Noradrenergic function in pathological gambling: blunted growth hormone response to clonidine.

The noradrenergic system has been linked to impulsive behaviour in animals and humans, yet little data on noradrenergic system exist in specific impulse control disorders. To explore the role of the noradrenergic system in pathological gamblers (PG), we assessed neuroendocrine growth hormone (GH) response to the alpha2-adrenergic receptor agonist clonidine and placebo in PG and controls. The net effects of clonidine are a decrease in neurotransmission by depressing locus coeruleus activity and stimulation of GH secretion through activation of post-synaptic alpha2-adrenergic receptors in the hypothalamus. Twenty-nine PG subjects, free of other comorbid conditions, and 27 healthy controls received a double-blinded, placebo-controlled, single dose of oral clonidine (0.15 mg/kg). Data observed included GH, clonidine levels and levels of the main noradrenergic metabolite, 3-methoxy-4-hydroxy-phenylglycol (MHPG). The area under the curve for GH response to clonidine was significantly lower (separate variance t with 44.3 df = 2.626, P = 0.012, d = 0.58) in the PG group (199.6) than in the control group (426.3). PG had significantly blunted GH responses compared with controls at 120 and 150 min post-clonidine. These results are consistent with the idea that the subsensitivity of post-synaptic alpha-2 receptors is possibly attributable to higher-than-normal noradrenergic secretion in PG. This peripheral noradrenergic dysfunction could be consistent with attenuated cortico-frontal noradrenergic function as shown in positron emission tomography (PET) studies of PG.

Pathological gambling.

With increasing access to gambling facilities through casinos, the Internet, and other venues, PG is a rapidly emerging mental health concern. This impulse-control disorder tends to be comorbid with a wide range of other disorders and is reportedly associated with a high rate of suicide. For most gamblers, gambling is a form of entertainment, but for many individuals, the activity leads to far-reaching disruption of family and work. The personal and societal financial ramifications are severe, and many individuals with PG end up in the criminal justice system. An understanding of the neurobiology of PG is beginning to surface. 5-HT is linked to behavioral initiation and disinhibition, which are important in the onset of the gambling cycle and the difficulty in ceasing the behavior. Norepinephrine is associated with the arousal and risk taking in patients with PG. Dopamine is linked to positive and negative reward, the addictive component of this disorder. Effective treatment strategies for pathological gamblers are emerging. Potentially useful pharmacologic agents include SRIs (clomipramine and fluvoxamine), mood stabilizers for pathological gamblers with comorbid bipolar disorders (lithium), and naltrexone. Cognitive-behavioral psychotherapies offer promising results in the treatment of patients with this disorder. To devise prevention and early-intervention programs, research is needed to identify specific features of the individuals at risk for gambling problems. Education targeting vulnerable youth that show early signs of gambling behavior may be worthwhile and should be investigated further. Funding is necessary to support these endeavors, so perhaps a portion of tax revenues generated from the gambling industry should go toward specialized treatment facilities, educational efforts, and research into the neurobiology and treatment of PG.

A randomized double-blind fluvoxamine/placebo crossover trial in pathologic gambling.

BACKGROUND: The study assessed the efficacy and tolerability of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine in the treatment of pathologic gambling (PG). METHODS: A 16-week randomized double-blind crossover design insured that each subject received 8 weeks of fluvoxamine and 8 weeks of a placebo. Fifteen patients entered and 10 subjects, all male, completed the study. RESULTS: Fluvoxamine resulted in a significantly greater percent improvement in overall gambling severity on the PG Clinical Global Impression (PG-CGI) scale. There was a significant drug effect on gambling urge and behavior as measured by the PG modification of the Yale-Brown Obsessive Compulsive Scale and PG-CGI scale improvement scores; however, there was a significant interaction of drug effect with the order of administration of drug and placebo. Post hoc analysis, treating each phase as a separate trial, demonstrated a significant difference between fluvoxamine and the placebo in the second phase of the trial but not in the first. Fluvoxamine side effects were of only mild intensity and consistent with SSRI treatment and were not associated with early withdrawal from the study. CONCLUSIONS: These findings suggest that fluvoxamine is well tolerated and may be effective in the treatment of PG in an acute trial, and that an early placebo effect in PG treatment appears to diminish over time. To confirm this finding and to determine whether improvement persists over an extended period of time, a longer duration parallel-design trial with long-term maintenance follow-up should be conducted in a larger and more diverse PG population.

B lymphocyte antigen D8/17 and repetitive behaviors in autism.

OBJECTIVE: Monoclonal antibody D8/17 identifies a B lymphocyte antigen with expanded expression in rheumatic fever, Sydenham's chorea, and subgroups of obsessive-compulsive disorder and Tourette's syndrome with repetitive behaviors. The authors examined the rate of D8/17 expression in children with autism and its correlation with severity of repetitive behaviors. METHOD: Blood samples from 18 patients with autism and 14 comparable medically ill children were evaluated for percentage of D8/17-positive B cells by immunofluorescence and for streptococcal antibodies. Severity of repetitive behaviors was also determined. RESULTS: The frequency of individuals with > or =11% D8/17-positive cells was significantly higher in the autistic patients (78%) than the comparison subjects (21%), severity of repetitive behaviors significantly correlated with D8/17 expression, and D8/17-positive patients had significantly higher compulsion scores than D8/17-negative patients. CONCLUSIONS: D8/17 expression is high in patients with autism and may serve as a marker for compulsion severity within autism.

Short-term single-blind fluvoxamine treatment of pathological gambling.

OBJECTIVE: The authors' goal was to assess the efficacy and tolerability of the selective serotonin reuptake inhibitor fluvoxamine in the treatment of pathological gambling. METHOD: Sixteen patients with pathological gambling entered an 8-week placebo lead-in phase, and 10 of these patients completed an 8-week single-blind fluvoxamine trial. RESULTS: Seven of the 10 patients who completed the fluvoxamine trial were judged treatment responders at the end of the study: 1) they had greater than 25% decreases in their gambling behavior scores on the pathological gambling modification of the Yale-Brown Obsessive Compulsive Scale, and 2) their clinician-rated Clinical Global Impression scores for gambling severity were very much improved or much improved. Fluvoxamine treatment resulted in gambling abstinence in seven of the 10 patients. CONCLUSIONS: Findings from this preliminary study suggest that fluvoxamine may be effective in reducing the urge to gamble. Randomized placebo-controlled and maintenance trials are required to confirm these findings and to determine whether improvement persists.

m-Chlorophenylpiperazine challenge in borderline personality disorder: relationship of neuroendocrine response, behavioral response, and clinical measures.

We have previously found that a subgroup of patients with impulsive personality disorders respond to m-chlorophenylpiperazine (m-CPP) administration with a distinctive spacy/high behavioral reaction and with increased cortisol responses. In this report we analyzed the relationship between behavioral and neuroendocrine responses to m-CPP in an enlarged sample of patients with borderline personality disorder (BPD). We also assessed the association of behavioral and neuroendocrine responses with clinical symptoms and with m-CPP blood levels. We found that in BPD patients the presence of a spacy/high behavioral response was significantly associated with increased prolactin and cortisol responses to m-CPP. In BPD patients increased m-CPP levels were significantly associated with neuroendocrine hypersensitivity and with a spacy/high behavioral response, while in controls increased m-CPP levels were not significantly associated with neuroendocrine hypersensitivity but were significantly associated with dysphoric behavioral responses. Taken together with previous work on m-CPP in obsessive-compulsive disorder, these results are partially consistent with the hypothesis that compulsive and impulsive symptoms fall at opposite ends of a phenomenologic and neurobiologic spectrum.

Diagnosis, neurobiology, and treatment of pathological gambling.

Pathological gambling is a disabling disorder that affects at least 2 1/2 million Americans and their families. Although pathological gambling has been characterized as an impulse control disorder, it has also been associated with compulsivity. Essential features of pathological gambling include constantly recurring gambling behavior that is maladaptive, in that personal, familial, and/or vocational endeavors are disrupted. Affective disorders and substance abuse often co-occur. Incidence of suicidality is extremely high. Despite the fact that this disorder is a widespread public health problem, few controlled studies of causes or treatment have been conducted. Preliminary neurobiological studies implicate serotonergic dysfunction in pathological gamblers. Treatment with serotonin reuptake inhibitors, such as clomipramine and fluvoxamine, may be effective in treating this disorder. Well-defined and controlled clinical trials in large samples of pathological gamblers are needed.

Specificity of neuropsychological impairment in obsessive-compulsive disorder: a comparison with social phobic and normal control subjects.

Specificity of neuropsychological dysfunction in obsessive-compulsive disorder (OCD) was assessed by comparing neuropsychological performance in 65 OCD patients, 17 social phobic patients, and 32 normal control subjects. Although both patient groups showed visual constructional impairment relative to normal subjects, only patients with social phobia showed executive dysfunction. Nonconcurrent state anxiety did not correlate with neuropsychological performance. Among anxiety disorders, neuropsychological dysfunction may not be specific to OCD, but the functions implicated may differ across patient groups.

Compulsive and impulsive symptomatology in trichotillomania.

Although classified as a disorder of impulse control, trichotillomania (hair pulling) may have some phenomenological overlap with obsessive-compulsive disorder (OCD). The question arises as to whether trichotillomania is best conceptualized as a disorder characterized by impulsivity or compulsivity. Impulsive and compulsive symptoms and traits were compared in 43 patients who presented for treatment of trichotillomania, OCD or impulsive personality disorder. Trichotillomania patients had significantly lower scores of obsessive-compulsive symptoms than OCD patients, and significantly higher impulsiveness scores than this group. Measures of aggression did not differ significantly between groups.

Serotonergic sensitivity in borderline personality disorder: preliminary findings.

Twelve patients with borderline personality disorder and 15 healthy comparison subjects were challenged with single doses of oral m-chlorophenylpiperazine (m-CPP) and placebo. Following m-CPP, the patients experienced decreased anger and fear. Seven of the 12 patients reported a "spacy," "high," depersonalized/derealized experience following m-CPP, which was confirmed by clinicians' ratings. Compared with the normal male subjects, the male patients with borderline personality disorder had higher cortisol levels and marginally blunted prolactin responses after receiving m-CPP. These results suggest serotonergic dysfunction in borderline personality disorder.

Computed tomography and neurological soft signs in obsessive-compulsive disorder.

Computed tomography was used to compare the following three groups: obsessive-compulsive disorder (OCD) patients with high scores on a soft neurological sign examination, OCD patients with low soft neurological sign scores, and control subjects. Neuranatomical structures were measured using quantitative volumetric analysis. OCD patients with high soft sign scores had significantly increased ventricular volumes compared with OCD patients with low soft sign scores and control subjects. Caudate and lenticular nucleus volumes did not differ between groups.

Quantitative electroencephalographic subtyping of obsessive-compulsive disorder.

Current neuropsychological, electrophysiological, and other imaging data strongly suggest the existence of a neurobiological basis for obsessive-compulsive disorder (OCD), which was long considered to be exclusively of psychogenic origin. The positive response of some OCD patients to neurosurgery, as well as the efficacy of agents that selectively block serotonin reuptake, lends further support to a biological involvement. However, a survey of the treatment literature reveals that only 45-62% of OCD patients improve with these specific medications. In a pilot study using a quantitative electroencephalographic (QEEG) method known as neurometrics, in which QEEG data from OCD patients were compared statistically with those from an age-appropriate normative population, we previously reported the existence of two subtypes of OCD patients within a clinically homogeneous group of patients who met DSM-III-R criteria for OCD. Following pharmacological treatment, a clear relationship was found between treatment response and neurometric cluster membership. In this study, we have expanded the OCD population, adding patients from a second site, and have replicated the existence of two clusters of patients in an enlarged, statistically more robust population. Cluster 1 was characterized by excess relative power in theta, especially in the frontal and frontotemporal regions; cluster 2 was characterized by increased relative power in alpha. Further, 80.0% of the members of cluster 1 were found to be nonresponders to drug treatment, while 82.4% of the members of cluster 2 were found to be treatment responders.(ABSTRACT TRUNCATED AT 250 WORDS)

Left hemispheric activation in depersonalization disorder: a case report.

Depersonalization disorder is classified in DSM-III-R (APA 1987) as a dissociative disorder characterized by altered perception or experience of the self. To date, there are no known reports of the neurobiological features of this disorder. We report clinical and biological correlates in a patient with depersonalization disorder previously unresponsive to a variety of anticonvulsant, monoamine oxidase inhibitor, and tricyclic antidepressant trials, but for whom fluoxetine partially reduced depersonalization symptoms, but not associated anxiety and depression. Neurophysiological, neuroanatomical and neuropsychological findings revealed left hemispheric frontal-temporal activation and decreased left caudate perfusion. These findings suggest a similarity to the neuropsychiatric data reported in obsessive-compulsive disorder patients.

Serotonergic function in obsessive-compulsive disorder. Behavioral and neuroendocrine responses to oral m-chlorophenylpiperazine and fenfluramine in patients and healthy volunteers.

To evaluate serotonergic (5-hydroxytryptamine) function in obsessive-compulsive disorder, behavioral and neuroendocrine responses to m-chlorophenylpiperazine (m-CPP; 0.5 mg/kg orally) and fenfluramine hydrochloride (60 mg orally) were examined in 20 patients and 10 healthy controls under double-blind, placebo-controlled conditions. Following m-CPP, but not fenfluramine or placebo, 55% (11/20) of the patients with obsessive-compulsive disorder experienced a transient exacerbation of obsessive-compulsive disorder. Prolactin response was blunted in patients following m-CPP but not following fenfluramine. Patients with greater behavioral response to m-CPP had smaller prolactin responses. Cortisol response to m-CPP and fenfluramine did not significantly differ between the groups. Behavioral and neuroendocrine responses appeared divergent. This does not suggest simply upregulation or downregulation of 5-hydroxytryptamine receptors, but rather complex mechanisms involving multiple neurotransmitter and neuromodulator systems.

Effects of fenfluramine on plasma homovanillic acid in healthy subjects.

The specificity of fenfluramine as a pharmacological probe of the serotonin system has been questioned, since animal studies with high dose l-fenfluramine show increases in striatal levels of the dopamine metabolite homovanillic acid. To test the specificity of fenfluramine in humans with clinical doses, we compared plasma homovanillic acid (pHVA) concentration in healthy volunteers after administration of fenfluramine (60 mg) and placebo. There were no significant effects on pHVA, which supports previous findings that at doses used in pharmacological challenge paradigms, the effect of fenfluramine on the dopamine system is insufficient to alter measures of its change.