Robert G. Cooke

Vagus nerve stimulation for treatment-resistant depression: A randomized, controlled acute phase trial

BACKGROUND Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy. METHODS This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (>/=50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD(24)]). RESULTS At 10-weeks, HRSD(24) response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology - Self-Report (IDS-SR(30)), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events. CONCLUSIONS This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.

Antidepressant Monotherapy vs Sequential Pharmacotherapy and Mindfulness-Based Cognitive Therapy, or Placebo, for Relapse Prophylaxis in Recurrent Depression

CONTEXT Mindfulness-based cognitive therapy (MBCT) is a group-based psychosocial intervention designed to enhance self-management of prodromal symptoms associated with depressive relapse. OBJECTIVE To compare rates of relapse in depressed patients in remission receiving MBCT against maintenance antidepressant pharmacotherapy, the current standard of care. DESIGN Patients who met remission criteria after 8 months of algorithm-informed antidepressant treatment were randomized to receive maintenance antidepressant medication, MBCT, or placebo and were followed up for 18 months. SETTING Outpatient clinics at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, and St Josephs Healthcare, Hamilton, Ontario. PARTICIPANTS One hundred sixty patients aged 18 to 65 years meeting DSM-IV criteria for major depressive disorder with a minimum of 2 past episodes. Of these, 84 achieved remission (52.5%) and were assigned to 1 of the 3 study conditions. INTERVENTIONS Patients in remission discontinued their antidepressants and attended 8 weekly group sessions of MBCT, continued taking their therapeutic dose of antidepressant medication, or discontinued active medication and were switched to placebo. MAIN OUTCOME MEASURE Relapse was defined as a return, for at least 2 weeks, of symptoms sufficient to meet the criteria for major depression on module A of the Structured Clinical Interview for DSM-IV. RESULTS Intention-to-treat analyses showed a significant interaction between the quality of acute-phase remission and subsequent prevention of relapse in randomized patients (P = .03). Among unstable remitters (1 or more Hamilton Rating Scale for Depression score >7 during remission), patients in both MBCT and maintenance treatment showed a 73% decrease in hazard compared with placebo (P = .03), whereas for stable remitters (all Hamilton Rating Scale for Depression scores ≤7 during remission) there were no group differences in survival. CONCLUSIONS For depressed patients achieving stable or unstable clinical remission, MBCT offers protection against relapse/recurrence on a par with that of maintenance antidepressant pharmacotherapy. Our data also highlight the importance of maintaining at least 1 long-term active treatment in unstable remitters.

Anxious and non-anxious bipolar disorder

Eighty-one outpatients with bipolar disorder (BD) were grouped by SADS anxiety symptom scores (high vs. low) or diagnosis of generalized anxiety disorder, and/or panic disorder. BD patients with high anxiety scores were more likely to have suicidal behaviour (44% vs. 19%), alcohol abuse (28% vs. 6%), cyclothymia (44% vs. 21%) and an anxiety disorder (56% vs. 25%) with a trend toward lithium non-responsiveness. Diagnosis of an anxiety disorder was related only to high anxiety and lower GAS scores. Thus, anxiety may have similar clinical relevance in BD as it does in unipolar patients.

Relationship between the five-factor model of personality and unipolar, bipolar and schizophrenic patients

The purpose of this study was to examine personality differences among three different Axis I disorders-recovered patients with unipolar depression (n = 62), euthymic patients with bipolar disorder (n = 34), and patients with schizophrenia in the residual phase of their illness (n = 41) using the five-factor model of personality (FFM). The dimensions of the FFM-Neuroticism (N), Extraversion (E), Openness (O), Agreeableness (A), and Conscientiousness (C)-were measured with composite scores derived from the NEO Personality Inventory (NEO PI) and the Revised NEO Personality Inventory (NEO PI-R). While no group differences emerged on N or C, the bipolar patients scored significantly higher on the Positive Emotion facet (subscale) of E than the unipolar patients. The schizophrenic patients scored lower on the Feelings, Values and Actions facets of O than did the unipolar and bipolar patients. The unipolar patients scored higher on A than the schizophrenic patients.

A comparison of Tridimensional Personality Questionnaire dimensions in bipolar disorder and unipolar depression

The harm avoidance (HA) personality dimension has been hypothesized to be a vulnerability factor for unipolar depression (UD) but not for bipolar disorder (BD). The reported difference on HA scores between these diagnostic groups may have been compromised by the assessment of BD patients who had not fully recovered. To test the diagnostic specificity of elevated HA scores and to elucidate whether assumptions about differences between patients with UD or BD might be attributed to the lingering effects of mood state, the Tridimensional Personality Questionnaire (TPQ) was administered to recovered patients with either BD or UD and a nonpatient comparison group. Both patient groups scored higher on the HA dimension than the nonpatient comparison group, but the patient groups did not differ from one another on this dimension. Moreover, novelty seeking (NS) scores were elevated in subjects with BD compared with both UD patients and nonpatient subjects. These results suggest that high HA scores may be associated with a mood disorder diagnosis, whereas high NS scores may be associated with the BD subtype.

Comorbidity of obsessive compulsive disorder in bipolar disorder

The comorbidity of OCD and bipolar disorder has not been systematically examined. Therefore, we determined the frequency of patients meeting DSM-III criteria for OCD syndrome in a sample of 149 inpatients with DSM-III major affective disorder who had received a clinically reviewed structured diagnostic interview. The frequency of OCD syndrome was not significantly different between subjects with major depression (35.2%, n = 105) and bipolar disorder (35.1%, n = 37). This suggests that OCD is equally common in bipolar as in unipolar patients.

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.

Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder

Disturbed intracellular calcium (Ca2+) homeostasis has been implicated in bipolar disorder (BD). Reduced mRNA levels of the transient receptor potential Ca2+ permeable channel melastatin type 2, TRPM2, in B lymphoblast cell lines (BLCL) from bipolar I disorder (BD‐I) patients showing elevated basal intracellular Ca2+ ([Ca2+]B), an index of altered intracellular Ca2+ homeostasis, along with its location within a putative BD susceptibility locus (21q22.3), implicates the involvement of this gene in the Ca2+ abnormalities and the genetic diathesis to BD. We tested this hypothesis by examining the association of selected single nucleotide polymorphisms (SNPs) and their haplotypes, spanning the TRPM2 gene, with BD and BLCL [Ca2+]B, in a case control design. The 5′ TaqMan SNP assay was used to detect selected SNPs. BLCL [Ca2+]B was determined by ratiometric fluorometry. SNP rs1618355 in intron 18 was significantly associated with BD as a whole (P < 7.0 × 10−5; odds ratio (OR) = 2.60), and when stratified into BD‐I (P < 7.0 × 10−5, OR = 2.48) and BD‐II (P = 7.0 × 10−5, OR = 2.88) subgroups. In addition, the alleles of the individual SNPs forming a seven marker at‐risk haplotype were in excess in BD (12.0% in BD vs. 0.9% in controls; P = 2.3 × 10−12). A weak relationship was also detected between BLCL [Ca2+]B and TRPM2 SNP rs1612472 in intron 19. These findings suggest genetic variants of the TRPM2 gene increase risk for BD and support the notion that TRPM2 may be involved in the pathophysiology of BD.

Chronic Lithium Treatment Attenuates Intracellular Calcium Mobilization

Elevated basal intracellular calcium (Ca2+) levels ([Ca2+]B) in B lymphoblast cell lines (BLCLs) from bipolar I disorder (BD-I) patients implicate altered Ca2+ homeostasis in this illness. Chronic lithium treatment affects key proteins modulating intracellular Ca2+ signaling. Thus, we sought to determine if chronic exposure to therapeutic lithium concentrations also modifies intracellular Ca2+ homeostasis in this surrogate cellular model of signal transduction disturbances in BD. BLCLs from BD-I (N=26) and healthy subjects (N=17) were regrown from frozen stock and incubated with 0.75 mM lithium or vehicle for 24 h (acute) or 7 days (chronic). [Ca2+]B, lysophosphatidic acid (LPA)-stimulated Ca2+ mobilization ([Ca2+]S), and thapsigargin-induced store-operated Ca2+ entry (SOCE) were determined using ratiometric fluorometry with Fura-2. Compared with vehicle, chronic lithium exposure resulted in significantly higher [Ca2+]B (F=8.47; p=0.006) in BLCLs from BD-I and healthy subjects. However, peak LPA-stimulated [Ca2+]S and SOCE were significantly reduced (F=11.1, p=0.002 and F=8.36, p=0.007, respectively). Acute lithium exposure did not significantly affect measured parameters. In summary, the effect of chronic lithium to elevate [Ca2+]B in BLCLs while attenuating both receptor-stimulated and SOCE components of intracellular Ca2+ mobilization in BLCLs suggests that modulation of intracellular Ca2+ homeostasis may be important to the therapeutic action of lithium.

Altered TRPC7 gene expression in bipolar-I disorder.

BACKGROUND As altered storage-operated calcium (Ca(2+)) entry (SOCE) may affect Ca(2+) homeostasis in bipolar disorder (BD), we determined whether changes occur in the expression of TRPC7 and SERCA2s, proteins implicated or known to be involved in SOCE, in B lymphoblast cell lines (BLCLs) from BD-I patients and comparison subjects. METHODS mRNA levels were determined in BLCL lysates from BD-I, BD-II, and major depressive disorder patients, and healthy subjects by comparative reverse transcriptase-polymerase chain reaction, and BLCL basal intracellular Ca(2+) concentration ([Ca(2+)]B) was determined by ratiometric spectrophotometry using Fura-2, in aliquots of the same cell lines, at 13-16 passages in culture. RESULTS TRPC7 mRNA levels were significantly lower in BLCLs from BD-I patients with high BLCL [Ca(2+)]B compared with those showing normal [Ca(2+)]B (-33%, p =.017) and with BD-II patients (-48%, p =.003), major depressive disorder patients (-47%, p =.049) and healthy subjects (-33%, p =.038). [Ca(2+)]B also correlated inversely with TRPC7 mRNA levels in BLCLs from the BD-I group as a whole (r = -.35, p =.027). CONCLUSIONS Reduced TRPC7 gene expression may be a trait associated with pathophysiological disturbances of Ca(2+) homeostasis in a subgroup of BD-I patients.