Jeffrey J. Rakofsky

BDNF function as a potential mediator of bipolar disorder and post-traumatic stress disorder comorbidity

Bipolar disorder (BD) and post-traumatic stress disorder (PTSD) frequently co-occur among psychiatric patients, leading to increased morbidity and mortality. Brain-derived neurotrophic factor (BDNF) function is associated with core characteristics of both BD and PTSD. We propose a neurobiological model that underscores the role of reduced BDNF function resulting from several contributing sources, including the met variant of the BDNF val66met (rs6265) single-nucleotide polymorphism, trauma-induced epigenetic regulation and current stress, as a contributor to the onset of both illnesses within the same person. Further studies are needed to evaluate the genetic association between the val66met allele and the BD-PTSD population, along with central/peripheral BDNF levels and epigenetic patterns of BDNF gene regulation within these patients.

Emerging targets for antidepressant therapies

Despite adequate antidepressant monotherapy, the majority of depressed patients do not achieve remission. Even optimal and aggressive therapy leads to a substantial number of patients who show minimal and often only transient improvement. In order to address this substantial problem of treatment-resistant depression, a number of novel targets for antidepressant therapy have emerged as a consequence of major advances in the neurobiology of depression. Three major approaches to uncover novel therapeutic interventions are: first, optimizing the modulation of monoaminergic neurotransmission; second, developing medications that act upon neurotransmitter systems other than monoaminergic circuits; and third, using focal brain stimulation to directly modulate neuronal activity. We review the most recent data on novel therapeutic compounds and their antidepressant potential. These include triple monoamine reuptake inhibitors, atypical antipsychotic augmentation, and dopamine receptor agonists. Compounds affecting extra-monoamine neurotransmitter systems include CRF(1) receptor antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, NMDA receptor antagonists, nemifitide, omega-3 fatty acids, and melatonin receptor agonists. Focal brain stimulation therapies include vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS).

Treating Nonspecific Anxiety and Anxiety Disorders in Patients With Bipolar Disorder: A Review

OBJECTIVE To review the evidence for treating anxiety in patients with bipolar disorder. DATA SOURCES A literature search from 1950 to week 1 of August 2009 was conducted via OVID and the National Institutes of Healths clinical trials online databases. Search terms included anxiety, anxiety disorders, bipolar disorder, panic disorder, generalized anxiety disorder, social phobia, social anxiety, obsessive compulsive disorder, specific phobia, posttraumatic stress disorder, and treatment. Reference lists of identified articles were also searched. STUDY SELECTION Fourteen treatment studies that included patients with bipolar disorder with either a syndrome-defined anxiety disorder or nonspecific anxiety were selected. DATA EXTRACTION Sample size, bipolar disorder subtype, comorbid anxiety disorders, baseline anxiety, treatment interventions, and outcome measurements were extracted. RESULTS The majority of studies focus on treating anxiety disorders and nonspecific anxiety occurring during bipolar mood episodes. Studies of syndrome-defined anxiety disorders reveal that risperidone monotherapy did not separate from placebo and that olanzapine was superior to lamotrigine when used to augment lithium treatment. A study using open-label divalproex sodium and an uncontrolled study of group cognitive-behavioral therapy both suggest some benefit from these treatments in patients with bipolar disorder with panic disorder. Studies of nonspecific anxiety reveal some benefit for divalproex, quetiapine, olanzapine, and olanzapine-fluoxetine combination. Weaker evidence supports the use of Mindfulness-Based Cognitive Therapy, and observational studies suggest potential efficacy for gabapentin and valproate. CONCLUSIONS Nonspecific anxiety symptoms occurring during a mood episode improve with treatment of the mood disturbance, though divalproex may be the mood stabilizer of choice for anxious patients with bipolar disorder. Given their reduced risk for manic induction and episode cycling, psychotherapy, benzodiazepines, and certain atypical antipsychotics are recommended for treatment of anxiety disorders present in patients with bipolar disorder not currently experiencing an acute mood episode.

Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10−8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Do alcohol use disorders destabilize the course of bipolar disorder

OBJECTIVES To determine whether long-term data implicate a negative effect of alcohol-use disorders (AUDs) on time to remission, risk of mood episode recurrence, and risk of mood switch/cycling in patients with bipolar disorder (BD). The short-term temporal sequence between alcohol use and onset of mood episodes was also examined. METHODS A MEDLINE literature search was conducted for measurement-based reports of alcohol and course of bipolar disorder. RESULTS Twenty-three original data publications were identified. Three out of 5 studies addressing the impact of AUDs on recovery from a mood episode demonstrated that alcohol did not prolong index mood episodes of any type. Six out of 11 reports evaluating the relationship between alcohol and the long term risk of mood episode recurrences suggested that high levels of alcohol intake increase the risk of a mood recurrence. Five out of 7 studies evaluating the short-term temporal sequence of AUDs and development of mood episodes among BD patients found that increased alcohol use preceded the development of new mood episodes. Four out of 5 studies examining the association between alcohol and rapid cycling indicated that AUDs were associated with higher rates of rapid-cycling. LIMITATIONS We limited our review to studies that were large enough to perform statistical testing, which may have led us to overlook informative smaller studies. CONCLUSIONS Although alcohol does not seem to affect time to mood episode remission, alcohol use destabilizes the course of illness over the long run as evidenced by associations with more rapid cycling and mood episode recurrence.

Prevalence of major depressive disorder and socio-demographic correlates: Results of a representative household epidemiological survey in Beijing, China

Abstract Background Major depressive disorder (MDD) is the most prevalent mental disorder in the general population and has been associated with socioeconomic factors. Beijing has undergone significant socioeconomic changes in last decade, however no large-scale community epidemiological surveys of MDD have been conducted in Beijing since 2003. Aims To determine the prevalence of MDD and its socio-demographic correlates in a representative household sample of the general population in Beijing, China. Method Data were collected from the 2010 representative household epidemiological survey of mental disorders in Beijing. The multistage cluster random sampling method was used to select qualified subjects in 18 districts and counties, and then face-to-face interviews were administered using the Chinese version of Structured Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Edition (SCID-I/P) during November 1, 2010 to December 31, 2010. Results 19,874 registered permanent residents were randomly identified and 16,032 (response rate=80.7%) completed face-to-face interviews. The time-point and life-time prevalence rates of MDD were estimated to be 1.10% (95% CI: 0.94–1.26%) and 3.56% (95% CI: 3.27–3.85%) respectively. Significant differences were found in sex, age, location of residence, marital status, education, employment status, personal/family monthly income, perception of family environment and relationship with others, when comparing residents with MDD to those without MDD. Those who were female, aged 45 or above, reported low family income, or reported an “average” or “poor” family environment were associated with a higher risk of MDD. Conclusions The prevalence of MDD reported in this survey is relatively lower than that in other western countries. Female sex, age older than 45, low family income, and poor family environment appear to be independent risk factors for MDD.

Conceptualizing Treatment Nonadherence in Patients with Bipolar Disorder and PTSD.

Treatment nonadherence is a concern among patients with bipolar disorder and posttraumatic stress disorder (PTSD). PTSD is common among patients with bipolar disorder and those with this comorbidity often have a more severe course of illness. While many factors have been associated with nonadherence in bipolar disorder patients and in PTSD patients, almost no research has focused on the factors associated with non-adherence in bipolar disorder patients with comorbid PTSD. Studies in primary bipolar disorder samples reveal patient, illness, drug and clinician characteristics associated with nonadherence while studies in primary PTSD samples reveal a significantly shorter list of patient, illness and drug characteristics. Shared risk factors between these two populations and the characteristics that predict noncompliance in only one population but often present in the other, suggest a high likelihood of nonadherence in the bipolar disorder-PTSD population. For bipolar disorder-PTSD patients with early childhood trauma, noncompliance may be related to the trauma-related meanings attributed to interactions with their physicians and their prescribed medications. Given the high side effect burden of bipolar disorder treatments and the importance of lifelong adherence, clinicians should vigilantly monitor for nonadherence in their bipolar disorder-PTSD patients and be particularly aware of patient-physician psychodynamics that might contribute to this behavior.

Perceptions of public attitudes towards persons with mental illness in Beijing, China: results from a representative survey

ObjectivesMany studies have examined the general public’s attitudes towards people with mental illness, but such studies are scarce in China. This study examined the perceptions of the Beijing population regarding their society’s prevalent attitudes towards people with mental illness.MethodsA total of 5000 individuals aged 18 or above living in Beijing were selected using a multistage, stratified, cluster and random sampling method. This was followed by a face-to-face interview which used a standardized questionnaire asking about societal attitudes towards individuals with mental illness.Results4602 out of 5000 eligible individuals met the inclusion criteria and participated in the interview. 4596 questionnaires were deemed valid and included in the analyses. A large proportion of respondents believed that most individuals within their society held negative attitudes and had a strong desire to distance themselves from people with mental illness. Respondents aged 60 or older, who lived farther to downtown Beijing, or with higher education tended to believe that most individuals have relatively positive and tolerant attitudes towards people with mental illness.ConclusionsMany people in Beijing perceive that most members of their society have negative beliefs towards people with mental illness. Further efforts are needed to determine if these perceptions are accurate and to reduce the stigma that is reinforced by these perceptions.

US psychiatric residents' treatment of patients with bipolar disorder.

Abstract We aimed to evaluate the practice patterns of US postgraduate year (PGY) levels 3 and 4 psychiatric residents in the treatment of patients with bipolar disorder (BD) types I and II. We also aimed to determine whether confidence in prescribing mood stabilizers is associated with residents’ practice patterns. The residency training directors of 182 Accreditation Council for Graduate Medical Education–accredited US psychiatric residencies were solicited for study participation via e-mail. Their chief residents were asked to forward an online survey Web link to all PGY-3 and PGY-4 residents in their program. The survey was a cross-sectional, online questionnaire, evaluating residents’ treatment choices for their BD patients in their psychopharmacology clinics during the last academic year (July 1, 2009, to May 1, 2010), along with resident confidence level in using mood stabilizers. The survey Web link was distributed to 769 residents, and 177 (23.0%) responded to the survey. The percentage of residents who did not initiate treatment in the past year with mood stabilizers was 24.5% for lithium, 26.9% for lamotrigine, 36.7% for valproate, and 73.6% for carbamazepine. Confidence in initiating treatment with each of the 4 mood stabilizers was significantly associated with the number of patients treated with each mood stabilizer in the past year. Residents reported having the lowest confidence with carbamazepine followed by lamotrigine, lithium, and valproate. Experience prescribing first-line treatments for BD, such as lithium and valproate, is inadequate for many US psychiatric residents. Psychiatry residency directors should ensure that their residents have sufficient opportunity to pharmacologically treat BD patients so that these young physicians may develop confidence using an array of evidence-based treatments.

Acute Swedish Massage Monotherapy Successfully Remediates Symptoms of Generalized Anxiety Disorder: A Proof-of-Concept, Randomized Controlled Study.

OBJECTIVE Generalized anxiety disorder (GAD) is a prevalent and costly disorder for which many patients may prefer nontraditional treatment. A proof-of-concept study of was conducted to evaluate the acute effects of Swedish massage therapy (SMT) as a monotherapy for the treatment of subjects with GAD. METHODS A randomized, single-masked, clinical trial was conducted between March 2012 and May 2013 at the Mood and Anxiety Disorders Program of Emory University. Forty-seven currently untreated subjects with a DSM-IV diagnosis of GAD were randomly assigned to twice-weekly SMT versus a light touch control condition for 6 weeks. The primary outcome measure was reduction in Hamilton Anxiety Rating Scale (HARS) scores after 6 weeks of treatment for SMT versus light touch, as determined by mixed model repeated-measures analysis of 40 evaluable subjects. RESULTS Mean HARS baseline scores were 20.05 (SD = 3.34) for SMT and 19.58 (SD = 4.90) for light touch. At week 6, the difference in mean (standard error of the mean [SEM]) HARS score reduction was 3.26 points (SMT: -11.67 [1.09]; light touch: -8.41 [1.01]; t₁₀₆ = -2.19; P = .030; effect size = -0.69). Treatment group differences were significant (P < .05) starting at the end of week 3. CONCLUSION This first monotherapy trial suggests that a complementary and alternative manual therapy, SMT, is an effective acute treatment for GAD. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01337713.