Anxiety Disorders: Coplan JD

Berkowitz RL, Coplan JD, Reddy DP, Gorman JM. · Department of Psychiatry, College of Physicians and Surgeons of Columbia University, Brooklyn, NY, USA. · Rev Neurosci. · Pubmed #18019606 No free full text.

Abstract: Numerous studies suggest that the amygdala is critical for the acquisition and expression of fear. Conditioned fear in animals has been considered a good model for human anxiety disorders, but animal models of anxiety have several limitations. Conditioned fear in animals can be directed to a specific stressor and is easily extinguished. Furthermore, animals do not seem to be able to develop the capacity to worry excessively about the future. While animal models are useful and can demonstrate psychiatric illnesses, they do not completely mimic the complex cognitive processes that occur in anxious humans. Thus, we hypothesize that human anxiety disorders are caused at least in part by differential activity in the prefrontal cortex, the brain region that most separates us from our nearest genetic neighbors. The human prefrontal cortex has not only been shown to be more developed than that of other mammals, but it also has unique morphology and gene expression. Neuroimaging studies repeatedly show abnormalities in the prefrontal cortex in anxious individuals. Thus, we suggest that the very same cortical complexity that allows us to produce a vibrant culture is also the seat of anxiety disorders. Interestingly, preclinical studies have shown that the prefrontal cortex inhibits the amygdala. There appears to be a distinction between two classes of anxiety disorders. Those disorders involving intense fear and panic--panic disorder, post-traumatic stress disorder, and phobias--seem to be characterized by an underactivity of the prefrontal cortex, thus disinhibiting the amygdala. Disorders such as generalized anxiety disorder and obsessive-compulsive disorder, which involve worry and rumination, on the other hand, seem to be characterized by an overactivity of the prefrontal cortex. Studies of prefrontal cortical function in psychiatric illness should be a fruitful method for identifying effective treatment approaches.

Mathew SJ, Coplan JD, Gorman JM. · Columbia University, College of Physicians and Surgeons, Department of Clinical Psychobiology, New York State Psychiatric Institute, Unit 84, 1051 Riverside Drive, New York, NY 10032, USA. · Psychopharmacol Bull. · Pubmed #12397890 links to  free full text

Abstract: Treatment resistance remains a relatively common problem in panic disorder (PD) despite the success of the selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT) as first-line agents. Factors contributing to medication treatment resistance include inadequacy of trial duration, improper dosage, poor tolerability, noncompliance, and medical and psychiatric comorbidity. Poor tolerability to the SSRIs can frequently be addressed by judicious lowering of the initial dose, with a gradual upward titration. For patients who have not responded to one or more adequate trials of SSRIs, options include combination treatment with a benzodiazepine or tricyclic antidepressant (TCA), augmentation with pindolol, or switching to a different class of medication. The newer antidepressants, particularly venlafaxine XR, seem promising as alternatives, and might be beneficial for the refractory patient with a comorbid mood disorder. Anticonvulsants and olanzapine might be particularly beneficial for the refractory patient with hypomania, irritability, and insomnia, who also has demonstrated acute SSRI hypersensitivity. Experimental therapeutics in refractory panic probably will continue to examine the role of corticotropin releasing factor and glutamate/GABA systems. The role of CBT in the medication refractory patient has been explored, with preliminary suggestions of efficacy.

Mathew SJ, Coplan JD, Gorman JM. · New York State Psychiatric Institute, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. · Am J Psychiatry. · Pubmed #11578981 links to  free full text

Abstract: OBJECTIVE: The authors critically surveyed several preclinical and clinical neurobiological models of social anxiety disorder. METHOD: The authors reviewed the recent literature regarding three animal models of particular relevance to social anxiety. They then examined the recent literature concerning clinical neurobiological aspects of social anxiety disorder, including the developmental neurobiology of anxiety, the genetics of fear and social anxiety, and challenge and imaging studies. RESULTS: The available animal models are useful paradigms for understanding the features of social subordination stress, attachment behavior, and environmental rearing, but they incompletely account for the known neurobiology of human social anxiety disorder. The clinical neurobiology literature surveyed implicates specific neurotransmitter system abnormalities, most notably of the dopamine system, but largely ignores neurodevelopmental processes and the functional interactions between neurotransmitters. Both heritable factors and environmental stress factors appear to be responsible for the onset of social anxiety disorder. CONCLUSIONS: Social anxiety disorder should be conceptualized as a chronic neurodevelopmental illness that might represent a fully compensated state in adulthood. Future investigations from this perspective are discussed.

Gorman JM, Kent JM, Sullivan GM, Coplan JD. · Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, USA. · Am J Psychiatry. · Pubmed #10739407 links to  free full text

Abstract: OBJECTIVE: In a 1989 article, the authors provided a hypothesis for the neuroanatomical basis of panic disorder that attempted to explain why both medication and cognitive behavioral psychotherapy are effective treatments. Here they revise that hypothesis to consider developments in the preclinical understanding of the neurobiology of fear and avoidance. METHOD: The authors review recent literature on the phenomenology, neurobiology, and treatment of panic disorder and impressive developments in documenting the neuroanatomy of conditioned fear in animals. RESULTS: There appears to be a remarkable similarity between the physiological and behavioral consequences of response to a conditioned fear stimulus and a panic attack. In animals, these responses are mediated by a "fear network" in the brain that is centered in the amygdala and involves its interaction with the hippocampus and medial prefrontal cortex. Projections from the amygdala to hypothalamic and brainstem sites explain many of the observed signs of conditioned fear responses. It is speculated that a similar network is involved in panic disorder. A convergence of evidence suggests that both heritable factors and stressful life events, particularly in early childhood, are responsible for the onset of panic disorder. CONCLUSIONS: Medications, particularly those that influence the serotonin system, are hypothesized to desensitize the fear network from the level of the amygdala through its projects to the hypothalamus and the brainstem. Effective psychosocial treatments may also reduce contextual fear and cognitive misattributions at the level of the prefrontal cortex and hippocampus. Neuroimaging studies should help clarify whether these hypotheses are correct.

Sullivan GM, Coplan JD, Kent JM, Gorman JM. · Columbia University College of Physicians & Surgeons, New York, New York, USA. · Biol Psychiatry. · Pubmed #10560026 No free full text.

Abstract: 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.

Mathew SJ, Amiel JM, Coplan JD, Fitterling HA, Sackeim HA, Gorman JM. · Department of Biological Psychiatry, New York State Psychiatric Institute, USA. · Am J Psychiatry. · Pubmed #16330605 links to  free full text

Abstract: OBJECTIVE: There is a need to identify novel pharmacotherapies for anxiety disorders. The authors examined the safety and efficacy of riluzole, an antiglutamatergic agent, in adult outpatients with generalized anxiety disorder. METHOD: In an 8-week, open-label, fixed-dose study, 18 medically healthy patients with DSM-IV generalized anxiety disorder received treatment with riluzole (100 mg/day) following a 2-week drug-free period. The primary efficacy measure was the Hamilton Anxiety Rating Scale (HAM-A) score at endpoint. RESULTS: Twelve of the 15 patients who completed the trial responded positively to riluzole. At 8 weeks, eight of the 15 patients had HAM-A score indicating remission of their anxiety. The median time to response was 2.5 weeks. CONCLUSIONS: Riluzole appears to be an effective, well-tolerated, and rapidly acting anxiolytic medication for some patients with generalized anxiety disorder. Larger, placebo-controlled studies are indicated.

Gorman JM, Martinez J, Coplan JD, Kent J, Kleber M. · Department of Psychiatry and the Laboratory of Clinical Psychobiology, Mount Sinai School of Medicine, New York, NY 10029, USA. · Biol Psychiatry. · Pubmed #15576063 No free full text.

Abstract: BACKGROUND: A number of studies have shown that patients with panic disorder are more likely to have panic attacks during carbon dioxide inhalation than are normal comparison subjects. Some studies have shown that antipanic medications can reduce the anxiogenic response to carbon dioxide, but none have shown if this is the case for cognitive behavioral therapy or if successful treatment reduces the respiratory physiologic response to carbon dioxide. METHODS: Twenty-five patients with panic disorder and 13 normal comparison subjects underwent baseline testing with 5% and 7% carbon dioxide inhalation. The patients were then retested after at least 12 weeks of treatment with either antipanic medication or cognitive behavioral therapy. Comparison subjects were retested after a similar interval. RESULTS: Successful treatment resulted in lower panic rates, and reduced anxiogenic response. Treatment had no effect, however, on the respiratory physiologic response. CONCLUSIONS: There is dissociation in treatment response between the subjective and objective responses to carbon dioxide inhalation in panic disorder patients, with the former but not the latter showing positive change. We hypothesize that the strengthening of higher cortical control over subcortical fear-related structures, whether via medication or cognitive behavioral therapy treatment, results in less anxiety and fear in response to provoked symptoms reminiscent of naturally occurring panic.

Martinez JM, Kent JM, Coplan JD, Browne ST, Papp LA, Sullivan GM, Kleber M, Perepletchikova F, Fyer AJ, Klein DF, Gorman JM. · Department of Psychiatry, Columbia University, New York, New York 10032, USA. · Depress Anxiety. · Pubmed #11754131 No free full text.

Abstract: Disordered breathing may play an important role in the pathophysiology of panic disorder. Several studies have now indicated that panic disorder patients have greater respiratory variability than normal controls. In this study, we examine baseline respiratory measures in four diagnostic groups to determine whether greater respiratory variability is specific to panic disorder and whether effective anti-panic treatment alters respiratory variability. Patients with panic disorder, major depression, or premenstrual dysphoric disorder, and normal control subjects underwent two respiratory exposures (5% and 7% CO(2) inhalation), while in a canopy system. Panic disorder patients returned after 12 weeks of either anti-panic medication or cognitive behavioral therapy, and were retested. Normal control subjects were also retested after a period of 12 weeks. Panic disorder patients had significantly greater respiratory variability at baseline than normal control subjects and patients with major depression. The premenstrual dysphoric patients also had greater variability than the normal control group. Panic disorder patients who panicked to 7% CO(2) inhalation had significantly greater baseline variability than panic disorder patients who did not panic. Anti-panic treatment did not significantly alter baseline respiratory variability. Our data suggest that increased respiratory variability may be an important trait feature for some panic disorder patients and may make them more vulnerable to CO(2)-induced panic.

Mathew SJ, Coplan JD, Perko KA, Goetz RR, de la Neuz M, Hollander E, Liebowitz MR, Fallon BA. · Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York, USA. · Depress Anxiety. · Pubmed #11754126 No free full text.

Abstract: The current study examines the neuroendocrine response to intravenous clomipramine (IV CMI) in oral CMI-resistant obsessive-compulsive disorder (OCD) patients on day 1 and day 14 of treatment to identify predictors of response. Forty-four OCD patients with an inadequate response or poorly tolerant to oral CMI were begun at 25 mg IV CMI, increasing to 250 mg by day 10, and continuing on that dose to day 14. On day 1, plasma levels of prolactin (PRL), growth hormone (GH), and cortisol were obtained immediately before the 25 mg IV infusion, and at five 30-minute time points after the infusion. On day 14, hormonal samples were obtained in a similar fashion. Response was assessed by the Clinical Global Impressions (CGI). Low PRL(MAX) to IV CMI and low cortisol levels overall on day 1 were both significantly associated with clinical response at day 14. An overall increase in growth hormone (GH) secretion during the day 14 testing was associated with positive response. A pronounced PRL response to IV CMI on day 14 was exhibited by the nonresponders, whereas a smaller and later but significant increase in PRL was noted in the responders. The findings suggest that in this sample of oral CMI-resistant patients with OCD, neuroendocrine measures derived from pharmacological challenge with IV CMI are capable of distinguishing IV CMI treatment responders from nonresponders. The limitations of IV CMI as a specific probe of serotonin function are discussed.

Papp LA, Coplan JD, Martinez JM, de Jesus M, Gorman JM. · Department of Clinical Psychobiology, New York State Psychiatric Institute, New York 10032,USA. · J Clin Psychopharmacol. · Pubmed #11001239 No free full text.

Abstract: Fifteen patients with panic disorder participated in a 12-week treatment trial with open-label nefazodone. Nefazodone was well-tolerated with minimal side effects; none of the patients reported sexual dysfunction, and only one patient experienced weight gain. Although the response rate was lower than that found with most other antipanic medications, given its favorable side effect profile, nefazodone may be a good alternative for patients apprehensive about potential adverse drug reactions.

Sinha SS, Coplan JD, Pine DS, Martinez JA, Klein DF, Gorman JM. · Department of Psychiatry, Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute, New York 10032, USA. · Psychiatry Res. · Pubmed #10397411 No free full text.

Abstract: It has been hypothesized that spontaneous panic is distinct from anticipatory anxiety, which activates the hypothalamic-pituitary-adrenal (HPA) axis. Panic attacks characterized by prominent respiratory symptoms, such as those induced by sodium lactate, are not associated with increases in cortisol. We examined blood cortisol responses to CO2-induced panic. Cortisol levels did not increase and actually decreased significantly in 10 panicking subjects with panic disorder. No reductions were noted after 20 min of CO2 inhalation in either eight normal comparison subjects or six non-panicking panic disorder patients. These results lend support to the hypothesis that the pathophysiological mechanism underlying CO2-induced panic is different from that underlying general or anticipatory anxiety.

Coplan JD, Tamir H, Calaprice D, DeJesus M, de la Nuez M, Pine D, Papp LA, Klein DF, Gorman JM. · College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York, NY, USA. · Neuropsychopharmacology. · Pubmed #10088140 links to  free full text

Abstract: The psychoneuroimmunology of panic disorder is relatively unexplored. Alterations within brain stress systems that secondarily influence the immune system have been documented. A recent report indicated elevations of serotonin (5-HT) and ganglioside antibodies in patients with primary fibromyalgia, a condition with documented associations with panic disorder. In line with our interest in dysregulated 5-HT systems in panic disorder (PD), we wished to assess if antibodies directed at the 5-HT system were elevated in patients with PD in comparison to healthy volunteers. Sixty-three patients with panic disorder and 26 healthy volunteers were diagnosed by the SCID. Employing ELISA, we measured anti-5-HT and 5-HT anti-idiotypic antibodies (which are directed at 5-HT receptors). To include all subjects in one experiment, three different batches were run during the ELISA. Plasma serotonin anti-idiotypic antibodies: there was a significant group effect [patients > controls (p = .007)] and batch effect but no interaction. The mean effect size for the three batches was .76. Following Z-score transformation of each separate batch and then combining all scores, patients demonstrated significantly elevated levels of plasma serotonin anti-idiotypic antibodies. Neither sex nor age as covariates affected the significance of the results. There was a strong correlation between anti-serotonin antibody and serotonin anti-idiotypic antibody measures. Plasma anti-serotonin antibodies: there was a significant diagnosis effect [patients > controls (p = .037)]. Mean effect size for the three batches was .52. Upon Z-score transformation, there was a diagnosis effect with antibody elevations in patients. Covaried for sex and age, the result falls below significance to trend levels. The data raise the possibility that psychoimmune dysfunction, specifically related to the 5-HT system, may be present in PD. Potential interruption of 5-HT neurotransmission through autoimmune mechanisms may be of pathophysiologic significance in certain patients with panic disorder. It remains to be demonstrated if the peripheral autoimmunity is representative of CNS 5-HT neuronal alterations. Replication appears warranted.

Bergold PJ, Pinkhasova V, Syed M, Kao HY, Jozwicka A, Zhao N, Coplan JD, Dow-Edwards D, Fenton AA. · Department of Physiology and Pharmacology, SUNY-Downstate Medical Center, Brooklyn, NY 11203, United States. · Neurosci Lett. · Pubmed #19429039 No free full text.

Abstract: Lactate uses an unknown mechanism to induce panic attacks in people and panic-like symptoms in rodents. We tested whether intraperitoneal (IP) lactate injections act peripherally or centrally to induce panic-like symptoms in rats by examining whether IP lactate directly affects the CNS. In Long-Evans rats, IP lactate (2 mmol/kg) injection increased lactate levels in the plasma and the cerebrospinal fluid. IP lactate also induced tachycardia and behavioral freezing suggesting the production of panic-like behavior. To enter intermediate metabolism, lactate is oxidized by lactate dehydrogenase (LDH) to pyruvate with co-reduction of NAD(+) to NADH. Therefore, we measured the ratio of NADH/NAD(+) to test whether IP lactate altered lactate metabolism in the CNS. Lactate metabolism was studied in the hippocampus, a brain region believed to contribute to panic-like symptoms. IP lactate injection lowered the ratio of NADH/NAD(+) without altering the total amount of NADH and NAD(+) suggesting oxidation of hippocampal redox state. Lactate oxidized hippocampal redox since intrahippocampal injection of the LDH inhibitor, oxamate (50mM) prevented the oxidation of NADH/NAD(+) by IP lactate. In addition to oxidizing hippocampal redox, IP lactate rapidly increased the firing rate of hippocampal neurons. Similar IP pyruvate injections had no effect. Neural discharge also increased following intrahippocampal lactate injection suggesting that increased discharge was a direct action of lactate on the hippocampus. These studies show that oxidation of brain redox and increased hippocampal firing are direct actions of lactate on the CNS that may contribute to the production of lactate-induced panic.

Mathew SJ, Mao X, Keegan KA, Levine SM, Smith EL, Heier LA, Otcheretko V, Coplan JD, Shungu DC. · Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA. · NMR Biomed. · Pubmed #18942064 No free full text.

Abstract: Chronic fatigue syndrome (CFS) is a controversial diagnosis because of the lack of biomarkers for the illness and its symptom overlap with neuropsychiatric, infectious, and rheumatological disorders. We compared lateral ventricular volumes derived from tissue-segmented T(1)-weighted volumetric MRI data and cerebrospinal fluid (CSF) lactate concentrations measured by proton MRS imaging ((1)H MRSI) in 16 subjects with CFS (modified US Centers for Disease Control and Prevention criteria) with those in 14 patients with generalized anxiety disorder (GAD) and in 15 healthy volunteers, matched group-wise for age, sex, body mass index, handedness, and IQ. Mean lateral ventricular lactate concentrations measured by (1)H MRSI in CFS were increased by 297% compared with those in GAD (P < 0.001) and by 348% compared with those in healthy volunteers (P < 0.001), even after controlling for ventricular volume, which did not differ significantly between the groups. Regression analysis revealed that diagnosis accounted for 43% of the variance in ventricular lactate. CFS is associated with significantly raised concentrations of ventricular lactate, potentially consistent with recent evidence of decreased cortical blood flow, secondary mitochondrial dysfunction, and/or oxidative stress abnormalities in the disorder.

Mathew SJ, Price RB, Mao X, Smith EL, Coplan JD, Charney DS, Shungu DC. · Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA. · Biol Psychiatry. · Pubmed #18028881 links to  free full text

Abstract: BACKGROUND: Previous research has suggested the therapeutic potential of glutamate-modulating agents for severe mood and anxiety disorders, potentially resulting from enhancement of neuroplasticity. We used proton magnetic resonance spectroscopic imaging ((1)H MRSI) to examine the acute and chronic effects of the glutamate-release inhibitor riluzole on hippocampal N-acetylaspartate (NAA), a neuronal marker, in patients with generalized anxiety disorder (GAD) and examined the relationship between changes in NAA and clinical outcome. METHODS: Fourteen medication-free GAD patients were administered open-label riluzole and then evaluated by (1)H MRSI before drug administration, and 24 hours and 8 weeks following treatment. Patients were identified as responders (n = 9) or nonresponders (n = 5). Seven untreated, medically healthy volunteers, comparable in age, sex, IQ, and body mass index to the patients, received scans at the same time intervals. Molar NAA concentrations in bilateral hippocampus, and change in anxiety ratings were the primary outcome measures. RESULTS: A group-by-time interaction was found, with riluzole responders showing mean increases in hippocampal NAA across the three time points, whereas nonresponders had decreases over time. In GAD patients at Week 8, hippocampal NAA concentration and proportional increase in NAA from baseline both were positively associated with improvements in worry and clinician-rated anxiety. CONCLUSIONS: These preliminary data support a specific association between hippocampal NAA and symptom alleviation following riluzole treatment in GAD. Placebo-controlled investigations that examine hippocampal NAA as a viable surrogate endpoint for clinical trials of neuroprotective and plasticity-enhancing agents are warranted.

Pollack MH, Otto MW, Roy-Byrne PP, Coplan JD, Rothbaum BO, Simon NM, Gorman JM. · Harvard Medical School and Center for Anxiety and Traumatic Stress Related Disorders, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Depress Anxiety. · Pubmed #17437259 No free full text.

Abstract: The Anxiety Disorders Association of America convened a conference of experts to address treatment-resistant anxiety disorders and review promising novel approaches to the treatment of refractory anxiety disorders. Workgroup leaders and other participants reviewed the literature and considered the presentations and discussions from the conference. Authors placed the emerging literature on new therapeutic approaches into clinical perspective and identified unmet needs and priority areas for future research. There is a relative paucity of efforts addressing inadequate response to anxiety disorder treatment. Systematic efforts to exhaust all therapeutic options and overcome barriers to effective treatment delivery are needed before patients can be considered treatment refractory. Cognitive behavioral therapy, especially in combination with pharmacotherapy, must be tailored to accommodate the effects of clinical context on treatment response. The literature on pharmacologic treatment of refractory anxiety disorders is small but growing and includes studies of augmentation strategies and non-traditional anxiolytics. Research efforts to discover new pharmacologic targets are focusing on neuronal systems that mediate responses to stress and fear. A number of clinical and basic science studies were proposed that would advance the research agenda and improve treatment of patients with anxiety disorders. Significant advances have been made in the development of psychotherapeutic and pharmacologic treatments for anxiety disorders. Unfortunately, many patients remain symptomatic and functionally impaired. Progress in the development of new treatments has great promise, but will only succeed through a concerted research effort that systematically evaluates potential areas of importance and properly uses scarce resources.

Coplan JD, Mathew SJ, Mao X, Smith EL, Hof PR, Coplan PM, Rosenblum LA, Gorman JM, Shungu DC. · Department of Psychiatry, Division of Neuropsychopharmacology, State University of New York, Downstate Medical Center, Brooklyn, 11023, USA. · Psychiatry Res. · Pubmed #16797939 No free full text.

Abstract: We have demonstrated, using proton magnetic resonance spectroscopy imaging ((1)H-MRSI), elevations of N-acetyl-aspartate/creatine (NAA/CR) in right dorsolateral prefrontal cortex (DLPFC) in patients with generalized anxiety disorder (GAD) in comparison to healthy volunteers. A recent study indicates that the volume of prefrontal cortical white matter may be disproportionately increased in man in comparison to other primate species, with evolutionary implications. We therefore re-analyzed the identical scans with a specific focus on the centrum semiovale (CSO) as a representative region of interest of cerebral white matter. The central hypothesis was, in accordance with our gray matter findings, that patients with GAD, in comparison to healthy controls, would exhibit either an increase in NAA in CSO, or alternatively demonstrate reductions in concentrations of choline (CHO)-containing compounds and/or creatine+phosphocreatine (CR). MRSI scans that were obtained from an earlier [Mathew, S.J., Mao, X., Coplan, J.D., Smith, E.L., Sackeim, H.A., Gorman, J.M., Shungu, D.C., 2004. Dorsolateral prefrontal cortical pathology in generalized anxiety disorder: a proton magnetic resonance spectroscopic imaging study. American Journal of Psychiatry 161, 1119-1121] sample of 15 patients with GAD [6 with early trauma (ET)] and 15 healthy age- and sex-matched volunteers were analyzed further for CSO metabolite alterations. Self-reported worry was scored using the Penn State Worry Questionnaire (PSWQ) and intelligence was assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serial multislice/multivoxel MRSI scans had been performed on a 1.5-T MRI. Using absolute quantification methods for metabolite concentrations, we examined NAA, CHO and CR. GAD patients without ET exhibited bilaterally decreased concentrations of CHO and CR in CSO in comparison to healthy volunteers, whereas GAD patients with ET were indistinguishable from controls. In patients with GAD, high IQ was paired with greater worry, whereas in healthy volunteers, high IQ was associated with less worry. In all subjects, IQ inversely predicted left and right CSO CHO concentrations, independent of age, sex, group assignment and PSWQ scores. The CSO may therefore represent a neural substrate that exhibits reductions in CHO and CR metabolite concentrations that are inversely associated with GAD symptomatology and, in the case of CHO, with intelligence. These conclusions are deemed preliminary due to small sample size, with further study of cerebral WM in anxiety disorders suggested.

Kent JM, Coplan JD, Mawlawi O, Martinez JM, Browne ST, Slifstein M, Martinez D, Abi-Dargham A, Laruelle M, Gorman JM. · Department of Psychiatry, Unit 41, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA. · Am J Psychiatry. · Pubmed #15994724 links to  free full text

Abstract: OBJECTIVE: Lack of appropriate top-down governance by frontal cortical regions over a hypersensitive amygdala-centered fear neurocircuitry has been hypothesized to be central in the pathophysiology of panic disorder. The aim of this study was to examine regional cerebral blood flow changes in response to anxiety/panic provocation in subjects with panic disorder and healthy comparison subjects. METHOD: Quantitative water method positron emission tomography was used to obtain brain images of five untreated subjects with panic disorder and five healthy comparison subjects before and during anxiogenic challenge with intravenous doxapram, an acute respiratory stimulant. RESULTS: Baseline perfusion of the orbitofrontal cortex predicted panic attacks: lower perfusion was associated with heightened anxiety in response to doxapram challenge. CONCLUSIONS: The orbitofrontal cortex may be important in the regulation of responding to fear and is a potential area of aberrant functioning in panic disorder.

Mathew SJ, Coplan JD, Schoepp DD, Smith EL, Rosenblum LA, Gorman JM. · Department of Psychiatry, Division of Clinical Psychobiology, Columbia University, New York, NY, USA. · CNS Spectr. · Pubmed #15573019 No free full text.

Abstract: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a pathologic feature of certain mood and anxiety disorders that results in the increased production and secretion of corticotropin-releasing factor. There is increasing preclinical evidence that glutamate, an excitatory amino acid, plays an important role in the regulation of the HPA axis. Activation of glutamatergic projections to limbic structures such as the amygdala and brainstem structures such as the nucleus tractus solitarius is implicated in the stress response. There are laboratory and clinical suggestions that glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists function as antidepressants, and that chronic antidepressant treatments have a significant impact on NMDA receptor function. Clinical investigations of glutamate antagonists in patients with mood and anxiety disorders are in their infancy, with a few reports suggesting the presence of mood-elevating properties. Ultimately, HPA axis modulators, serotonin-enhancing agents, and glutamate antagonists might serve to increase neurotropic factors in key brain regions for affective and anxiety regulation, providing a putative final common pathway.

Feder A, Coplan JD, Goetz RR, Mathew SJ, Pine DS, Dahl RE, Ryan ND, Greenwald S, Weissman MM. · Department of Psychiatry, College of Physicians and Surgeons, Columbia University, USA. · Biol Psychiatry. · Pubmed #15271589 No free full text.

Abstract: BACKGROUND: Previous studies found few abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function in prepubertal children with anxiety or depressive disorders. In this study, we combined data from two independent, consecutive studies to achieve a larger sample size. Our goal was to identify potential alterations in the circadian pattern of cortisol secretion in anxious or depressed children. METHODS: A total of 124 prepubertal subjects from two independent samples (76 with major depressive disorder, 31 with anxiety disorders, and 17 healthy control subjects) were studied. Blood samples collected for cortisol at hourly intervals over a 24-hour period were examined. Analyses were performed aligning cortisol samples by clock-time. Additional analyses aligning samples by sleep-onset time were performed with a subsample of subjects. RESULTS: In the combined sample, significant findings emerged that were previously undetected. Anxious children exhibited significantly lower nighttime cortisol levels and an initially sluggish rise in cortisol during the nighttime when compared with depressed and healthy control children. In contrast, depressed children did not show a clear-cut pattern of differences compared with healthy control children. CONCLUSIONS: Anxious children seem to exhibit an altered pattern of nighttime cortisol secretion, with an initially sluggish or delayed nocturnal rise before reaching similar peak levels of cortisol near the time of awakening. These findings suggest subtle alterations in HPA axis function in prepubertal children with anxiety disorders.

Mathew SJ, Mao X, Coplan JD, Smith EL, Sackeim HA, Gorman JM, Shungu DC. · Department of Biological Psychiatry, New york State Psychiatric Institute, Columbia Unversity, New York, NY 10032, USA. · Am J Psychiatry. · Pubmed #15169704 links to  free full text

Abstract: OBJECTIVE: Few neuroimaging studies of generalized anxiety disorder have been conducted. The present study used proton magnetic resonance spectroscopy to assess concentrations of N-acetylaspartate, often considered a marker of neuronal viability, in generalized anxiety disorder patients. METHOD: N-Acetylaspartate/creatine resonance ratios were measured in the left and right dorsolateral prefrontal cortex and hippocampus of 15 medication-free generalized anxiety disorder patients and 15 age- and sex-matched healthy volunteers. RESULTS: Generalized anxiety disorder patients had a 16.5% higher N-acetylaspartate/creatine ratio in the right dorsolateral prefrontal cortex compared with healthy participants; 13 of 15 matched patient-comparison subject pairs displayed a difference in this direction. In addition, generalized anxiety disorder patients reporting childhood abuse had lower N-acetylaspartate/creatine ratios in the right dorsolateral prefrontal cortex than did nonabused patients. Metabolite differences were not detected in other regions. CONCLUSIONS: Generalized anxiety disorder is associated with asymmetric increases in the N-acetylaspartate/creatine ratio, a suggested marker of neuronal viability, in the prefrontal cortex. The findings also support prior research linking childhood abuse to reduced neuronal viability.

Kent JM, Coplan JD, Lombardo I, Hwang DR, Huang Y, Mawlawi O, Van Heertum RL, Slifstein M, Abi-Dargham A, Gorman JM, Laruelle M. · New York State Psychiatry Institute, New York, NY 10032, USA. · Psychopharmacology (Berl). · Pubmed #12457263 No free full text.

Abstract: RATIONALE: Although selective serotonin reuptake inhibitors (SSRIs) are widely used in the treatment of anxiety and depressive disorders, the occupancy of the serotonin reuptake transporter (SERT) achieved in humans at typical clinical doses by these agents remains poorly characterized. OBJECTIVE: The purpose of this study was to determine the occupancy of the SERT achieved in vivo by the SSRI paroxetine in social phobia patients at typical antianxiety doses. METHODS: Measures of SERT availability were obtained with positron emission tomography and the SERT radiotracer [(11)C](+)-McN 5652 in five patients with social phobia before and during treatment with paroxetine at usual therapeutic doses (20-40 mg per day). RESULTS: Occupancy of the SERT by paroxetine was high in all subjects and in all regions measured after 3-6 months of continuous treatment. CONCLUSIONS: The results of this study in an anxiety disorder sample are consistent with previously reported results in a depressed sample and suggest that paroxetine at therapeutic doses achieves very high occupancy levels of the SERT.

Coplan JD, Moreau D, Chaput F, Martinez JM, Hoven CW, Mandell DJ, Gorman JM, Pine DS. · Department of Psychiatry, SUNY-Downstate, Brooklyn, NY, USA. · Biol Psychiatry. · Pubmed #11958784 No free full text.

Abstract: BACKGROUND: Considerable research implicates over-activity of the hypothalamic-pituitary adrenal axis in the pathophysiology of adult mood and anxiety disorders. The current study evaluates the association between salivary cortisol concentrations and response to carbon-dioxide inhalation in children and adolescents with anxiety disorders, mood disorders, or no psychiatric illness. The central question was whether response to carbon-dioxide inhalation is associated with levels of hypothalamic-pituitary adrenal axis activation. If confirmed, this would relate hypothalamic-pituitary adrenal axis activation in juveniles, as in adults, and response to a well-studied respiratory procedure. METHODS: Serial salivary cortisol samples were examined in 98 subjects (ages 9-17 years), including 62 subjects with an anxiety and/or mood disorder and 36 nonpsychiatrically ill comparisons. Samples were obtained upon arrival at the laboratory, following a tilt test, then before and immediately after a standard 5% carbon dioxide inhalation procedure. RESULTS: Salivary cortisol levels pre-carbon-dioxide inhalation were significantly higher in patients sensitive to the anxiogenic effects of carbon dioxide (n = 20) than in patients who did not respond to carbon dioxide (n = 42) and in healthy subjects, none of whom were sensitive to carbon dioxide (n = 36); cortisol concentrations in the latter two groups were indistinguishable. Salivary cortisol did not increase during carbon-dioxide inhalation, irrespective of diagnostic group or degree of reactivity to the procedure. CONCLUSIONS: The current data resemble data from studies of laboratory-induced panic among adult patients. In both groups, activation of the hypothalamic-pituitary adrenal axis is associated with the response to a standardized stressor. Similarly, as in adults, carbon-dioxide inhalation in juveniles does not produce a significant change in hypothalamic-pituitary adrenal axis activation.

Coplan JD, Smith EL, Altemus M, Scharf BA, Owens MJ, Nemeroff CB, Gorman JM, Rosenblum LA. · Department of Psychiatry, SUNY Health Science Center, Brooklyn, New York 11203, USA. · Biol Psychiatry. · Pubmed #11513819 No free full text.

Abstract: 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.

Rosenblum LA, Forger C, Noland S, Trost RC, Coplan JD. · Primate Behavior Laboratory, Department of Psychiatry, State University of New York, Health Science Center at Brooklyn, Brooklyn, NY 11203, USA. · Dev Psychobiol. · Pubmed #11507708 No free full text.

Abstract: When primate infants are reared during the first half-year of life in an environment in which their mothers face uncertain requirements for food procurement (variable foraging demand [VFD]), long-lasting behavioral and neurodevelopmental consequences ensue, including increases in timidity and social subordinance as well as alterations in stress-related neuroendocrine profiles. We examined the nature and persistence of the effects of VFD rearing by exposing VFD-reared and normally reared adolescent bonnet macaques to a mild fear-provoking stimulus 2 years after the end of differential rearing. VFD-reared subjects at baseline were less gregarious than normally reared monkeys. VFDs also were considerably less responsive to the fear stimulus, and their behavior and affect returned to baseline levels more quickly than normally reared subjects. The extent and persistence of the sequelae of VFD rearing suggest parallels with predisposing factors in human anxiety disorders.