An exploratory evaluation of tyrosine hydroxylase inhibition in planaria as a model for parkinsonism.

Planaria are the simplest organisms with bilateral symmetry and a central nervous system (CNS) with cephalization; therefore, they could be useful as model organisms to investigate mechanistic aspects of parkinsonism and to screen potential therapeutic agents. Taking advantage of the organism's anti-tropism towards light, we measured a significantly reduced locomotor velocity in planaria after exposure to 3-iodo-L-tyrosine, an inhibitor of tyrosine hydroxylase that is an enzyme catalyzing the first and rate-limiting step in the biosynthesis of catecholamines. A simple semi-automatic assay using videotaped experiments and subsequent evaluation by tracking software was also implemented to increase throughput. The dopaminergic regulation of locomotor velocity was confirmed by bromocriptine, a drug whose mechanisms of action to treat Parkinson's disease is believed to be through the stimulation of nerves that control movement.

Paroxetine treatment of compulsive hoarding.

OBJECTIVE: Compulsive hoarding, found in many patients with obsessive-compulsive disorder (OCD), has been associated with poor response to serotonin reuptake inhibitor (SRI) medications in some reports. However, no prior study has quantitatively measured response to standardized pharmacotherapy in compulsive hoarders. We sought to determine whether compulsive hoarders would respond as well as non-hoarding OCD patients to the SRI, paroxetine. METHODS: Seventy-nine patients with OCD (32 patients with the compulsive hoarding syndrome and 47 patients without prominent hoarding symptoms) were treated openly with paroxetine (mean dose 41.6+/-12.8 mg/day; mean duration 80.4+/-23.5 days) according to a standardized protocol, from 3/1993 to 7/2005. All subjects were free of psychotropic medication for at least four weeks prior to study entry. No psychotherapy or psychotropic medications except paroxetine were allowed during the study period. Subjects were assessed before and after treatment with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Scale (Ham-A), Global Assessment Scale (GAS), and Clinical Global Impression/Improvement (CGI) scale. RESULTS: Both compulsive hoarders and non-hoarding OCD patients improved significantly with treatment (p<0.001), with nearly identical changes in Y-BOCS, HDRS, Ham-A, and GAS scores. There were no significant differences between groups in the proportions of patients who completed or responded to treatment. Hoarding symptoms improved as much as other OCD symptoms. CONCLUSIONS: Compulsive hoarders responded as well to paroxetine treatment as non-hoarding OCD patients, suggesting that SRI medications are effective for compulsive hoarding. Controlled trials of SRI medications for compulsive hoarding are now warranted.

Risperidone and haloperidol augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder: a crossover study.

BACKGROUND: Although serotonin reuptake inhibitors (SRIs) are the first-line treatment for obsessive-compulsive disorder (OCD), approximately half of patients with OCD do not respond adequately to SRI monotherapy. Patients with predominant obsessions are common in OCD and are often difficult to treat, necessitating adjunctive treatment. METHOD: This was a 9-week, double-blind, placebo-controlled, crossover study comparing the benefits of 2-week adjunctive treatments with risperidone, haloperidol, and placebo in patients with OCD (DSM-IV criteria) who continued to have severe symptoms despite taking a stable dose of an SRI. Eligible patients must have been receiving a therapeutic dose of an SRI for at least 12 weeks and at the screening visit had a score > or = 10 on items 1-5 (obsession) and a total score > or = 16 on the Yale-Brown Obsessive Compulsive Scale (YBOCS). Data were collected from January 1999 through April 2002. RESULTS: Sixteen patients were enrolled and 12 completed the study. On the YBOCS, both risperidone and haloperidol significantly reduced obsession (p < .05) when compared with placebo. There was a tendency that haloperidol, and to a lesser degree risperidone, also reduced the compulsion and the total YBOCS scores. These results were accompanied by a reduction in the Hopkins Symptom Checklist 90-revised (SCL-90R) anxiety scale score. According to the 17-item Hamilton Rating Scale for Depression, the SCL-90R depression scale, and the Profile of Mood States, risperidone, but not halo-peridol, also improved depressed mood. Neither risperidone nor haloperidol changed neurocogni-tive function during the 2-week treatment. All 12 patients completed the 2-week risperidone treatment, but 5 of the 12 terminated haloperidol treatment early owing to intolerable side effects. CONCLUSION: Adjunctive risperidone improved obsessions and depressed mood and was well tolerated in patients with SRI-refractory OCD.

Cerebral glucose metabolism in obsessive-compulsive hoarding.

OBJECTIVE: Compulsive hoarding and saving symptoms, found in many patients with obsessive-compulsive disorder (OCD), are part of a discrete clinical syndrome that includes indecisiveness, disorganization, perfectionism, procrastination, and avoidance and has been associated with poor response to medications and cognitive behavior therapy. The authors sought to identify cerebral metabolic patterns specifically associated with the compulsive hoarding syndrome using positron emission tomography (PET). METHOD: [(18)F]Fluorodeoxyglucose PET scans were obtained for 45 adult subjects who met DSM-IV criteria for OCD (12 of whom had compulsive hoarding as their most prominent OCD symptom factor) and 17 normal comparison subjects. All subjects had been free of psychotropic medication for at least 4 weeks. Regional cerebral glucose metabolism was compared between the groups. RESULTS: In relation to the comparison subjects, the patients with compulsive hoarding syndrome had significantly lower glucose metabolism in the posterior cingulate gyrus and cuneus, whereas the nonhoarding OCD patients had significantly higher glucose metabolism in the bilateral thalamus and caudate. In relation to nonhoarding OCD patients, compulsive hoarders had significantly lower metabolism in the dorsal anterior cingulate gyrus. Across all OCD patients, hoarding severity was negatively correlated with glucose metabolism in the dorsal anterior cingulate gyrus. CONCLUSIONS: OCD patients with the compulsive hoarding syndrome had a different pattern of cerebral glucose metabolism than nonhoarding OCD patients and comparison subjects. Obsessive-compulsive hoarding may be a neurobiologically distinct subgroup or variant of OCD whose symptoms and poor response to anti-obsessional treatment are mediated by lower activity in the cingulate cortex.

Basal ganglia systems in ritualistic social displays: reptiles and humans; function and illness.

Complex, situation-specific territorial maintenance routines are similar across living terrestrial vertebrates (=amniotes). Decades ago, Paul MacLean et al., at the Laboratory of Brain Evolution and Behavior of the National Institute of Mental Health, postulated that these are evolutionarily conserved behaviors whose expression is mediated by the similarly conserved amniote basal ganglia and related brain systems (BG systems). Therefore, they undertook studies in nonhuman primates and in small social lizards (the common green anole, Anolis carolinensis) to examine this idea. MacLean et al. also postulated that when BG systems misfunction in humans, behavioral abnormalities result, some of them under the rubric of psychiatric illnesses. Obsessive-compulsive disorder (OCD) was singled out as one likely candidate. In the last dozen years, functional brain imaging studies of OCD patients have validated the contention that this is, in fact, a condition involving dysfunctioning BG systems. Inspired by the MacLean group's original investigations, my colleagues and I have now applied related functional imaging techniques in naturalistic experiments using Anolis to better understand BG systems' roles in the mediation of complex behavioral routines in healthy amniotes. Here, I will review this functional imaging work in primates (man, and a little in monkey) and in lizards. I believe the literature not only supports MacLean et al.'s contentions about BG systems and behavior in general, but also validates Paul MacLean's life-long contention that human behavioral medicine can profit from a broad comparative approach.

Differential brain metabolic predictors of response to paroxetine in obsessive-compulsive disorder versus major depression.

OBJECTIVE: Serotonin reuptake inhibitor (SRI) medications are effective in the treatment of both major depressive disorder and obsessive-compulsive disorder (OCD), but it is unknown whether the neural substrates of treatment response for the two disorders are the same or different. The authors sought to identify pretreatment cerebral glucose metabolic markers of responsiveness to SRI treatment in patients with OCD versus major depressive disorder and to determine whether the pretreatment patterns associated with improvement of OCD symptoms were the same as or different from those associated with improvement of major depressive disorder symptoms. METHOD: [(18)F]Fluorodeoxyglucose positron emission tomography was used to measure cerebral glucose metabolism in 27 patients with OCD alone, 27 with major depressive disorder alone, and 17 with concurrent OCD and major depressive disorder, who were all then treated with 30-60 mg/day of paroxetine for 8-12 weeks. Correlations were calculated between pretreatment regional metabolism and pre- to posttreatment changes in the severity of OCD symptoms, depressive symptoms, and overall functioning. RESULTS: While improvement of OCD symptoms was significantly correlated with higher pretreatment glucose metabolism in the right caudate nucleus (partial r=-0.53), improvement of major depressive disorder symptoms was significantly correlated with lower pretreatment metabolism in the amygdala (partial r=0.71) and thalamus (partial r=0.34) and with higher pretreatment metabolism in the medial prefrontal cortex and rostral anterior cingulate gyrus (Talairach coordinates: x=0, y=62, z=10) (z=2.91). CONCLUSIONS: These findings suggest that, although both OCD and major depressive disorder respond to SRIs, the two syndromes have different neurobiological substrates for response. Elevated activity in the right caudate may be a marker of responsiveness to antiobsessional treatment, while lower right amygdala activity and higher midline prefrontal activity may be required for response of depressive symptoms to treatment.

Brain metabolic changes during cigarette craving.

BACKGROUND: In functional brain imaging studies, exposure to cues related to cocaine, opiates, and alcohol in dependent individuals is associated with activation of the anterior cingulate gyrus, amygdala, orbitofrontal cortex, and dorsolateral prefrontal cortex. Craving for these substances positively correlates with activity in the orbitofrontal cortex, dorsolateral prefrontal cortex, and anterior insula. The objective of this study was to determine changes in regional cerebral glucose metabolism and correlations between craving and regional metabolism in heavy cigarette smokers exposed to cigarette-related cues. METHODS: Twenty heavy smokers (who smoked > or =20 cigarettes per day) and 20 nonsmoking control subjects underwent 2 fluorine 18-fluorodeoxyglucose positron emission tomography scans 10 days apart in randomized order: one while watching a videotape that presented cigarette-related cues and handling a cigarette, and the other while watching an educational (nature) videotape and handling a neutral object (pen). RESULTS: From the neutral to the cigarette cue scan, heavy smokers had greater increases than nonsmoking controls in relative glucose metabolism in the perigenual anterior cingulate gyrus spanning the midline. Significant positive correlations were found between intensity of craving and metabolism in the orbitofrontal cortex, dorsolateral prefrontal cortex, and anterior insula bilaterally. An unexpected positive association was found between craving and metabolism in the right sensorimotor cortex. CONCLUSIONS: Brain regions associated with arousal, compulsive repetitive behaviors, sensory integration, and episodic memory are activated during exposure to cigarette-related cues and cigarette craving. These regional brain activations and associations with craving are similar to findings with other addictive substances.

Differential cerebral metabolic changes with paroxetine treatment of obsessive-compulsive disorder vs major depression.

BACKGROUND: Serotonin reuptake inhibitors (SRIs) effectively treat both major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). We compared and contrasted the functional neuroanatomical effects of SRIs in OCD and MDD as these 2 disorders occurred separately and concurrently by measuring pretreatment to posttreatment cerebral glucose metabolic changes in OCD vs MDD vs concurrent OCD + MDD. METHODS: We obtained [(18)F]fluorodeoxyglucose positron emission tomography (PET) brain scans on 25 subjects with OCD, 25 with MDD, and 16 with concurrent OCD + MDD before and after 8 to 12 weeks of treatment with paroxetine hydrochloride. Controls (n = 16) were scanned 10 to 12 weeks apart without treatment. Treatment response was defined as a more than 25% decline in OCD symptom severity, a more than 50% decline in MDD severity, and "much improved" clinical global impression. RESULTS: Although all patient groups received the same paroxetine dose for the same duration, regional metabolic changes differed significantly among diagnostic groups. Subjects with OCD alone showed significant metabolic decreases in the right caudate nucleus, right ventrolateral prefrontal cortex (VLPFC), bilateral orbitofrontal cortex, and thalamus that were not seen in any other group. Both the MDD and concurrent OCD + MDD groups showed metabolic decreases in the left VLPFC and increases in the right striatum. Treatment response was associated with a decrease in striatal metabolism in nondepressed OCD patients but with an increase in striatal activity in patients with OCD + MDD. CONCLUSIONS: Brain metabolic responses to SRIs are both disorder-specific and response-specific. They vary according to the underlying pathophysiology of the patient and the degree of symptomatic improvement.

Psychiatry Resident and Medical Student Perspectives on ECT: Influence of Exposure and Education.

We surveyed medical students doing the required psychiatry clerkship at our hospital and first-year psychiatry residents in our residency training program for their attitudes, knowledge, and opinions about electroconvulsive therapy (ECT) before and after their inpatient rotations. The students' knowledge was lower and their attitudes more negative toward ECT than those of residents at baseline. Upon completion of the rotation, students and residents had more knowledge and highly positive attitudes about ECT and stated that they would undergo ECT if it were recommended. Willingness to undergo ECT if it were recommended correlated with the knowledge measures of ECT.

Electroconvulsive Therapy and Brain Glucose Metabolism.

The local cerebral metabolic rate for glucose (LCMRGlc) was evaluated in four patients before undergoing a course of electroconvulsive therapy (ECT) and after its completion. There was no reduction in LCMRGlc when studied 1 day after the last course of ECT. There was, however, the suggestion that metablic rates may increase in the middle frontal gyrus after significant time has elapsed since the last course of ECT.

Patient and Family Perspectives of Electroconvulsive Therapy: Correlation with Outcome.

We surveyed 25 patients about to undergo electroconvulsive therapy (ECT) and one relative of each patient for their attitudes, knowledge, and opinions about ECT; and then resurveyed them after the course of ECT. Patients were rated with the Hamilton Depression Rating Scale or Young Mania Rating Scale, based on diagnosis, before and after ECT. Patients and family members had highly positive attitudes toward ECT both before and after treatment, and after the course felt strongly that the ECT was beneficial. Baseline depression severity gave a high correlation with positive post-ECT attitudes.

Informing Patients About Electroconvulsive Therapy: Effects of a Videotape Presentation.

Issues of information given for consent purposes are particularly problematic with electroconvulsive therapy (ECT). The authors investigated the efficacy of an informative videotape recording in this process. The videotape contained factual information about ECT, an interview with a patient before and after treatment, and the presentation of an actual treatment. A patient group assigned to watch the videotape, in addition to the usual consent process involving written and verbal information from the treating resident psychiatrist, showed only one postconsent difference from a group that had the usual consent process without the videotape. Those who saw the videotape were less sure that they had adequate information to decide whether to have ECT than those who did not see it (p < 0.05). Although patients likely to benefit from such an audiovisual approach may be identifiable, it seems that an informative videotape offers no universal advantage over more conventional information giving in the consent process.

The Experience of Electroconvulsive Therapy in the 1980s: A Prospective Study of the Knowledge, Opinions, and Experience of California Electroconvulsive Therapy Patients in the Berkeley Years.

In 1982, the city of Berkeley, California voted to make the use of electroconvulsive therapy (ECT) a crime. Though later overturned, this ordinance generated much publicity and underscored the public's general negative view of ECT. In this climate, the authors surveyed first-time ECT recipients (n = 35), and a group with prior ECT (n = 20) to examine patient knowledge, experience, and opinions of ECT in California in the 1980s. Patients in both groups believed ECT should be available and did not think it was used for punishment or control. First-time ECT patients showed good understanding of the ECT process, thought that they had adequate information with which to decide about ECT, and were optimistic about the outcome. In comparison, those with prior ECT were less knowledgeable, less sure about the ECT process, less optimistic about the outcome, and more frightened of the procedure. After treatment, first-time ECT patients believed they had made a good decision to have ECT and that they were helped. Complaints of memory dysfunction were common. Patients who received ECT in the past may have had a more negative experience with ECT than those undergoing the procedure in the 1980s. These more negative experiences may have determined present media presentations and, therefore, had an influence on present day public attitudes against ECT. Accurate portrayals of ECT, as it is done today, may improve public attitudes toward ECT and forestall adverse legislation.

Nursing Students' Perception of Electroconvulsive Therapy: Impact of Instruction with an Electroconvulsive Therapy Videotape.

There has been little study of attitudes toward and knowledge of electroconvulsive therapy (ECT). Likewise, there have been no studies of how accurate information about ECT may be communicated. The authors studied the attitudes and opinions toward ECT of thirty-five nursing students before they had received any formal instruction on its use. The same subjects then viewed a didactic videotape explaining and demonstrating ECT. There were significant improvements in overall knowledge and positive opinions of ECT after this educational exposure.