Jeremy D. Coplan

Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates

New neurons are generated in the adult hippocampus of many species including rodents, monkeys, and humans. Conditions associated with major depression, such as social stress, suppress hippocampal neurogenesis in rodents and primates. In contrast, all classes of antidepressants stimulate neuronal generation, and the behavioral effects of these medications are abolished when neurogenesis is blocked. These findings generated the hypothesis that induction of neurogenesis is a necessary component in the mechanism of action of antidepressant treatments. To date, the effects of antidepressants on newborn neurons have been reported only in rodents and tree shrews. This study examines whether neurogenesis is increased in nonhuman primates after antidepressant treatment. Adult monkeys received repeated electroconvulsive shock (ECS), which is the animal analog of electroconvulsive therapy (ECT), the most effective short-term antidepressant. Compared with control conditions, ECS robustly increased precursor cell proliferation in the subgranular zone (SGZ) of the dentate gyrus in the monkey hippocampus. A majority of these precursors differentiated into neurons or endothelial cells, while a few matured into glial cells. The ECS-mediated induction of cell proliferation and neurogenesis was accompanied by increased immunoreactivity for the neuroprotective gene product BCL2 (B cell chronic lymphocytic lymphoma 2) in the SGZ. The ECS interventions were not accompanied by increased hippocampal cell death or injury. This study demonstrates that ECS is capable of inducing neurogenesis in the nonhuman primate hippocampus and supports the possibility that antidepressant interventions produce similar alterations in the human brain.

The noradrenergic system in pathological anxiety: a focus on panic with relevance to generalized anxiety and phobias

Over the past three decades of psychiatric research, abnormalities in the noradrenergic system have been identified in particular anxiety disorders such as panic disorder. Simultaneously, neuroscience research on fear pathways and the stress response have delineated central functions for the noradrenergic system. This review focuses on the noradrenergic system in anxiety spectrum disorders such as panic disorder, generalized anxiety disorder, and phobias for the purpose of elucidating current conceptualizations of the pathophysiologies. Neuroanatomic pathways that are theoretically relevant in anxiogenesis are discussed and the implications for treatment reviewed.

Depression and anxiety in urban hemodialysis patients.

Depression is well established as a prevalent mental health problem for people with ESRD and is associated with morbidity and mortality. However, depression in this population remains difficult to assess and is undertreated. Current estimates suggest a 20 to 30% prevalence of depression that meets diagnostic criteria in this population. The extent of other psychopathology in patients with ESRD is largely unknown. The aim of this study was to expand the research on psychiatric complications of ESRD and examine the prevalence of a broad range of psychopathology in an urban hemodialysis center and their impact on quality of life. With the use of a clinician-administered semistructured interview in this randomly selected sample of 70 predominately black patients, >70% were found to have a psychiatric diagnosis. Twenty-nine percent had a current depressive disorder: 20% had major depression, and 9% had a diagnosis of dysthymia or depression not otherwise specified. Twenty-seven percent had a current major anxiety disorder. A current substance abuse diagnosis was found in 19%, and 10% had a psychotic disorder. The mean Beck Depression Inventory score was 12.1 +/- 9.8. Only 13% reported being in current treatment by a mental health provider, and only 5% reported being prescribed psychiatric medication by their physician. A total of 7.1% had compound depression or depression coexistent with another psychiatric disorder. The construct of depression was also disentangled from the somatic effects of poor medical health by demonstrating a unique relationship between depressive affect and depression diagnosis, independent of health status. This study also suggests the utility of cognitive variables as a meaningful way of understanding the differences between patients who have ESRD with clinical depression or other diagnoses and those who have no psychiatric comorbidity. The findings of both concurrent and isolated anxiety suggest that the prevalence of psychopathology in patients with ESRD might be higher than previously expected, and the disorders may need to be treated independently. In addition, the data suggest that cognitive behavioral therapeutic techniques may be especially advantageous in this population of patients who are treated with many medications.

Clinical utility of the selective serotonin reuptake inhibitors in the spectrum of anxiety.

The selective serotonin reuptake inhibitors (SSRIs) are now being employed in the treatment of the full spectrum of anxiety disorders. In comparative trials, the SSRIs are proving to be equal or superior in efficacy to traditional antianxiety medications. Due to their favorable side effect profile, safety, and tolerability, they are rapidly replacing older agents in the treatment of anxiety. Neuroanatomical pathways that may be important in the antianxiety effect of the SSRIs are outline and discussed, followed by a review of the clinical evidence supporting the efficacy of this class of medications in the treatment of anxiety disorders.

Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates

Background Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. Materials/Methodology Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels. Results Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation. Conclusion We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.

Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates

BACKGROUND The authors previously reported elevated cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations in juvenile primates nursed by mothers undergoing experimentally imposed unpredictable foraging conditions in comparison to normally reared controls. The purpose of the present study was to determine if these changes would endure into young adulthood. METHODS Cisternal CSF samples were obtained from those unpredictably reared young adult primates who had been previously studied as juveniles and age-matched ad libitum normally reared controls. Samples were assayed for CSF CRF. RESULTS Concentrations of CSF CRF were significantly elevated in the unpredictably reared sample in comparison to the ad libitum-reared control group. A significant positive correlation was noted between juvenile and young adult CSF CRF values within the unpredictably reared cohort. CONCLUSIONS Disturbances of maternal-infant attachment processes have an enduring impact on primate CRF function into young adulthood. The CRF elevations following unpredictable maternal foraging conditions appear traitlike in nature.

Heart period variability and psychopathology in urban boys at risk for delinquency

To examine associations between heart period variability (HPV) and psychopathology in young urban boys at risk for delinquency, a series of 697-11-year-old younger brothers of adjudicated delinquents received a standardized psychiatric evaluation and an assessment of heart period variability (HPV). Psychiatric symptoms were rated in two domains: externalizing and internalizing psychopathology. Continuous measures of both externalizing and internalizing psychopathology were associated with reductions in HPV components related to parasympathetic activity. These associations could not be explained by a number of potentially confounding variables, such as age, ethnicity, social class, body size, or family history of hypertension. Although familial hypertension predicted reduced HPV and externalizing psychopathology, associations between externalizing psychopathology and HPV were independent of familial hypertension. Psychiatric symptoms are associated with reduced HPV in young urban boys at risk for delinquency.

Course of Depression and Anxiety Diagnosis in Patients Treated with Hemodialysis: A 16-month Follow-up

BACKGROUND AND OBJECTIVES There is growing identification of the need to seriously study the psychiatric presentations of end-stage renal disease patients treated with hemodialysis. This study reports on the course of depression and anxiety diagnoses and their impact on quality of life and health status. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The 16-mo course of psychiatric diagnoses in 50 end-stage renal disease patients treated with hemodialysis was measured by structured clinical interview. RESULTS Three different pathways were identified: one subset of patients not having a psychiatric diagnosis at either baseline or 16-mo follow-up (68% for depression, 51% for anxiety), one group having an intermittent course (21% for depression, 34% for anxiety), and one group having a persistent course (11% for depression, 15% for anxiety), with diagnoses at both time 1 and time 2. For depression, the people with the persistent course showed marked decreases in quality of life and self-reported health status compared with the nondepressed and intermittently depressed cohorts. The most powerful predictor of depression at time 2 is degree of depressive affect at time 1(P < 0.05). CONCLUSIONS Patients at risk for short- and long-term complications of depression can be potentially identified by high levels of depressive affect even at a single time point. As nearly 20% of the sample had chronic depression or anxiety, identifying a psychiatric diagnosis in hemodialysis patients and then offering treatment are important because, in the absence of intervention, psychiatric disorders are likely to persist in a substantial proportion of patients.

Early-Life Stress and the Development of Obesity and Insulin Resistance in Juvenile Bonnet Macaques

Stress is a risk factor for chronic illnesses such as obesity, type 2 diabetes, and hypertension and has been postulated to cause the metabolic syndrome via perturbation of the hypothalamo-pituitary-adrenal (HPA) axis. In our model of early-life stress (variable foraging demand [VFD]), food insecurity is imposed on monkey mothers for 16 weeks beginning when their nursing offspring are 3–5 months of age. Under VFD, food availability is never restricted, and the infants growth is unaffected. VFD rearing does, however, cause a range of neurobiological abnormalities, including dysregulation of the HPA axis, manifested in abnormal cerebrospinal fluid cortisol and corticotropin-releasing factor levels. We previously reported spontaneous occurrence of metabolic syndrome in 14% of normally reared peripubertal bonnet macaques given ad libitum access to standard monkey chow. Here, we show that compared with normally reared monkeys, peripubertal VFD juveniles exhibit greater weight, BMI, abdominal circumference, and glucagon-like peptide-1 and decreased glucose disposal rates during hyperinsulinemic-euglycemic clamps. Our data suggest that early-life stress during a critical period of neuro development can result in the peripubertal emergence of obesity and insulin resistance.

Risk and Resilience: Early Manipulation of Macaque Social Experience and Persistent Behavioral and Neurophysiological Outcomes.

OBJECTIVE To review the contributions of research on nonhuman primates, specifically macaque monkeys, to the understanding of early social stress and its effects on behavior and neurophysiology. METHOD Review and synthesis of two bodies of work on macaque monkeys and early social manipulation: peer rearing and variable foraging demands. The literature was searched with Medline using key terms macaque, variable foraging, and peer rearing. The reference lists of these articles were also used to generate potential studies for review. RESULTS Nonhuman primate macaques show similarities to humans in their social development and functioning. Peer rearing of young macaques and rearing of young macaques with mothers experiencing variable foraging conditions both result in increased anxious, impulsive, and aggressive temperament and behavior; more reactive stress physiology; altered neurotransmitter functioning; and immune and metabolic changes. Functional variants of specific genes that code for neuromodulators are mediators of these effects. CONCLUSIONS Disrupted social relations during macaque rearing contribute to the risk for developing emotional and neurophysiological disturbance. In the face of such disruption, certain genotypes contribute to resilience. This can be alternately stated that, for animals of high-risk genotypes, resilience is conferred by quality relationships during rearing. This interaction of genetics with early social environment also applies to child mental health, implicating biological mediators identified in macaques as contributing to more complex outcomes in humans.