Amir Garakani

Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists

Drugs acting at metabotropic glutamate receptors (mGluRs) are among the most promising agents under development for the treatment of psychiatric disorders. The research in this area is at a relatively early stage, as there are no drugs acting at mGluRs that have been approved for the treatment of any psychiatric disorder. However, in the areas of schizophrenia, anxiety disorders and mood disorders, research conducted in animal models appears to translate well into efficacy in human laboratory-based models of psychopathology and in preliminary clinical trials. Further, the genes coding for mGluRs are implicated in the risk for a growing number of psychiatric disorders. This review highlights the best studied mGluR strategies for psychiatry, based on human molecular genetics, studies in animal models and preliminary clinical trials. It describes the potential value of mGluR2 and mGluR5 agonists and positive allosteric modulators for the treatment of schizophrenia. It also reviews evidence that group II mGluR agonists and positive allosteric modulators as well as group I mGluR antagonists might also treat anxiety disorders and some forms of depression, while mGluR2 and group I mGluR antagonists (particularly mGluR5 antagonists) might have antidepressant properties. This review also links growing insights into the role of glutamate in the pathophysiology of these disorders to hypothesized mGluR-related treatment mechanisms.

Psychobiology of the acute stress response and its relationship to the psychobiology of post-traumatic stress disorder.

The literature to date that examines the biology of the acute stress reactions suggests that relatively lower baseline cortisol is associated with the development of PTSD. This is particularly informative because of the ongoing controversy surrounding baseline cortisol in PTSD. Studies have found low baseline cortisol, normal range, and elevated baseline cortisol in chronic PTSD, and it has been unclear whether this reflects methodologic differences across studies or true heterogeneity within the disorder. Thus, the few studies to date support the finding of low-normal baseline cortisol in chronic PTSD and suggest that it is a pre-existing functional trait. Whether it plays an etiologic role or is an epiphenomenon of some other process is unclear. What does seem clear, however, is that this characteristic is relatively nonspecific to PTSD, given the fact that low cortisol has been observed in multiple subject populations, including normal individuals under chronic stress as well as chronic medical conditions (for review see [23]). For example, it is possible that reduced baseline cortisol reflects the net result of input to the hypothalamus from cortical and subcortical regions of the brain linked to increased vigilance, sensitization to trauma because of prior traumatic experiences, or genetic factors. For example, primate studies have demonstrated persistent alterations in HPA axis functioning in animals reared by mothers living in moderately stressful conditions [24]. The development of PTSD is associated with sensitization of the startle response. Because the neurobiology of startle is well characterized, this finding implicates a role for specific neurocircuitry in PTSD [25]. Non-habituation of the startle response in PTSD appears related to sensitization specifically to contextual cues (i.e., the environment) that signal the presence of potential threat of danger-related fears [26]. This may be the neurobiological correlate to the over-generalization seen in PTSD that distinguishes the disorder from a simple trauma-induced phobia. The bed nucleus of the stria terminalis (BNST) is specifically implicated from preclinical research in the mediation of context-dependent cues [1]. Treatments that result in down-regulation of the BNST are therefore of particular interest in therapeutic models of prevention after trauma. The fact that a number of vulnerability factors associated with increased risk for developing PTSD are also likely to be biologically based (e.g., a genetic component, prior psychiatric history, prior family of history of psychiatric disorder), provides further evidence in support of a role for psychobiological factors in producing PTSD. Nevertheless, the considerable overlap on these measures between those who will develop PTSD, and those who eventually recover spontaneously, belies any attempt to identify any single or pathognomonic biological marker for risk. For now, the standard of care in predicting level of symptomatology and prognosis in the acute setting continues to be based on careful, informed, serial assessments of symptoms and functioning. Because the capacity to learn from and adapt to adverse conditions are essential to the survival of any species, understanding the neurobiological pathways that mediate learning from traumatic experiences in an adaptive way is as important as understanding the etiology of PTSD and other trauma-related maladaptive consequences. Biological models that trace the causal cascade of post-traumatic events in the brain and neuroendocrine systems may offer a multiplicity of possibilities for intervention. It is well established that conditioned responses are robust and persistent. Moreover, the primary mechanism of habituation is overlearning rather than extinction. Interventions that promote overlearning may therefore prove to be the most powerful and efficient preventative treatments. The therapeutics literature supports this hypothesis, in that brief psychosocial interventions based on sophisticated cognitive-behavioral models have proven effective in reducing suffering, symptom severity, and chronicity in individuals presenting with acute PTSD symptoms [27-29]. No acutely administered pharmacologic treatment to date has been shown effective in accelerating the process of recovery or in preventing the development of chronic PTSD. However, pharmacologic interventions that would prevent sensitization of circuits related to context-dependent threat perception, dysregulation of affect, and/or dysregulation of normal circadian rhythms are of theoretical interest and deserve further study.

A randomized, double-blind, and placebo-controlled trial of quetiapine augmentation of fluoxetine in major depressive disorder.

The objective of this study was to investigate whether quetiapine, when compared with placebo, can speed the onset of action and improve the quality of response to fluoxetine treatment in patients suffering from major depressive disorder. A total of 114 patients with major depressive disorder were enrolled in an 8-week treatment study. Patients were initiated on a course of fluoxetine treatment and randomized to quetiapine or placebo. Quetiapine was flexibly dosed starting at 25 mg to a maximum of 100 mg daily. Mixed-effects regression showed that quetiapine plus fluoxetine did not achieve 50% reduction in the Montgomery–Åsberg Depression Rating Scale score or improvement in Hamilton Anxiety Scale, Clinical Global Improvement (CGI)-Severity, and CGI-Improvement scores sooner than the fluoxetine plus placebo group; however both groups improved in all scores over time. Mixed-effects linear regression of insomnia scores showed that the quetiapine plus fluoxetine group improved significantly more rapidly compared with the fluoxetine plus placebo group. The study indicates that quetiapine plus fluoxetine did not achieve a reduction in the Montgomery–Åsberg Depression Rating Scale score or improvement in Hamilton Anxiety Scale or CGI scores from baseline sooner than the fluoxetine plus placebo group. The combination of quetiapine and fluoxetine, however, improved sleep over fluoxetine alone over the first few weeks of treatment.

The Pharmacological Treatment of Bipolar Disorder: The Question of Modern Advances

Introduction: Lithium has been the mainstay of treatment for patients with bipolar disorder in the United States since 1970. Major treatment guidelines recommend lithium as a first‐line treatment for mania and maintenance treatment of bipolar disorder, yet lithium has fallen out of favor while other agents have grown in popularity. The purpose of this review is to examine the evidence for treatments that were available in 1970 and to determine if the field has made any significant advance in the treatment of mania, bipolar depression, and maintenance. Methods: We conducted a MEDLINE search through 2009, and examined only English‐language, randomized/controlled, placebo, or comparison studies. Tolerability as a factor was not considered for this review. Results: Lithium, valproate, benzodiazepines, and antipsychotics have been reported effective for mania—which was essentially the state of the field in 1970. Despite an FDA indication for the use of lamotrigine for depression and depression maintenance, the supporting evidence is conflicting. For bipolar maintenance, the evidence is overwhelming in support of lithium and very thin for valproate and carbamazepine. There is emerging evidence that several atypical antipsychotics may have efficacy in prevention. Discussion: The gold standard for treating bipolar disorder in 1970 was lithium, and the gold standard in 2009 remains lithium. Newer agents may increase our armamentarium to some extent, but it is not clear if they represent a major advance in treatment. They still need to be tested against the gold standard.

The Effect of Doxapram on Brain Imaging In Patients with Panic Disorder

Administration of doxapram hydrochloride, a respiratory stimulant, is experienced by panic disorder patients to be similar to panic attacks but has reduced emotional effect in normal volunteers, thus providing a laboratory model of panic for functional imaging. Six panic patients and seven normal control subjects underwent positron emission tomography with (18)F-deoxyglucose imaging after a single-blinded administration of either doxapram or a placebo saline solution. Saline and doxapram were administered on separate days in counterbalanced order. Patients showed a greater heart rate increase on doxapram relative to saline than controls, indicating differential response. On the saline placebo day, patients had greater prefrontal relative activity than controls. In response to doxapram, patients tended to decrease prefrontal activity more than controls, and increased cingulate gyrus and amygdala activity more than controls. This suggests that panic disorder patients activate frontal inhibitory centers less than controls, a tendency that may lower the threshold for panic.

Cerebrospinal fluid levels of glutamate and corticotropin releasing hormone in major depression before and after treatment

BACKGROUND Glutamate and corticotropin releasing hormone (CRH) are pro-stress neurotransmitters and may be altered in the plasma and cerebrospinal fluid (CSF) of persons with major depressive disorder (MDD). The goal of this study was to compare the CSF levels of glutamate, glutamine and CRH between patients with depression and healthy controls. METHODS Eighteen patients with MDD and 25 healthy controls underwent a lumbar puncture (LP); CSF samples were withdrawn and assays were done for glutamine, glutamate, and CRH. Patients with MDD underwent 8 weeks of treatment with the antidepressant venlafaxine and then had a repeat LP post treatment. RESULTS Patients had higher baseline scores on depression and suicide rating scales and those scales improved significantly post-treatment. Higher suicidal ratings at baseline were correlated with higher glutamate levels (p=0.016). There were no significant differences between the control and patient group in any baseline CSF measures of glutamate (p=0.761), glutamine (p=0.226) or CRH (p=0.675). Despite no significant change in glutamate (p=0.358) and CRH (p=0.331) in the treatment group, there was a post-treatment decrease in glutamine (p=0.045) in patients. LIMITATIONS There was a small sample size, age discordance between patients and controls, lack of a follow-up LP in controls, absence of dexamethasone suppression testing, and fluctuating sample sizes among various measures. CONCLUSION Although no significant differences were noted between patients and controls at baseline there was an association of high CSF glutamate and suicidal ideation and lower glutamine post-treatment which may be correlated with attenuation of dysfunction in the glutamatergic system after antidepressant treatment.

Psychosis and Low Cyanocobalamin in a Patient Abusing Nitrous Oxide and Cannabis

Nitrous oxide (N2O) is an inhalant used primarily as anesthesia in dental procedures. It also has been reported as a substance of abuse among adolescents and young adults with a lifetime prevalence ranging between 2% and 15.8%. Abuse, or even occupational N2O exposure, 3,4 can cause vitamin B12 (cyanocobalamin) deficiency. Several case studies have also reported myelopathy, myeloneuropathy, and subacute combined degeneration in abusers of N2O, and even possible related deaths. To date, however, there have been only a handful of case studies of psychosis in a person abusing N2O. 12–14 We report a case of paranoid delusions and vitamin B12 deficiency in a man abusing N2O “whippits” along with cannabis.

Mental Health Approaches to Child Victims of Acts of Terrorism

It has long been recognized that human beings exposed to severe stress may develop psychological symptoms. With recent terrorist acts around the world including the New York City World Trade Center September 11, 2001 atrocity, there has been a growing interest in the specific impact of terrorist acts on the victims and witnesses. One area that has received less study is the specific impact on children. This paper reviews some of the general effects of traumatic stress on children and the history of the research in this area including a specific discussion of post-traumatic stress disorder in children. This is followed by a review of how children might react to the trauma of a terrorist attack differentiating between three different subgroups of children (preschool age children, school-age children, and adolescents). Then there is a review of what a comprehensive evaluation of childhood victims of terrorism should entail. Finally, treatment modalities that have been shown to be effective are reviewed.

New-Onset Panic, Depression with Suicidal Thoughts, and Somatic Symptoms in a Patient with a History of Lyme Disease

Lyme Disease, or Lyme Borreliosis, caused by Borrelia burgdorferi and spread by ticks, is mainly known to cause arthritis and neurological disorders but can also cause psychiatric symptoms such as depression and anxiety. We present a case of a 37-year-old man with no known psychiatric history who developed panic attacks, severe depressive symptoms and suicidal ideation, and neuromuscular complaints including back spasms, joint pain, myalgias, and neuropathic pain. These symptoms began 2 years after being successfully treated for a positive Lyme test after receiving a tick bite. During inpatient psychiatric hospitalization his psychiatric and physical symptoms did not improve with antidepressant and anxiolytic treatments. The patients panic attacks resolved after he was discharged and then, months later, treated with long-term antibiotics for suspected “chronic Lyme Disease” (CLD) despite having negative Lyme titers. He however continued to have subsyndromal depressive symptoms and chronic physical symptoms such as fatigue, myalgias, and neuropathy. We discuss the controversy surrounding the diagnosis of CLD and concerns and considerations in the treatment of suspected CLD patients with comorbid psychiatric diagnoses.

Urinary retention with a high dose of escitalopram

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for depressive disorders, having replaced tricyclic antidepressants (TCAs). One concern about TCAs is the prevalence of side effects, in particular, anticholinergic symptoms such as dry mouth, sedation and constipation [1]. Urinary retention is another potential adverse effect of TCAs but is also rarely seen with SSRIs [1]. The following is a case of an otherwise healthy man with major depression who developed acute urinary retention after taking a high dose of escitalopram, an SSRI, early in treatment.