Detection of Bipolar Disorder

Mechanisms and Pathways

There were a number of excellent presentations at the APA Annual meeting which highlighted recent advances in the detection and management of bipolar disorder. Wayne Drevets, MD, National Institute of Mental Health, presented a summation of recent data on the pathophysiology of bipolar depression with the potential to enhance diagnostic accuracy and targeting of intervention strategies.^[1] The subgenual prefrontal cortex has long been implicated in the pathophysiology of the mood disorders — especially bipolar disorder — with studies demonstrating reduced metabolic activity, decreased volume, and decreased cell counts.^[2,3] Recent data have also implicated the glutamatergic system as a potential target in the pathophysiology of bipolar depression with the demonstration that glutamatergic drugs like lamotrigine^[4] and riluzole^[5] are efficacious in bipolar depression. The demonstration of decreased serotonin transporter binding in the brainstem raphe in depressed bipolar depressed subjects vs healthy controls^[6] and decreased muscarinic binding in bipolar depressed subjects^[7] suggests that these may be molecular targets for the future.

Husseini Manji, MD, National Institutes of Mental Health, spoke eloquently about recent insights into cellular mechanisms in the understanding of bipolar disorder.^[8] He characterized bipolar disorder as an abnormality of cellular plasticity cascades and a disorder of synapses and circuits, which could explain the enormous comorbidity of other illness with bipolar disorder. A series of studies have shown that prototypical mood stabilizers like lithium and valproate specifically modulate intracellular signaling pathways like protein kinase C (PKC).^[9] Recent demonstration of the antimanic effects of tamoxifen, a protein kinase C inhibitor, also raised hope for the development of novel drugs to treat bipolar disorder.^[10,11] The demonstration of a rapid antidepressant effect with ketamine in patients with treatment-resistant depression demonstrated proof of concept for the development of novel, rapidly acting treatment strategies for bipolar disorder.^[12] Another extremely promising area for the development of novel therapeutics is BCL-2, an important neurotrophic/ neuroprotective protein, which mediates synaptic plasticity and protects against free radicals, ischemia, glutamate, growth factor deprivation, and toxins.^[13]

Clinical Instruments

In an industry-supported symposium, Gary Sachs, MD, Massachusetts General Hospital, spoke of the problem of diagnostic error and practical strategies for reducing error and described the use of systematic evaluation and collateral sources to obtain an index of diagnostic confidence.^[14] There is an urgent need to search for a history of mania/hypomania in patients with mood disorders. The conceptualization of a “bipolarity index” was useful in clinical practice with an emphasis on the 5 cardinal parameters: age of onset, course of illness, response to treatments, family history, and current signs and symptoms.^[15] Unpublished data from the STEP-BD program suggested that the use of the bipolarity index could aid clinical judgment The need for the use of the index was suggested when there were elements of lack of clarity regarding the diagnosis. In combination with an uncertain clinical picture, a score of greater than 65 on the bipolarity index should aid clarity of diagnosis, while a score less than 65 in conjunction with an unclear clinical picture suggests proceeding with caution.

Genetics

Francis McMahon, MD, NIMH Intramural Program, presented an overview of current understanding of the genetic basis of bipolar disorder.^[16] Bipolar disorder has high heritability (80%-90%) making it especially amenable to a study of causative or modulatory genes.^[17] Of a number of different ways of studying the genetic basis of psychiatric disorders — including family-based studies, twin studies, adoption studies, and association studies — the use of single nucleotide polymorphisms (SNPs) is possibly the most exciting. In addition, the ability to perform analysis of the whole genome lends itself to the ability to discover the genetic basis for a number of complex psychiatric disorders such as bipolar disorder. A recent study from Dr McMahon’s group carried out a genome-wide association study of bipolar disorder by genotyping over 550,000 SNPs in 2 independent case-control samples of European origin.^[18] A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples but no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at gene for diacylglycerol kinase eta (DGKH), a key protein in the lithium-sensitive phosphatidyl inositol pathway. This genome-wide association study of bipolar disorder showed that several genes, each of modest effect, reproducibly influence disease risk. Another recent genome-wide association study of bipolar disorder from the Wellcome Trust Case Control Consortium studied 2000 cases and 3000 controls.^[19] While no single gene stood out, there were some interesting associations with 3 genes that have face validity in the pathophysiology of bipolar disorder. These are PALB2 (partner and localizer of BRCA2), which is involved in stability of key nuclear structures including chromatin and the nuclear matrix; NDUFAB1 (NADH dehydrogenase [ubiquinone] 1, alpha/beta subcomplex, 1), which encodes a subunit of complex I of the mitochondrial respiratory chain; and DCTN5 (dynactin 5), which encodes a protein involved in intracellular transport that is known to interact with the gene “disrupted in schizophrenia 1” (DISC1). Efforts such as these will eventually lead the way to a better and more sophisticated understanding of the pathophysiology and genetic basis of bipolar disorder.

Management of Bipolar Disorder

In an industry-supported symposium, Mark Frye, MD, Professor of Psychiatry at the Mayo Clinic College of Medicine, presented current state of the art knowledge about the management of bipolar depression.^[20] There is a clear need for the development of more treatments as there are only 2 US Food and Drug Administration (FDA) approved treatments for bipolar depression: olanzapine/fluoxetine combination therapy^[21] and quetiapine.^[22] Results of 2 unpublished studied were discussed; both examined the role of quetiapine monotherapy in the treatment of bipolar depression compared with placebo and lithium (EMBOLDEN I), and paroxetine (EMBOLDEN II). EMBOLDEN I studied patients treated with quetiapine at 300 mg (n = 265) or 600 mg (n = 268), placebo (n = 133), or lithium with a mean lithium level 0.61 mmol/L (n = 136).^[23] Both doses of quetiapine resulted in a statistically significantly greater response rate compared with placebo while the higher dose of quetiapine also showed a statistically significant remission rate compared with placebo. However, lithium did not show statistical significant effects on either response or remission. This may have been due to the serum level of lithium in these patients even though there is little guidance for lithium levels in bipolar depression. A previous study had shown that lithium levels may need to be greater than 0.8 mmol/L to result in optimal effect and the fact that patients in the EMBOLDEN I study had levels lower may have caused a lack of separation from placebo for the lithium-treated patients.^[24] Embolden II studied relatively similar numbers of patients with quetiapine 300 mg and 600 mg, paroxetine, and placebo.^[25] Like the previous trial, EMBOLDEN II found that both doses of quetiapine resulted in statistically significantly higher number of patients who responded compared with placebo, while the quetiapine 600-mg dose resulted in a greater remission rate as well. Paroxetine did not separate from placebo on both measures.

A number of other recent studies hold promise for the treatment of bipolar depression. There is reason to believe that the demonstrated efficacy of lamotrigine in the prophylaxis and maintenance of bipolar depression^[4] may extend to the acute phase of the illness based on an unpublished meta-analysis of the studies in acute bipolar depression.^[26] Data from the STEP-BD study also suggested that the use of adjunctive, standard antidepressant medication, as compared to the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch.^[27] In a study of 85 bipolar depressed patients the response and remission rates were significantly higher in patients treated with modafinil at a dose of 100-200 mg/day compared with the placebo.^[28] Adjunctive pramipexole, a dopamine D₂/D₃ receptor agonist, has also been shown to have some efficacy in the treatment of bipolar depression in 2 small controlled studies.^[29,30] The use of psychotherapeutic interventions has shown to be efficacious in the treatment of bipolar depression, as a STEP-BD study showed that intensive psychosocial treatment as an adjunct to pharmacotherapy was more beneficial than brief treatment in enhancing stabilization.^[31]

Gary Sachs, MD, Massachusetts General Hospital, presented recent data on the management of bipolar depression.^[32] The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was a collaboration sponsored by the National Institute of Mental Health designed to evaluate the effectiveness of treatments for bipolar disorder and to provide results that were could be generalized to routine clinical practice. In this double-blind, placebo-controlled study, patients with bipolar depression were randomly allocated to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo.^[27] The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Of the patients treated, 24% of patients receiving a mood stabilizer plus adjunctive antidepressant treatment had a “durable recovery,” as did 27% of patients receiving a mood stabilizer plus a matching placebo. Interestingly rates of treatment-emergent affective switch were also similar across both groups. Another STEP-VD study assessed the effectiveness and safety of antidepressant augmentation with lamotrigine, inositol, and risperidone.^[33] Bipolar depressed patients nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant were randomly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure. However, the recovery rate with lamotrigine was 23.8%, whereas the recovery rates with inositol and risperidone were 17.4% and 4.6%, respectively. Psychosocial treatments are often underutilized in bipolar disorder but there is now convincing evidence for their use in the illness. Intensive psychosocial treatment as an adjunct to pharmacotherapy was more beneficial than brief treatment in enhancing stabilization from bipolar depression.^[31] Outpatients with bipolar disorder and depression treated with protocol pharmacotherapy were randomly assigned to one of 3 intensive psychotherapy programs or collaborative care, a brief psychoeducational intervention. While rates of attrition did not differ across the intensive psychotherapy (35.6%) and collaborative care (30.8%) conditions patients receiving intensive psychotherapy had significantly higher year-end recovery rates (64.4% vs 51.5%) and shorter times to recovery than patients in collaborative care. Patients in intensive psychotherapy were more likely to be clinically well during any study month than those in collaborative care.

Management of Suicidal Behavior in Bipolar Disorder

Maria A. Oquendo, MD, Professor of Clinical Psychiatry at Columbia University and Vice-Chair for Education in the Department of Psychiatry at Columbia spoke of recent developments in the management of suicidal behavior in bipolar disorder.^[34] A prospective follow-up study of 176 patients with bipolar disorder showed that previous suicide attempts, hopelessness, and depressive phase were the key indicators of risk of suicide.^[35] A more recent study from Columbia showed that most predictors of future suicidal behavior were correlates of past suicidal behavior.^[36] Family history of suicide acts and comorbid borderline personality disorder predicted early attempts, while younger age, high hostility scores, number of past attempts, subjective pessimism as reflected in depression and suicidal ideation, and few reported reasons for living predicted suicidal acts during the whole period. In addition to the general antisuicide effect of lithium, there is evidence of a superior antisuicide effect of lithium in bipolar disorder when compared with carbamazepine or valproate.^[37-39] Dr. Oquendo presented data from her studies to support the notion that lithium has an a beneficial effect in preventing suicides and that it may be especially useful in older bipolar patients.