine whether the chronological relationship between the onset of dysthymia and the onset of the first major depression influences treatment outcome in patients with double depression (DD). METHOD: Clinical and outcome measures previously collected in 77 consecutive outpatients who presented with major depression and who had pre-existing dysthymia (i.e. DD) were reviewed for the current retrospective analysis. Subjects had been administered the Schedule for Affective Disorders and Schizophrenia, Lifetime Version (SADS-LV), and the Hamilton Rating Scale for Depression (HAM-D) prior to open antidepressant treatment and after 5 and 12 weeks of therapy. Response was defined as a 50% decline in HAM-D to score +/-8. Subjects were divided into those with the onset of dysthymia before the first major depression (DysB; n = 47), onset of dysthymia after major depression (DysA; n = 12) and those with onset of both condition within 2 years of each other (INDIST; n = 18). RESULTS: There were no significant differences between these three groups in baseline HAM-D. However, DysA subjects had significantly higher mean HAM-D scores than the DysB subjects at week 5 and the INDIST subjects at week 12. Response rates at week 12 were lower in subjects with DysA (33%) as compared with DysB (57%; Fisher's exact test, P = 0.06) and INDIST (78%; Fisher's Exact test P = 0.02). CONCLUSIONS: These findings suggest that the onset of the first episode of dysthymia after the first major depressive episode (i.e. DysA) may adversely affect response to subsequent treatments in patients with DD.

Hormonal and subjective responses to intravenous meta-chlorophenylpiperazine in bulimia nervosa.

BACKGROUND: Several lines of evidence point to serotonergic abnormalities in patients with bulimia nervosa (BN). Our goal was to further examine central serotonergic function in bulimic patients using neuroendocrine and subjective responses to the postsynaptic serotonin receptor agonist meta-chlorophenylpiperazine (mCPP). METHOD: Using a double-blind, randomized, placebo-controlled design, we assessed neuroendocrine and subjective responses to intravenous mCPP (0.1 mg/kg) and placebo in 16 patients with BN, free of medication, and 14 normal control subjects. Plasma prolactin and cortisol levels were used as neuroendocrine measures, whereas subjective responses were measured using a visual analog scale of 10 different mood states. RESULTS: Compared with controls, the BN group exhibited blunted prolactin and net cortisol responses following mCPP challenge. Subjective responses, while preliminary, also differed between groups on items related to anxiety, calmness, and altered self-awareness. CONCLUSION: Evidence of dysfunction at or downstream of central serotonergic receptors in BN confirms and extends findings of prior research.

Thyroid hormone levels before unsuccessful antidepressant therapy are associated with later response to T3 augmentation.

Thyroid function was measured in 24 patients before antidepressant treatment, and following failure of acute desipramine treatment but before triiodothyronine (T3) augmentation. While all measures of thyroid function were within the euthyroid range, eventual T3 augmentation responders were found to have, prior to any antidepressant treatment, lower levels of TSH and higher levels of thyroxine (T4) and free thyroxine index (FTI) than non-responders. This suggests that T3 augmentation may be of particular importance in subjects with comparatively elevated levels of serum FTI.

Bipolar disorder, unipolar depression and the Five-Factor Model of personality.

We examined differences between personality characteristics of euthymic bipolar disorder patients (BD) (n = 34) and recovered unipolar depressed patients (UD) (n = 74) using the taxonomy of the Five-Factor Model of personality (FFM) as measured by composite scales derived from the NEO Personality Inventory (NEO PI) and the revised NEO PI (NEO PI-R). Euthymic BD patients scored significantly higher on the Openness (O) dimension and the Positive Emotions facet of the E dimension than did recovered UD patients. For O, euthymic BD patients scored higher on the Feelings facet. These results suggest not only that euthymic BD patients are more likely to experience positive affects than recovered UD patients, but also that euthymic BD patients are more receptive to their positive and negative feelings than are recovered UD patients.

Seasonal and non-seasonal depression and the five-factor model of personality.

The purpose of this study was to compare the personality characteristics of patients with non-psychotic, major depression, seasonal subtype (SAD) to patients with non-psychotic, major depression, without seasonality (non-SAD). The patients were consecutive referrals to a university-affiliated mood disorders outpatient clinic. The personality characteristics were assessed using the five-factor model of personality (FFM) as measured by the revised NEO Personality Inventory (NEO PI-R). Patients were assessed during the acute depressive episode. Controlling for severity of depression, differences were found on only one of the five dimensions, with the SAD patients (n = 43) scoring significantly higher on the Openness dimension than non-SAD patients (n = 57). Based on these results we infer SAD patients may represent a psychologically distinct subgroup of depressed patients-more imaginative, more emotionally sensitive and likely to entertain unconventional ideas than non-SAD patients. This personality constellation may explain why individuals with SAD are more sensitive to and may amplify the mild dysphoria typically associated with winter months.