Showing papers in "Journal of Psychiatry & Neuroscience in 2000"

Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking.

Abstract: Relapse is a major characteristic of drug addiction, and remains the primary problem in treating drug abuse. Without an understanding of the factors that determine renewed drug-seeking, the urge to use drugs, and the persistent craving for them, it is unlikely that health care professionals can provide effective treatment. Using an animal model of relapse, the author and her team are studying factors that induce reinstatement of drug-taking behaviour after short and long periods of abstinence, and they are exploring the neurobiological basis of these effects. In their experiments, rats are trained to self-administer drugs intravenously by pressing 1 of 2 levers. During a subsequent period, the drug is no longer available, but the rats are free to try to obtain the drug (a period of "extinction training"). After extinction of responding, the investigators test for the ability of various events to reinitiate drug-seeking. On this background of renewed drug-seeking or relapse, the investigators search for pharmacological and neurochemical manipulations that might block or attenuate such behaviour. They have found that the 2 most effective events for reinstating responding after both short and long drug-free periods are re-exposure to the drug itself and exposure to a brief period of stress. The critical neurochemical pathways mediating drug-induced relapse are not identical to those mediating stress-induced relapse. Relapse induced by "priming" injections of heroin or cocaine involves activation of the mesolimbic dopaminergic pathways, whereas relapse induced by stress involves actions of corticotropin-releasing factor (CRF) in the brain, and of brain noradrenergic (NE) systems. In addition, evidence shows that CRF and NE may interact at the level of the bed nucleus of the stria terminalis in stress-induced relapse. By contrast, relapse induced by "priming" injections of drugs is relatively unaffected by manipulation of CRF and NE systems of the brain.

Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action.

Abstract: RATIONALE AND OBJECTIVE: While the blockade of dopamine D2 receptors are necessary for antipsychotic action, antipsychotic agents differ nearly a thousand-fold in their affinity for the D2 receptor This affinity is determined by the rate at which the antipsychotic agent binds to (kon) and the rate at which it dissociates from (koff) the D2 receptors The objective of this study was to determine the relationship between kon, koff and the affinity (Ki) of antipsychotic agents for the D2 receptors, with particular reference to typical and atypical antipsychotic agents DESIGN: The koff of several typical as well as atypical antipsychotic agents (nemonapride, spiperone, haloperidol, chlorpromazine, raclopride, olanzapine, sertindole, clozapine and quetiapine) was measured in vitro using the 3H-radiolabelled analogues of these drugs The affinity of these drugs for the D2 receptor was determined by competition with 3H-raclopride in vitro The kon was derived from values of affinity and ++koff MAIN OUTCOME MEASURES: kon, koff, and the Ki of antipsychotic drugs RESULTS: The range of affinity values was similar to that conventionally accepted (0025-155 nmol/L) The koff values varied a thousand-fold from 0002 to 3013 min-1, with relatively little variation in kon The rate at which antipsychotic agents come off the receptor (koff) accounted for 99% of the variation in their affinity for the D2 receptor; differences in kon did not account for differences in affinity CONCLUSIONS: The differences in the affinity of antipsychotic agents are entirely determined by how fast they come off the D2 receptor These differences in koff may lead to functionally different kinds of dopamine blockade Drugs with a higher koff will be faster in blocking receptors, and once blocked, will provide more access to surges in dopamine transmission Since atypical drugs show a lower affinity and a faster dissociation, a higher koff for the D2 receptor is proposed as a mechanism for "atypical" antipsychotic effect

Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders.

Abstract: Recent evidence shows that the temporal alignment between the sleep-wake cycle and the circadian pacemaker affects self-assessment of mood in healthy subjects. Despite the differences in affective state between healthy subjects and patients with psychiatric disorders, these results have implications for analyzing diurnal variation of mood in unipolar and bipolar affective disorders and sleep disturbances in other major psychiatric conditions such as chronic schizophrenia. In a good proportion of patients with depression, mood often improves over the course of the day; an extension of waking often has an antidepressant effect. Sleep deprivation has been described as a treatment for depression for more than 30 years, and approximately 50% to 60% of patients with depression respond to this approach, especially those patients who report that their mood improves over the course of the day. The mechanisms by which sleep deprivation exerts its antidepressant effects are still controversial, but a reduction in rapid eye movement sleep (REM sleep), sleep pressure and slow-wave sleep (SWS), or a circadian phase disturbance, have been proposed. Although several studies support each of these hypotheses, none is sufficient to explain all observations reported to date. Unfortunately, the disturbed sleep-wake cycle or behavioural activities of depressed patients often explain several of the abnormalities reported in the diurnal rhythms of these patients. Thus, protocols that specifically manipulate the sleep-wake cycle to unmask the expression of the endogenous circadian pacemaker are greatly needed. In chronic schizophrenia, significant disturbances in sleep continuity, REM sleep, and SWS have been consistently reported. These disturbances are different from those observed in depression, especially with regard to REM sleep. Circadian phase abnormalities in schizophrenic patients have also been reported. Future research is expected to clarify the nature of these abnormalities.

Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria.

Abstract: OBJECTIVE: To establish specific criteria by which selective serotonin reuptake inhibitor (SSRI) discontinuation syndrome may be identified. DATA SOURCES: MEDLINE and PSYCHLIT databases were searched for case reports published from 1986 to 1997 inclusive, and references of relevant articles were also searched. STUDY SELECTION: Forty-six case reports of symptoms following the discontinuation of fluoxetine, fluvoxamine, paroxetine or sertraline were selected. Three studies of SSRI discontinuation were also reviewed. DATA EXTRACTION: Demographic and treatment information, as well as the timing, duration, number, nature and frequency of dicontinuation symptoms. DATA SYNTHESIS: Paroxetine was most frequently implicated. The drug had been tapered in half of the cases. In some cases, symptom onset began during taper, whereas, in most cases, symptoms began within 1 to 3 days of drug discontinuation. Fifty-three different symptoms were reported, with dizziness being the most common. Other common symptoms were nausea or emesis, fatigue, headache, gait instability and insomnia. Shock-like sensations, paresthesia and visual disturbances were the most rare. Without intervention, symptoms persisted for more than a week in half of the cases. In cases in which the SSRI was restarted, symptoms resolved within 72 hours. In some cases, withdrawal symptoms recurred when the same SSRI was again discontinued. CONCLUSIONS: Findings were used to construct diagnostic criteria for the SSRI discontinuation syndrome. These criteria are 2 or more of the following symptoms developing within 1 to 7 days of discontinuation or reduction in dosage of an SSRI after at least 1 month's use, when these symptoms cause clinically significant distress or impairment and are not due to a general medical condition or recurrence of a mental disorder: dizziness, light-headedness, vertigo or feeling faint; shock-like sensations or paresthesia; anxiety; diarrhea; fatigue; gait instability; headache; insomnia; irritability; nausea or emesis; tremor; and visual disturbances.

Pathophysiology of seasonal affective disorder: a review.

Abstract: The study of the pathophysiology of seasonal affective disorder (SAD, also known as winter depression) has historically been intimately linked to investigations into the mechanisms of action of light therapy. This paper reviews the studies on the pathophysiology of SAD with emphasis on circadian, neurotransmitter, and genetic hypotheses. There is substantial evidence for circadian phase shift and serotonergic hypotheses, but conflicting results may indicate that SAD is a biologically heterogeneous condition. Recent progress in defining the molecular mechanisms of the human circadian clock and retinal phototransduction of light will provide important new directions for future studies of the etiology and pathophysiology of SAD.

Citalopram--a review of pharmacological and clinical effects.

Abstract: OBJECTIVE: To provide clinicians with a critical evaluation of citalopram, a selective serotonin reuptake inhibitor (SSRI) that has been available in Canada since March 1999. DATA SOURCES: Commercial searches (MEDLINE and BiblioTech) and an "in-house" search (InfoDrug) were used to find published English-language references for clinical and preclinical publications. There was no restriction of publication dates. Primary index terms used were: pharmacological properties, receptors, pharmacological selectivity, pharmacokinetics, age-related pharmacokinetics, sex-related pharmacokinetics, renal dysfunction, hepatic dysfunction, cytochrome activity, drug interactions, adverse reactions, antidepressant switching, precautions, overdose, drug discontinuation, children, geriatric, depression, combination therapy, placebo control, refractory depression, anxiety disorders and medical disorders. STUDY SELECTION: A total of 74 studies were reviewed. Twenty-one of these studies specifically examined the clinical efficacy and tolerability of citalopram in depressive disorders as well as other disorders. In depressive disorders, clinical studies were required to have either placebo or active comparison controls for a minimum of 3 weeks. For other disorders, in the absence of double-blind trials, open-label studies were included. Pharmacological studies were limited to animal studies focusing on citalopram's selectivity and receptor specificity, and positron emission tomography studies were incorporated to include human pharmacological data. Pharmacokinetic studies focused on the metabolism, safety and tolerability of citalopram, specifically with reference to adverse reactions, drug interactions and overdose in addition to citalopram's effect on vulnerable populations, such as children, the elderly and patients with metabolic diseases. DATA EXTRACTION: Data on clinical studies were summarized according to test measures, study duration and outcome of study. Pharmacokinetic and pharmacodynamic studies were summarized according to properties and interactions. Adverse reactions were extracted to outline citalopram's safety profile. DATA SYNTHESIS: Citalopram is an SSRI antidepressant with a more specific and selective pharmacological profile than other antidepressants of its class. It is well tolerated, and drug interactions are not a significant concern. It is also reasonably safe for populations vulnerable to pharmacokinetic effects, such as the elderly and patients with metabolic diseases. In addition to its tolerability, citalopram is effective in the treatment of major depression, other depressive disorders and panic disorder. It has the potential to effectively treat other anxiety disorders and substance-use disorders; in addition, it may be useful in several medical conditions. CONCLUSIONS: There is evidence to support the role of citalopram as a well-tolerated and effective SSRI antidepressant. There is a need for further evaluation of its role in psychiatric disorders other than major depressive disorder.

Functional activities of the amygdala: an overview.

Abstract: Research to date into the amygdala shows that it has an integrative role in behavioural, vegetative and endocrine activities of animals in their relation with their environment. Animal studies show that amygdala has a role in emotional response, integrating input signals and initiating activities related to them. Different nuclei seem to have different effects. A complete picture of the functional roles of the amygdala is unavailable, and it has been suggested that the amygdala is functionally and anatomically heterogeneous. Amygdaloid subnuclei appear to have a role in the modulation of fear, in memory and attention, and in some sexual and sex-related behaviour of rats. In humans, functional magnetic resonance imaging shows that the amygdala responds preferentially to emotionally charged stimuli. Bilateral amygdala damage in humans can compromise the recognition of fear in facial expressions, an important ability in social judgement. Future study of the amygdala promises to shed light on emotional disorders in humans.

Use of slow-release melatonin in treatment-resistant depression.

Abstract: OBJECTIVE: To examine antidepressant augmentation with and hypnotic effects of slow-release melatonin (SR-melatonin) in patients with treatment-resistant depression. DESIGN: Open-label trial. SETTING: Tertiary care outpatient depression clinic. PATIENTS: Nine outpatients who had failed to respond to 2 or more 8-week trials of antidepressant medication. INTERVENTIONS: Patients received SR-melatonin 5 mg per day for the first 2 weeks and 10 mg per day for the final 2 weeks, in addition to their antidepressant medication. OUTCOME MEASURES: Structured Clinical Interview for DSM-IV, Axis 1 Disorders, Hamilton Rating Scale for Depression (HRSD), Beck Depression Inventory, Response Style Questionnaire, sleep and fatigue measures. RESULTS: One patient was excluded after 1 week because of the development of a mixed affective state. In the remaining 8 patients there was a 20% mean decrease in HRSD scores after 4 weeks of treatment, with no individual achieving an improvement of 50% or more. There was a 36% decrease on the 3-item HRSD related to insomnia, with 4 of 8 patients showing at least a 50% improvement on this measure. The greatest decrease in insomnia occurred during the last 2 weeks of the study, following the increase in dosage to 10 mg per day of SR-melatonin. Patients also reported significantly lower levels of fatigue post-treatment. CONCLUSIONS: SR-melatonin may be a useful adjunct for sleep, but does not substantially augment existing antidepressant therapies in some patients with treatment-resistant depression.

Antipsychotic agents and QT changes.

Abstract: Recently, antipsychotic medications of the novel or atypical classes have received increased attention because of concerns with respect to potential lengthening of the QT interval, yet the currently available and commonly prescribed conventional antipsychotics are significantly more cardiotoxic, particularly agents in the butyrophenone and phenothiazine classes. Lengthening of the QT interval can be associated with a fatal paroxysmal ventricular arrhythmia known as torsades de pointes. The specific duration of the QT interval at which the risk of an adverse cardiac event is greatest, is not established. There is not only significant variation in the applied definition of an abnormal interval, but the maximal QT interval in healthy volunteers is greater than the currently accepted standards. The QT interval is influenced by normal physiological and pathologic factors, but the mechanisms remain unclear. Using recombinant technology, haloperidol and sertindole have been demonstrated to be high-affinity antagonists of a human cardiac potassium channel encoded by the human ether-a-go-go-related gene. Pimozide, however, has been shown to act principally through calcium channel antagonism, and chlorpromazine may affect sodium channels. Nevertheless, it is possible that these effects are significant only in the presence of predisposing factors, either genetic or acquired. Despite proven efficacy in clinical trials and subsequent supervised use in Europe, a number of recently developed antipsychotic medications are not available to patients in North America. Yet, conventional antipsychotic medications that would not be approved by current safety standards continue to be widely used.

Premenstrual syndrome and premenstrual dysphoric disorder: guidelines for management.

Abstract: The inclusion of research diagnostic criteria for premenstrual dysphoric disorder (PMDD) in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, recognizes the fact that some women have extremely distressing emotional and behavioural symptoms premenstrually. PMDD can be differentiated from premenstrual syndrome (PMS), which presents with milder physical symptoms, headache, and more minor mood changes. In addition, PMDD can be differentiated from premenstrual magnification of physical or psychological symptoms of a concurrent psychiatric or medical disorder. As many as 75% of women with regular menstrual cycles experience some symptoms of PMS, according to epidemiologic surveys. PMDD is much less common; it affects only 3% to 8% of women in this group. The etiology of PMDD is largely unknown, but the current consensus is that normal ovarian function (rather than hormone imbalance) is the cyclical trigger for PMDD-related biochemical events within the central nervous system and other target organs. The serotonergic system is in a close reciprocal relation with the gonadal hormones and has been identified as the most plausible target for interventions. Thus, beyond conservative treatment options such as lifestyle and stress management, other non-antidepressant treatments, or the more extreme intervneitons that eliminate ovulation altogether, selective serotonin reuptake inhibitors (SSRIs) are emerging as the most effective treatment option. Results from several randomized, placebo-controlled trials in women with PMDD have clearly demonstrated that SSRIs have excellent efficacy and minimal side effects. More recently, several preliminary studies indicate that intermittent (premenstrual only) treatment with selective SSRIs is equally effective in these women and, thus, may offer an attractive treatment option for a disorder that is itself intermittent.

Relation of serum cholesterol, lipid, serotonin and tryptophan levels to severity of depression and to suicide attempts.

Abstract: OBJECTIVE: To determine if there is a relation to low serum cholesterol, lipoprotein, serotonin or tryptophan levels in patients with depression who have recently attempted suicide. DESIGN: Biochemical and behavioural study. SETTING: Inpatient and outpatient treatment at the Instituto Mexicano de Psiquiatria. PARTICIPANTS: Thirty-three patients with a diagnosis of major depressive episode. Eighteen of these patients had attempted suicide in the month before the start of the study; 15 patients had never attempted suicide. OUTCOME MEASURES: Serum levels of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, serotonin (5-HT) and tryptophan. Scores on Hamilton Depression Rating Scale, Carroll Depression Rating Scale, Beck Hopelessness Scale and Beck Suicide Attempt Severity Scale. RESULTS: There were no significant differences between patients who had attempted suicide and those who had not in terms of serum cholesterol, HDL, LDL and triglyceride levels. Serum levels of 5-HT and tryptophan were significantly lower in patients with depression who had a recent suicide attempt than in those patients who had never attempted suicide. A comparison of patients not taking antidepressant medication found serum 5-HT levels to be more than 3 times lower in those patients with a recent suicide attempt than in patients with no history of suicide attempt. CONCLUSIONS: The study found no difference in lipid profiles between patients who had attempted suicide and those who had not. Low serum levels of 5-HT may increase the risk of suicide attempt in patients who are depressed.

Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects.

Abstract: OBJECTIVE: Because the initial phase of treatment of depression with a selective serotonin reuptake inhibitor is often complicated by a delayed onset of action of the antidepressant or severe insomnia or both, we investigated whether tryptophan, an amino acid with both antidepressant-augmenting and hypnotic effects, would benefit patients with depression at the beginning of treatment with fluoxetine. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: Thirty individuals with major depressive disorder. INTERVENTIONS: Treatment over 8 weeks with 20 mg of fluoxetine per day and either tryptophan (2 to 4 g per day) or placebo. OUTCOME MEASURES: Mood was assessed using the 29-item Hamilton Depression Rating Scale (HDRS-29) and the Beck Depression Inventory (BDI). Laboratory sleep studies were done at baseline and after 4 and 8 weeks of treatment using standard procedures. RESULTS: During the first week of treatment, there was a significantly greater decrease in HDRS-29 depression scores, and a similar trend in BDI scores, in the tryptophan/fluoxetine group than in the placebo/fluoxetine group. No significant differences were noted at later time points. With respect to sleep measures, there was a significant group-by-time interaction for slow-wave sleep at week 4. Further analysis revealed a significant decrease in slow-wave sleep after 4 weeks of treatment in the placebo/fluoxetine group, but not in the tryptophan/fluoxetine group. No cases of serotonin syndrome occurred, and the combination was well tolerated, although the 4 g per day dosage of tryptophan produced daytime drowsiness. CONCLUSIONS: Combining 20 mg of fluoxetine with 2 g of tryptophan daily at the outset of treatment for major depressive disorder appears to be a safe protocol that may have both a rapid antidepressant effect and a protective effect on slow-wave sleep. Further large-scale studies are needed to confirm these initial findings.

Novel antipsychotics: issues and controversies. Typicality of atypical antipsychotics.

Abstract: The typicality of atypical antipsychotic drugs remains debatable. Preclinical studies and findings from randomized, controlled and open trials of clozapine, olanzapine, risperidone, quetiapine, sertindole, ziprasidone and a substituted benzamide were examined. A MEDLINE search was conducted using key words, including "extrapyramidal side effects," "cognition," "schizophrenia" and the generic drug names. Over 140 articles from peer-reviewed journals were reviewed, some of which were based on a meta-analysis. New-generation neuroleptic agents were found to have greater efficacy on the negative symptoms of schizophrenia and to cause fewer unwanted extrapyramidal side effects (EPS) than the traditional antipsychotic drugs. On one hand, atypical neuroleptic agents could be strictly defined as any neuroleptic agent with antipsychotic effects at a dosage that does not cause extrapyramidal side effects. Thus, clozapine is regarded as the "standard" atypical antipsychotic drug. On the other hand, typicality is about dimension rather than category, and we suggest the use of the term "spectrum of atypicality." For example, an emphasis is placed on quetiapine to illustrate where a new compound fits in this spectrum. Although dose-related, atypicality may be more a question of prescription attitude than of a specific characteristic of a compound. The degree to which a new compound is clinically superior to another atypical antipsychotic drug, in terms of improving positive, negative or affective symptoms, cognitive function and long-term outcome, will require further a priori hypotheses based on conceptual frameworks that are clinically meaningful. In addition, the results from industry-sponsored trials should be more comparable to those obtained from investigator-leading trials. Finally, the patient characteristics that define a patient's response to a specific antipsychotic drug are unknown.

Statistical mapping analysis of serotonin synthesis images generated in healthy volunteers using positron-emission tomography and alpha-[11C]methyl-L-tryptophan.

Abstract: Objectives: To assess the suitability of analyzing functional images of brain serotonin (5-HT) synthesis with statistical parametric mapping (SPM), and to investigate further possible sex-related regional differences. Design: Prospective study. Participants: Six healthy men and 5 healthy women. Intervention: Participants’ brains were scanned with positron-emission tomography (PET) after intravenous injection of α -[ 11 C]methylL-tryptophan (α -[ 11 C]MTrp). Outcome measures: Tissue radioactivity images were converted into functional images using the Patlak plot approach, and analyzed with 2 methods for global normalization in the SPM program: proportional scaling and analysis of covariance (ANCOVA). Results: The data structure suggests that PET α -[ 11 C]MTrp data meet the criteria for analysis with SPM, and that the proportional scaling method is more appropriate than the ANCOVA method for normalization. Regional differences in 5HT synthesis were identified between men and women, and the significance of these findings was supported by region of interest (ROI) analyses. Conclusion: SPM analyses of PET α -[ 11 C]MTrp data may be of value for identifying regional differences in brain 5-HT synthesis between groups, and in investigating the effects of psychotropic drugs. Since we found regional differences between male and female subjects, men and women should not be grouped for data analysis in PET α -[ 11 C]MTrp studies.

Psychopharmacotherapy of anorexia nervosa, bulimia nervosa and binge-eating disorder.

Abstract: On considere que la pharmacotherapie est d'une efficacite limitee contre l'anorexie nerveuse. Beaucoup d'etudes comportent toutefois des limites methodologiques et l'on n'a pas encore etudie l'utilite de nouveaux medicaments dans le traitement de l'anorexie. Meme s'il y a eu des etudes plus fructueuse sur l'efficacite des medicaments dans la prise en charge de la boulimie nerveuse, de nombreuses questions demeurent encore sans reponse au sujet de la prise en charge optimale d'une remission partielle au cours de la phase de traitement aigu, ainsi que de l'intensite de la duree de la pharmacotherapie necessaire pour obtenir une prophylaxie optimale. Les inhibiteurs selectifs du recaptage de la serotonine (ISRS) controlent les episodes de frenesie alimentaire dans les cas de troubles d'alimentation excessive, mais d'autres etudes s'imposent pour analyser l'utilite des ISRS et d'autres agents dans un traitement de maintien. Nous passons en revue la situation actuelle de la pharmacotherapie contre l'anorexie nerveuse, la boulimie nerveuse et le trouble d'alimentation excessive et nous evaluons les avantages des nouveaux agents dans le traitement de ces troubles.

Antidepressants upregulate messenger RNA levels of the neuroprotective enzyme superoxide dismutase (SOD1).

Abstract: OBJECTIVE: To investigate the effect of amitriptyline, bupropion, doxepin or venlafaxine on the gene expression of the neuroprotective enzyme superoxide dismutase (SOD1) in a catecholamine cell in vitro model. DESIGN: Molecular study of a cultured cell line. INTERVENTIONS: Rat pheochromocytoma (PC12) cells were incubated in 1 and 10 mumol/L of various antidepressant medications for 24 or 48 hours. OUTCOME MEASURES: Northern blot analysis. RESULTS: Amitriptyline up-regulated SOD1 messenger RNA in a time- and dose-dependent manner. The greatest up-regulation was following incubation with 10 mumol/L amitriptyline for 48 hours. The addition of bupropion, doxepin or venlafaxine to PC12 cell cultures also up-regulated SOD1 mRNA. CONCLUSIONS: These findings suggest that some antidepressants have the ability to positively regulate neuroprotective genes.

Cholecystokinin-induced anxiety in rats: relevance of pre-experimental stress and seasonal variations.

Abstract: OBJECTIVE: To examine the influence of pre-experimental stress on the anxiogenic-like action of caerulein, an agonist of cholecystokinin (CCK) receptors. Differences in the anxiety levels of rats in summer and winter, and the role of CCK in these behavioural alterations, were also examined. DESIGN: Prospective animal study. INTERVENTIONS: Male Wistar rats were injected with the CCK agonist caerulein, or the CCK antagonists L-365,260 or devazepide, after being exposed to pre-experimental stress (handling and isolation). OUTCOME MEASURES: Performance in the plus-maze model of anxiety; serum levels of prolactin, thyrotropin and growth hormone; brain density and affinity of dopamine D2, serotonin 5-HT2 and CCK receptors. RESULTS: Caerulein (5 micrograms/kg, subcutaneous injection) caused the strongest action in animals brought to the experimental room immediately before the experiment and kept in isolation after the administration of caerulein. Caerulein did not cause any reduction of exploratory activity in rats made familiar with the experimental room and kept in the home-cage after the injection of the CCK agonist. The anti-exploratory action of caerulein in stressed rats was reversed by the CCK antagonist L-365,260 (100 micrograms/kg, intraperitoneal injection), demonstrating the involvement of the CCKB receptor subtype. In addition, seasonal fluctuations occur in the exploratory activity of rats; such activity was much lower in July than in November. The rats displaying the reduced exploratory activity had an increased number of CCK receptors in the frontal cortex and hippocampus. Simultaneously, the density of serotonin 5-HT2 receptors in the frontal cortex, but not that of dopamine D2 receptors in the striatum, was elevated. The blood level of growth hormone was also higher in July. CONCLUSIONS: The anti-exploratory action of caerulein appears to be dependent on the pre-experimental stress of rats. Moreover, the seasonal variations of exploratory behaviour of rats are evident in the plus-maze model of anxiety. The reduced exploratory activity in summer appears to be related to the elevated density of CCK and 5-HT2 receptors in the brain.

Association and linkage studies of candidate genes involved in GABAergic neurotransmission in lithium-responsive bipolar disorder.

Abstract: OBJECTIVE: To test for genetic linkage and association with GABAergic candidate genes in lithium-responsive bipolar disorder. DESIGN: Polymorphisms located in genes that code for GABRA3, GABRA5 and GABRB3 subunits of the GABAA receptor were investigated using association and linkage strategies. PARTICIPANTS: A total of 138 patients with bipolar 1 disorder with a clear response to lithium prophylaxis, selected from specialized lithium clinics in Canada and Europe that are part of the International Group for the Study of Lithium-Treated Patients, and 108 psychiatrically healthy controls. Families of 24 probands were suitable for linkage analysis. OUTCOME MEASURES: The association between the candidate genes and patients with bipolar disorder versus that of controls and genetic linkage within families. RESULTS: There was no significant association or linkage found between lithium-responsive bipolar disorder and the GABAergic candidate genes investigated. CONCLUSIONS: This study does not support a major role for the GABAergic candidate genes tested in lithium-responsive bipolar disorder.

Measuring neuropsychological change in schizophrenia with novel antipsychotic medications.

Abstract: The recent introduction of second-generation antipsychotic medications has stimulated considerable interest in cognitive changes to pharmacotherapeutic treatment. Cognitive impairment has been an integral consequence of schizophrenia since the inception of the diagnosis and has proven resistant to treatment with firstgeneration antipsychotic medication. This commentary summarizes the relevance of cognitive impairment to treatment outcome and reviews the research to date regarding the apparent cognitive efficacy of clozapine, olanzapine, risperidone and quetiapine. Emphasis is given to the value of comprehensive neuropsychological assessments that can provide information on the differential effects of the novel antipsychotic treatments on discrete domains of cognitive skill. Methodologic suggestions are also offered regarding secondary factors that may confound a cerebral interpretation of the changes, specific suggestions regarding the types of instruments that may be of value to this assessment, a general consideration of computerized testing, and the importance of translating cognitive improvement into changes in lifestyle. The novel interest in prospective alterations of cognitive skills to second-generation antipsychotic medications may provide an important stimulus to further research on traditional neuropsychological issues relating to a localization of cerebral pathology and a confident articulation of the onset and course of the dysfunction.

An examination of the sensitivity of the six-item Hamilton Rating Scale for Depression in a sample of patients suffering from major depressive disorder.

Abstract: OBJECTIVES: To compare the sensitivity of the 6-item Hamilton Rating Scale for Depression (HRSD6) with the more widely used 17-item Hamilton Rating Scale for Depression (HRSD17) in patients suffering from major depressive disorder, with or without melancholia and/or dysthymic disorder. A secondary objective was to compare the sensitivity of the HRSD6 to the Montgomery-Asberg Depression Rating Scale (MADRS). DESIGN: Retrospective analysis of 4 clinical trials that tested antidepressant therapies. SETTING: Outpatient treatment in a major psychiatric hospital. PARTICIPANTS: One hundred and forty-three male and female outpatients meeting the criteria of the DSM-III-R or DSM-IV for major depressive disorder. OUTCOME MEASURES: HRSD17, HRSD6 and MADRS. RESULTS: The HRSD6 correlated strongly with the HRSD17, both at baseline and termination of treatment, and for the subgroups of double depression and melancholia. The HRSD6 was also correlated significantly with the MADRS at both measurement times, and for the subgroups. Paired t-tests with the HRSD6, HRSD17 and MADRS demonstrated equal sensitivity to change over the course of treatment, both in the full sample and in the dysthymic and melancholic subgroups. CONCLUSIONS: The HRSD6 appears to be as sensitive to change over treatment as the HRSD17 and the MADRS. A shorter, less time-consuming measure of depression may have utility in clinical practice and research.

Influence of a chronic ultramild stress procedure on decision-making in mice.

Abstract: OBJECTIVE: To test the influence of a chronic ultra mild stress (CUMS) procedure, based solely on socio-environmental stressors, on cognitive-behavioural function in mice. DESIGN: Behavioural study. PARTICIPANTS: B6D2F1 mice. INTERVENTIONS: Mice were exposed to various stressors and then tested using a decision-making task. RESULTS: We observed that stress facilitated "choice" behaviour, with an absence of "no choice" behaviour. Stress also facilitated a more rapid capacity to process information, a decrease in the level of evaluation of the choice situation and less hesitation. These stress-related consequences on decision making may be attributed to a higher level of distractability in the stressed mice. CONCLUSIONS: The CUMS model may be useful for the study of stress-related disorders by proposing a new method for assessing gene-environment interactions in cognitive-affective behaviours.

Effects of clozapine and typical antipsychotic drugs on plasma 5-HT turnover and impulsivity in patients with schizophrenia: a cross-sectional study.

Abstract: OBJECTIVE: To compare the efficacy of clozapine with typical antipsychotic drugs in controlling impulsivity and to explore the possible correlation of impulsivity with plasma 5-hydroxytryptamine (5-HT) levels, plasma 5-hydroxyindoleacetic acid (5-HIAA) levels and plasma 5-HT turnover. DESIGN: Prospective, cross-sectional study open to medication and blinded to biochemical analyses. PARTICIPANTS: Healthy control subjects (n = 24) and 46 inpatients and outpatients meeting the DSM-IV criteria for schizophrenia; 20 were being treated with clozapine and 26 were taking typical antipsychotic drugs. INTERVENTIONS: All psychotropic drugs other than clozapine or typical antipsychotic drugs were discontinued for at least 5 days and subjects fasted overnight before they were assessed. OUTCOME MEASURES: Coccaro Impulsivity Scale scores, plasma 5-HT levels, 5-HIAA levels and 5-HT turnover. RESULTS: Patients treated with clozapine and those treated with typical antipsychotics had significantly higher impulsivity scores than the control group, and the mean impulsivity score of the typical antipsychotic group was significantly higher than that of patients treated with clozapine. The mean concentration of 5-HT of the typical antipsychotic group was significantly lower than that of the control group and patients treated with clozapine; however, mean plasma levels of 5-HIAA were significantly higher for the clozapine group than the other 2 groups. 5-HT turnover was significantly higher for the 2 drug-treatment groups than for the control group. CONCLUSIONS: These results suggest that treatment with clozapine should be considered for patients with schizophrenia who are impulsive and aggressive.

Citalopram controls phobic symptoms in patients with panic disorder: randomized controlled trial.

Abstract: OBJECTIVE: To examine the effects of long-term treatment with citalopram or clomipramine on subjective phobic symptoms in patients with panic disorder. DESIGN: Double-blind, parallel-group, five-arm study. PATIENTS: Patients aged 18 to 65 years with panic disorder (DMS-III-R diagnosis) and with no major depressive symptoms. INTERVENTIONS: Four hundred and seventy-five patients were randomized to 8 weeks of treatment with either citalopram (10 to 15 mg per day; 20 to 30 mg per day; or 40 to 60 mg per day), clomipramine (60 to 90 mg per day) or placebo. Two hundred and seventy-nine patients continued treatment after the 8-week acute phase. OUTCOME MEASURES: Phobic symptoms were assessed using the Phobia Scale and the Symptom Checklist's (SCL-90) phobia-related factors. RESULTS: At all dosages, citalopram was more efficacious than placebo, with 20 to 30 mg generally being the most effective dosage. Citalopram (20 to 30 mg) generally decreased phobic symptoms significantly more than placebo after Month 3. Interpersonal sensitivity decreased when measured on the respective SCL-90 sub-scale. Alleviation of phobic symptoms generally continued to increase towards the end of the treatment. The effect of clomipramine was not as consistent. CONCLUSIONS: All active treatment groups, especially the group receiving 20 to 30 mg per day of citalopram, effectively controlled phobic symptoms in patients with panic disorder. Long-term treatment with citalopram further decreased phobic symptoms.

Neurochemical and metabolic aspects of antidepressants: an overview.

Abstract: Antidepressants, in addition to being effective therapeutic agents for depression, have also proved to be multifaceted drugs useful for treating a number of other psychiatric and neurologic disorders. Despite the widespread use of these drugs, much remains to be understood about their mechanisms of action and other important aspects, such as their metabolism and potential interactions with other drugs. This article reviews research conducted in the authors' laboratories on various aspects of antidepressants, including trace amines and antidepressants, gamma-aminobutyric acid and antidepressants, drug metabolism, development and application of rapid, sensitive assay procedures for antidepressants and their metabolites; and drug development based on analogues of the antidepressants phenelzine and tranylcypromine. The significance of this work to future drug development is also discussed.

Treating cognitive dysfunction in patients with schizophrenia.

Abstract: Cognitive dysfunction is a common, chronically disabling component of schizophrenia. It has been proposed that many of the symptoms of schizophrenia can be understood as a result of disruption of fundamental cognitive processes. This paper reviews treatment strategies aimed at improving cognitive function in patients with schizophrenia. Nonpharmacologic interventions include instruction in the performance of tasks such as the Wisconsin Card Sorting Test. Mixed results have been achieved, but it appears that instruction methods involving reinforcement of information held in working memory are more successful. Computer-aided remediation has also been used with variable success. Novel antipsychotic drugs appear to have an advantage over conventional antipsychotic drugs in terms of their effect on cognitive function. The development of more precisely tailored methods of remedial teaching, along with optimal pharmacologic treatment, may lead to more effective treatment of cognitive dysfunction in patients with schizophrenia.

Treatment Compliance and the Therapeutic Alliance

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Variations in response to citalopram in men and women with alcohol dependence.

Abstract: OBJECTIVE: To examine the differential effects of citalopram on alcohol consumption in nondepressed women and men with mild to moderate alcohol dependence. DESIGN: Prospective, placebo-controlled study. PARTICIPANTS: Sixty-one subjects (34 men and 27 women). INTERVENTIONS: After a 2-week baseline, subjects were randomly assigned to 12 weeks of citalopram (40 mg per day) (n = 15 women, 16 men) or placebo (n = 12 women, 18 men). All received brief standard psychosocial interventions. OUTCOME MEASURES: Alcohol Dependence Scale, Montgomery-Asberg Depression Scale, Michigan Alcohol Screening Test, State-Trait Anxiety Inventory and daily alcohol intake. RESULTS: Pretreatment sex differences were evident in alcohol consumption, alcohol dependence, alcohol-related problems and on anxiety and depression measures. After treatment, analyses of covariance with depression and anxiety scores as covariates revealed a differential benefit of citalopram for men. Men receiving citalopram reduced average drinks per day by 44%, whereas women exhibited a 27% decrease (p < 0.05). CONCLUSIONS: Men may benefit more than women from citalopram in the treatment of alcohol dependence. These findings highlight the importance of examining sex as a significant variable in evaluating response to pharmacotherapy.

Proton magnetic resonance spectroscopy (1H-MRS) of the cerebellum in men with schizophrenia

Abstract: OBJECTIVE: To investigate whether there are cerebellar vermis abnormalities in schizophrenia. DESIGN: Prospective imaging study with proton magnetic resonance spectroscopy (1H-MRS). SETTING: Schizophrenia clinic at a large urban hospital. PATIENTS AND CONTROLS: Twelve right-handed male patients with schizophrenia, and 12 control subjects with no psychiatric history. INTERVENTIONS: MRS data were acquired from a 2.0 x 2.0 x 2.0 cm volume of interest that included the entire cerebellar vermis. OUTCOME MEASURES: Spectral peak arising from N-acetylaspartate (NAA), phosphocreatine/creatine (Cr) and choline (Cho). RESULTS: There were no significant differences between the patients with schizophrenia and the controls in cerebellar vermis ratios of NAA to Cr (p = 0.71) or Cho to Cr (p = 0.50). CONCLUSIONS: This study does not support earlier structural studies that found abnormalities of the cerebellar vermis in schizophrenia, although it does support reported neurochemical studies. It does not rule out cerebellar involvement in schizophrenia through mechanisms such as aberrant circuitry. Larger in vivo structural/neurochemical and functional imaging studies in other parts of the cerebellum are needed.