Lawrence H. Price

Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Treatment-Resistant Depression

BACKGROUND We investigated the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) for treatment refractory depression. METHODS Fifteen patients with chronic, severe, highly refractory depression received open-label DBS at three collaborating clinical sites. Electrodes were implanted bilaterally in the VC/VS region. Stimulation was titrated to therapeutic benefit and the absence of adverse effects. All patients received continuous stimulation and were followed for a minimum of 6 months to longer than 4 years. Outcome measures included the Hamilton Depression Rating Scale-24 item (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Global Assessment of Function Scale (GAF). RESULTS Significant improvements in depressive symptoms were observed during DBS treatment. Mean HDRS scores declined from 33.1 at baseline to 17.5 at 6 months and 14.3 at last follow-up. Similar improvements were seen with the MADRS (34.8, 17.9, and 15.7, respectively) and the GAF (43.4, 55.5, and 61.8, respectively). Responder rates with the HDRS were 40% at 6 months and 53.3% at last follow-up (MADRS: 46.7% and 53.3%, respectively). Remission rates were 20% at 6 months and 40% at last follow-up with the HDRS (MADRS: 26.6% and 33.3%, respectively). The DBS was well-tolerated in this group. CONCLUSIONS Deep brain stimulation of the VC/VS offers promise for the treatment of refractory major depression.

Decreased Adrenocorticotropic Hormone and Cortisol Responses to Stress in Healthy Adults Reporting Significant Childhood Maltreatment

BACKGROUND Preclinical research findings suggest that exposure to stress and concomitant hypothalamus-pituitary-adrenal (HPA) axis activation during early development can have permanent and potentially deleterious effects. A history of early-life abuse or neglect appears to increase risk for mood and anxiety disorders. Abnormal HPA response to stress challenge has been reported in adult patients with major depressive disorder and posttraumatic stress disorder. METHODS Plasma adrenocorticotropin hormone (ACTH) and cortisol reactivity to the Trier Social Stress Test were examined in healthy adults (n = 50) without current psychopathology. Subjects with a self-reported history of moderate to severe childhood maltreatment (MAL) (n = 23) as measured by the Childhood Trauma Questionnaire were compared with subjects without such a history (CTL) (n = 27). RESULTS Compared with CTLs, MAL subjects exhibited significantly lower cortisol and ACTH baseline-to-peak deltas. A significant group effect was seen in the (repeated measures) cortisol response to the stress challenge, reflecting lower concentrations among MAL subjects. A significant group x time effect characterized the relatively blunted ACTH response of the MAL group. Emotional neglect (-.34, p = .02) and sexual abuse (.31, p = .03) strongly predicted maximal cortisol release. CONCLUSIONS In adults without diagnosable psychopathology, childhood maltreatment is associated with diminished HPA axis response to a psychosocial stressor. Possible explanations for the finding are discussed.

Childhood Adversity and Epigenetic Modulation of the Leukocyte Glucocorticoid Receptor: Preliminary Findings in Healthy Adults

Background A history of early adverse experiences is an important risk factor for adult psychopathology. Changes in stress sensitivity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the association between stress and risk for psychiatric disorders. Preclinical work in rodents has linked low levels of maternal care to increased methylation of the promoter region of the glucocorticoid receptor (GR) gene, as well as to exaggerated hormonal and behavioral responses to stress. Recent studies have begun to examine whether early-life stress leads to epigenetic modifications of the GR gene in humans. Methods We examined the degree of methylation of a region of the promoter of the human GR gene (NR3C1) in leukocyte DNA from 99 healthy adults. Participants reported on their childhood experiences of parental behavior, parental death or desertion, and childhood maltreatment. On a separate day, participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, a standardized neuroendocrine challenge test. Results Disruption or lack of adequate nurturing, as measured by parental loss, childhood maltreatment, and parental care, was associated with increased NR3C1 promoter methylation (p<.05). In addition, NR3C1 promoter methylation was linked to attenuated cortisol responses to the Dex/CRH test (p<.05). Conclusions These findings suggest that childhood maltreatment or adversity may lead to epigenetic modifications of the human GR gene. Alterations in methylation of this gene could underlie the associations between childhood adversity, alterations in stress reactivity, and risk for psychopathology.

Childhood Maltreatment and Telomere Shortening: Preliminary Support for an Effect of Early Stress on Cellular Aging

BACKGROUND Psychological stress and trauma are risk factors for several medical and psychiatric illnesses. Recent studies have implicated advanced cellular aging as a potential mechanism of this association. Telomeres, DNA repeats that cap the ends of chromosomes and promote stability, shorten progressively with each cell division; their length is a marker of biological aging. Based on previous evidence linking psychosocial stress to shorter telomere length, this study was designed to evaluate the effect of childhood adversity on telomere length. METHODS Thirty-one adults with no current or past major Axis I psychiatric disorder participated. Subjects reported on their history of childhood maltreatment and telomere length was measured from DNA extracted from frozen whole blood using quantitative polymerase chain reaction. RESULTS Participants reporting a history of childhood maltreatment had significantly shorter telomeres than those who did not report a history of maltreatment. This finding was not due to effects of age, sex, smoking, body mass index, or other demographic factors. Analysis of subscales showed that both physical neglect and emotional neglect were significantly linked to telomere length. CONCLUSIONS These results extend previous reports linking shortened leukocyte telomere length and caregiver stress to more remote stressful experiences in childhood and suggest that childhood maltreatment could influence cellular aging.

Association between Plasma IL-6 Response to Acute Stress and Early-Life Adversity in Healthy Adults

Increased production of peripheral cytokines and other pro-inflammatory markers has been linked to psychiatric disorders such as major depressive disorder and post-traumatic stress disorder. Recent research has pointed to early-life stress, particularly childhood maltreatment, as an independent and preventable risk factor for systemic inflammation in adulthood. Some data suggest that adults with a history of childhood maltreatment exhibit a heightened inflammatory response to acute stress challenge. To further elucidate the relationship between childhood maltreatment and pro-inflammatory cytokine production, we examined plasma IL-6 response to the Trier Social Stress Test (TSST) in 69 healthy adult subjects without depression or post-traumatic stress disorder. Serial plasma IL-6 concentrations were measured during a standardized psychosocial stressor in n=19 subjects with moderate–severe childhood maltreatment (MAL), and n=50 controls without maltreatment (CTL), as indicated by self-ratings on the childhood trauma questionnaire (CTQ). CTQ total scores were positively correlated with overall change in IL-6 response, as well as the maximum IL-6 concentration during the TSST. Greater acute IL-6 release and higher IL-6 concentrations over time were observed for the MAL group relative to the CTL group. Inflammation may be an important developmental mediator linking adverse experiences in early life to poor adult physical and mental health. The results of this preliminary study warrant further investigation in a larger sample.

Neurosurgery for intractable obsessive-compulsive disorder and depression: critical issues

Intractable OCD and depression cause tremendous suffering in those affected and in their families. The impaired ability to function of those affected imposes a heavy burden on society as a whole. Existing data suggest that lesion procedures offer benefit to a large proportion (ranging from about 35%-70%) of patients with intractable OCD and depression. The literature also suggests that although serious long-term adverse events have occurred, these are relatively infrequent overall. Methodologic limitations of the earlier reports on any of these procedures were described previously in this article. The major academic centers conducting this work have since been obtaining systematic prospective data using modern assessment tools. Nevertheless, even with improved methodologies, more recent studies confront some remaining issues that have been difficult to overcome fully. First, the number of patients who have received any one procedure has been relatively small, constraining statistical power. This limits the ability of researchers to enhance patient selection based on clinical characteristics. This is important, because patients with intractable OCD and depression referred for neurosurgery have high rates of comorbid Axis I diagnoses, personality disorders, and functional impairments, which may have value in predicting response. Other features, such as age of onset, chronicity, and symptom subtypes, may be likewise useful. Another key factor in response may be postoperative management, which has varied most over time but also across patients enrolled in trials. As noted previously, randomized controlled trials of neurosurgical treatment for intractable psychiatric illness have not been reported, although one has been proposed for gamma knife capsulotomy in intractable OCD [23]. The development of deep brain stimulation has also made sham-controlled studies possible and also allows within-patient designs to be considered. Bearing these problems in mind, the literature does provide important guidance on a number of key points, including approaches to referral, patient selection, and the need for long-term prospective follow-up and postoperative management. Nevertheless, important gaps in knowledge remain in all these areas. Research is expected to narrow these gaps in a number of ways, including patient selection, optimizing the procedures themselves, and understanding the mechanisms of therapeutic action. Neuroimaging studies will play a key role in achieving these aims (see the article by Rauch in this issue). So will cross-species translational research on the anatomy and physiology of the pathways implicated in the pathophysiology and response to treatment in these disorders. Future research in psychiatric neurosurgery must proceed cautiously. A recent editorial statement of the OCD-DBS Collaborative Group [26] recommends a minimum set of standards for any multidisciplinary teams contemplating work in this domain. The rationale for those standards is found throughout this issue and is especially developed in the article by Fins. The need for safe and effective therapeutic options for people suffering with these severe illnesses is just as clear. The experience over the last several decades provides grounds for careful optimism that refined lesion procedures or reversible deep brain stimulation may relieve suffering and improve the lives of people with these devastating disorders.

Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders.

Recently, the addition of drugs with prominent 5-HT2 receptor antagonist properties (risperidone, olanzapine, mirtazapine, and mianserin) to selective serotonin reuptake inhibitors (SSRIs) has been shown to enhance therapeutic responses in patients with major depression and treatment-refractory obsessive–compulsive disorder (OCD). These 5-HT2 antagonists may also be effective in ameliorating some symptoms associated with autism and other pervasive developmental disorders (PDDs). At the doses used, these drugs would be expected to saturate 5-HT2A receptors. These findings suggest that the simultaneous blockade of 5-HT2A receptors and activation of an unknown constellation of other 5-HT receptors indirectly as a result of 5-HT uptake inhibition might have greater therapeutic efficacy than either action alone. Animal studies have suggested that activation of 5-HT1A and 5-HT2C receptors may counteract the effects of activating 5-HT2A receptors. Additional 5-HT receptors, such as the 5-HT1B/1D/5/7 receptors, may similarly counteract the effects of 5-HT2A receptor activation. These clinical and preclinical observations suggest that the combination of highly selective 5-HT2A antagonists and SSRIs, as well as strategies to combine high-potency 5-HT2A receptor and 5-HT transporter blockade in a single compound, offer the potential for therapeutic advances in a number of neuropsychiatric disorders.

Risperidone Treatment of Children and Adolescents With Pervasive Developmental Disorders: A Prospective, Open-Label Study

OBJECTIVE To investigate the short-term safety and efficacy of risperidone in the treatment of children and adolescents with pervasive developmental disorders. METHOD This was a 12-week, prospective, systematic, open-label trial that included 18 subjects (15 boys and 3 girls) with a mean age of 10.2 +/- 3.7 years. The sample included 11 subjects with autistic disorder, 3 with Aspergers disorder, 1 with childhood disintegrative disorder, and 3 with pervasive developmental disorder not otherwise specified. Fourteen subjects had comorbid mental retardation. Behavioral ratings were obtained during two baseline visits and again after 12 weeks of risperidone treatment. RESULTS The optimal dose of risperidone for the 18 subjects was 1.8 +/- 1.0 mg/day. On the basis of the global improvement item of the Clinical Global Impression Scale, 12 of 18 subjects were considered responders. Significant improvement was seen in measures of interfering repetitive behavior, aggression and impulsivity, and some elements of impaired social relatedness. The most common side effect was weight gain (range 10 to 35 lb). CONCLUSIONS These preliminary results suggest that risperidone may be effective for improving interfering behavioral symptoms in some children and adolescents with pervasive developmental disorders. Double-blind, placebo-controlled studies are needed before definitive statements of safety and efficacy can be made.

Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder

Obsessive compulsive disorder (OCD) is characterized by recurrent and intrusive thoughts that are distressing (obsessions) and/or repetitive behaviors or mental acts that the person feels driven to perform (compulsions). OCD has a partly genetic basis. For treatment of OCD, potent serotonin reuptake inhibitor (SRI) drugs (clomipramine (Anafranil), fluvoxamine (Luvox), fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil)), which act on the serotonin transporter protein, are uniquely efficacious. A polymorphism in the promoter region of the gene (SLC6A4) encoding this protein,1 was recently reported to affect protein expression and to be associated with measures of anxiety and depression2 and with autism (using a family-controlled transmission disequilibrium test (TDT) design).3 SLC6A4 therefore has strong a priori support for potentially influencing risk for OCD: the protein it encodes is a medication target; a polymorphism in the gene affects function; and that polymorphism has been shown to be associated with behavioral phenotypes. We used the TDT with a set of 34 European-American family trios, 30 unrelated and four drawn from an extended pedigree, to test for linkage disequilibrium between OCD and alleles at the SLC6A4 promoter polymorphic locus. Of 35 heterozygous parents, 24 transmitted the ‘l’ SLC6A4 allele and 11 transmitted the ‘s’ allele (χ2TDT = 4.83; P<0.03). considering only the 13 sri drug nonresponders, there were 13 heterozygous parents, of whom 10 transmitted the ‘l’ allele and three the ‘s’ allele (χ2TDT = 3.77; P<0.052). these data provide preliminary support for association and linkage disequilibrium between the slc6a4 ‘l’ allele and ocd.

Concurrent cocaine-ethanol ingestion in humans: pharmacology, physiology, behavior, and the role of cocaethylene.

Simultaneous abuse of cocaine and ethanol is a common occurrence. Cocaethylene, the ethyl ester of benzoylecgonine, has been detected in the urine of patients reporting concurrent use of cocaine and ethanol, and high levels have been found in the blood of victims of fatal drug overdose. This placebo-controlled, double-blind study examined the pharmacokinetic, physiologic, and behavioral effects of dual cocaine and ethanol administration in humans (n=6). Cocaethylene was found in the plasma only after administration of both cocaine and ethanol, and appeared to be eliminated more slowly than cocaine. Plasma cocaine concentrations were significantly higher during cocaine/ethanol administration. Euphorigenic effects were both enhanced and prolonged, and heart rate was significantly increased, following cocaine/ethanol administration as compared to administration of cocaine or ethanol alone.