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Manic patients, excited schizoaffective patients, and agitated schizophrenic patients were rated using a "manic interpersonal interaction scale" that evaluated a number of interpersonal interactions including testing of limits, projection of responsibility, sensitivity to others' soft spots, attempts to divide staff, flattering behavior, and ability to evoke anger. Manic patients showed an elevation in each of these items; overall, elevations were greater than those of schizoaffective and schizophrenic patients. The intensity of the manic state also correlated with the degree of elevation of the manic interpersonal interaction scale scores.

Mood disorders are highly prevalent and are the leading cause of disability worldwide. The neurobiological mechanisms underlying depression remain poorly understood, although theories regarding dysfunction within various neurotransmitter systems have been postulated. Over 50 years ago, clinical studies suggested that increases in central acetylcholine could lead to depressed mood. Evidence has continued to accumulate suggesting that the cholinergic system plays a important role in mood regulation. In particular, the finding that the antimuscarinic agent, scopolamine, exerts fast-onset and sustained antidepressant effects in depressed humans has led to a renewal of interest in the cholinergic system as an important player in the neurochemistry of major depression and bipolar disorder. Here, we synthesize current knowledge regarding the modulation of mood by the central cholinergic system, drawing upon studies from human postmortem brain, neuroimaging, and drug challenge investigations, as well as animal model studies. First, we describe an illustrative series of early discoveries which suggest a role for acetylcholine in the pathophysiology of mood disorders. Then, we discuss more recent studies conducted in humans and/or animals which have identified roles for both acetylcholinergic muscarinic and nicotinic receptors in different mood states, and as targets for novel therapies.

Background: Lithium has been shown to increase serum creatinine levels in a subgroup of patients. However, lithium-induced increases in serum creatinine have not been well studied with regard to timing, trajectory, or predictability. Methods: The medical records of 16 intellectually disabled individuals treated with lithium between 1980 and 2010 in whom serum creatinine levels peaked at 1.5 mg/100 mL or higher (ie, who developed renal insufficiency) were reviewed. These individuals were compared with a group of 36 similar lithium-treated individuals in whom serum creatinine did not reach 1.5 mg/100 mL. Results: The 16 lithium-treated individuals who developed renal insufficiency had a mean peak serum creatinine level of 1.8 ± 0.3 mg/100 mL while on lithium. The mean time from institution of lithium until the 1.5 mg/100 mL serum creatinine level was first reached was 7.9 years. After lithium was discontinued, overall mean serum creatinine levels did not significantly change. Reaching a serum creatinine level of 1.3 or 1.4 mg/100 mL predicted reaching a 1.5 mg/100 mL level or higher. No significant differences in the age lithium was started, baseline serum creatinine levels, years receiving lithium, sex, or race differentiated those who developed renal insufficiency. Conclusions: Prescribing lithium led to elevated serum creatinine levels in some individuals. A serum creatinine level of 1.3 and/or 1.4 mg/100 mL predicted renal insufficiency. Clinical implications of this study are that if 1 serum creatinine result reaches 1.3 mg/100 mL or more, intensive monitoring for further increases is indicated.

The current study evaluated the effects of chronic administration of lithium on renal functioning in an intellectually disabled population.Fifty-seven lithium-treated individuals were compared with 24 behaviorally symptomatic controls using a retrospective chart review method. Serum creatinine levels and creatinine clearance activities were compared at baseline, at the time of peak creatinine levels, and at the end of the study in 2006.The mean length of lithium administration was 8.76 years (range, 1-23 years). Chronic lithium administration yielded a significant increase in peak serum creatinine levels and a decrease in the corresponding creatinine clearance activity. Of the subjects, 22.8% had peak creatinine levels of 1.5 mg or higher per 100 mL (a common threshold for renal insufficiency). This contrasted with 0% (none) for the symptomatic control subjects (P = 0.008). In addition, 26.3% of the lithium-treated subjects had creatinine clearance activities less than 55 mL/min and 17.5% had less than 50 mL/min, both indicative of renal insufficiency, versus none of the symptomatic control subjects (P = 0.004 and P = 0.029, respectively). With lithium withdrawal, further deterioration of renal function did not occur in most cases, and many showed improvement, with decreases in serum creatinine levels and increases in creatinine clearance activity.Chronic administration of lithium led to clinically significant increases in serum creatinine levels and decreases in creatinine clearance in lithium-treated intellectually disabled individuals.

The antagonistic effects of scopolamine, methscopolamine, and a combination of methscopolamine and scopolamine were evaluated in preventing physostigmine induced lethality in Swiss Webster mice. Low dose scopolamine was found to be highly effective in reversing high dose (3 X the LD100) physostigmine induced lethality, in contrast to methscopolamine, which was ineffective except in very high doses. A combination of scopolamine and methscopolamine was more effective than either drug alone.

Severe intellectual and developmental disabilities are frequently associated with aggression toward self and others, destruction of property, and disruption. Antipsychotic medications are a mainstay of treatment of such behaviors. National and state guidelines suggest stopping these medications or decreasing their dosages when possible if patients have maintained stability. The current study evaluated the likelihood of future antipsychotic drug withdrawal-induced relapses in those individuals where such a relapse had occurred previously. Subjects were 57 institutionalized adults with severe or profound intellectual disability. Between 1990 and 2000, each had experienced an initial activation of maladaptive aggressive behaviors after an attempt at antipsychotic drug withdrawal and/or termination. Quarterly behavioral reports were evaluated to determine whether subsequent antipsychotic drug withdrawal attempts were also associated with future relapses. Initial relapse was followed by subsequent antipsychotic drug withdrawal attempts in 49 of the 57 individuals. Between 1990 and 2005, 28.6% of these 49 subjects had experienced 1, 38.7% had 2, 20.4% had 3, and 8.2% had 4 additional relapses. Two (4.1%) had not relapsed. Eight individuals remained on antipsychotic agents without a subsequent withdrawal attempt. By the end of 2005, only 4 (7%) of the 57 individuals had become antipsychotic drug free, 22.8% were receiving first-generation antipsychotic agents alone, 45.6% were receiving second-generation antipsychotic agents alone, and 24.6% were receiving a combination of first- and second-generation antipsychotic agents. Thus, if relapse occurs after an antipsychotic drug withdrawal attempt, subsequent attempts at withdrawal are also very likely to lead to further relapses.

Bipolar disorder is a unique illness characterized by fluctuations between mood states of depression and mania. Originally, an adrenergic-cholinergic balance hypothesis was postulated to underlie these different affective states. In this review, we update this hypothesis with recent findings from human and animal studies, suggesting that a catecholaminergic-cholinergic hypothesis may be more relevant. Evidence from neuroimaging studies, neuropharmacological interventions, and genetic associations support the notion that increased cholinergic functioning underlies depression, whereas increased activations of the catecholamines (dopamine and norepinephrine) underlie mania. Elevated functional acetylcholine during depression may affect both muscarinic and nicotinic acetylcholine receptors in a compensatory fashion. Increased functional dopamine and norepinephrine during mania on the other hand may affect receptor expression and functioning of dopamine reuptake transporters. Despite increasing evidence supporting this hypothesis, a relationship between these two neurotransmitter systems that could explain cycling between states of depression and mania is missing. Future studies should focus on the influence of environmental stimuli and genetic susceptibilities that may affect the catecholaminergic-cholinergic balance underlying cycling between the affective states. Overall, observations from recent studies add important data to this revised balance theory of bipolar disorder, renewing interest in this field of research.

Depression in mentally retarded individuals is not uncommon and usually is treatable. However, studies of the diagnosis and treatment of psychiatric illnesses in general and depression specifically in this population are relatively rare. Although Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria can be applied to mildly and moderately retarded individuals, the diagnosis of depression in those with intelligence quotients below 35 is challenging. However, the diagnosis of depression in the latter group is possible using modified criteria emphasizing observational data. Criteria include symptoms such as sadness, irritability, decreased social interaction, regression of skills, sleep disturbances, diurnal variation, and aggression. Furthermore, there is a growing body of evidence that antidepressant treatments, especially administration of selective serotonin reuptake inhibitors, are effective in treating depression in mentally retarded patients. This article reviews numerous studies elaborating on the diagnosis, phenomenology, and treatment of depression in mentally retarded individuals.

Retrospective review of records from 1990 to 1997 revealed unsuccessful attempts to withdraw antipsychotic medications from a total of 34 intellectually disabled individuals. The lowest dose of antipsychotic medication necessary to maintain symptom suppression and the dose at which relapse occurred were noted. Target behaviors observed indicating relapse included increased self-injurious behavior, aggression, and destructive/disruptive behaviors. Nineteen subjects received a low potency antipsychotic agent (ie, thioridazine or chlorpromazine) and 15 received a high potency antipsychotic agent (ie, haloperidol, loxapine, thiothixene). The mean lowest effective dose of chlorpromazine/thioridazine was 149.3 mg/d and relapse occurred at a mean dose of 93.6 mg/d. The mean lowest effective dose of haloperidol or related high potency drugs (expressed as haloperidol equivalents) was 5.9 mg/d, and relapse occurred at a mean dose of 3.8 mg/d.

An inverse relationship exists between an individual's degree of negative affect and the interpersonal perception of friendliness, sympathy and empathy, acceptance, warmth, regard, and genuineness, and the converse relationship persists for the perception of sadness and anger. Thus, a "negative interpersonal bias" exists in those with diagnoses of depression or dysphoria. There is evidence that psychostimulants (ie, amphetamine or methylphenidate) and antidepressants can reverse or improve these negative interpersonal perceptions in a positive way, especially in individuals with dysphoria, depression, and anxiety. The theoretic and therapeutic implications of these relationships are discussed herewith.

This study reviews the treatment response to the antiepileptic drug topiramate (Topamax-mean dose 202 mg/d, range 150-350 mg/d) of a group of 22 institutionalized intellectually disabled adults (8 males, 14 females, mean age 46.5 years, age range 25-70 years). These individuals were predominantly classified as having severe or profound intellectual disability and as having a mood disorder. The individuals studied were treated for aggression, self-injurious behaviors, destructive/disruptive behaviors or a combination of these, and/or other challenging and maladaptive behaviors. All subjects were receiving concurrent psychotropic and/or anticonvulsant medications. Effectiveness was determined by retrospective review of summaries of quarterly multidisciplinary Neuropsychiatric Behavioral Reviews. Assignment of global severity scores and evaluation of longitudinal behavioral graphs of target symptoms occurred. Overall, statistically significant decreases in global severity scores and in the cumulative aggression and worst behavior rates occurred in the subjects, especially when the 3 months before and the 3 to 6 months after starting topiramate were compared. The overall subject group showed no significant weight changes. One subject developed delirium, 1 developed hypoglycemia, 1 developed sedation, and 2 developed constipation. The results suggest that topiramate may have a role in the treatment of challenging/maladaptive behaviors in intellectually disabled individuals.

Background: Animal studies suggest that preference for relatively high concentrations of sweet solutions and lack of control over sweet solution consumption is related to a preference for alcohol over water. There also is evidence in humans that alcoholics prefer high concentration sweet solutions. This study was designed to determine whether patients with cocaine use disorder also prefer high concentrations of sweet solutions. Methods: Sixteen patients with cocaine abuse/dependency were compared with 16 inpatient controls with an affective disorder as to their preferences for increasing concentrations of sucrose solutions. Patients were administered aqueous sucrose solutions ranging from 0.05 to 0.83 M. They were then asked to rate their degree of preference for, and the degree of sweetness of each solution. Results: Cocaine abusing/dependent patients significantly more often preferred the highest sucrose concentration (0.83M). Conclusions: The above information suggests that cocaine abusing/dependent patients, like alcoholics, and in contrast to inpatient controls, share a preference for high concentrations of sucrose.

Summary: Objective: The current study was designed to compare the distribution of Myers Briggs Type Indicator (MBTI) personality types in patients with Unipolar Depression compared to normative data.Method: The MBTI divides individuals into four dichotomous types: Extroverted and Introverted, Sensing and Intuitive, Thinking and Feeling, and fudging and Perceiving. This yields eight single-factor and sixteen four-factor types. One-hundred-thirty Unipolar Depressed patients were administered the MBTI-Form F.Results: Unipolar Depressed patients were significantly more often Introverted, Sensing, Feeling, and Perceiving single-factor types respectively, and Introverted-Sensing-Feeling-Perceiving, and Introverted-Intuitive-Feeling-Perceiving four-factor types. The male Introverted-Sensing-Feeling-Perceiving four-factor type was the most dramatically over-represented.Conclusion: The MBTI effectively discriminates a patient group with Unipolar Depression from a normative population.

The adrenergic-cholinergic balance hypothesis of mania and depression suggests that depression may be due to an over-activity or a hypersensitivity to central acetylcholine. From this hypothesis, it is logical that scopolamine, a centrally acting antimuscarinic agent, would be useful as an antidepressant. Authors, working at the Intramural Program at NIMH in Bethesda Maryland have shown that intravenous scopolamine is a rapidly acting, effective antidepressant and have than replicated this finding. They now report that this antidepressant effect occurs in bipolar, as well as unipolar depressed patients. The clinical and theoretical implications of this finding for difficult to treat bipolar depressed patients is considerable, and the finding is in need of independent replication.

A growing body of information suggests that core or underlying personality is a significant concomitant of depression and suicidality. Introversion (ie, low extroversion) is especially promising in its relationship to the phenomenology and outcome of depression, and may represent an underlying heritable trait of etiologic significance. Furthermore, the presence of introversion has implications for differentiating unipolar and bipolar depression. It is likely that introversion acts in concert with other core personality variables, including neuroticism and having a feeling-type personality to influence depression. Considering depression from the perspective of core personality allows for novel psychotherapeutic approaches based on targeting underlying personality variables.

There is now more information to assimilate in clinical psychopharmacology and newer ways to acquire this information. Educational materials should be designed for and targeted to meet the diverse needs of such groups as medical students, psychiatry residents, clinical practitioners, industry and federal scientists, and clinical research organizations. As a starting point, the authors developed, in 1997, a model curriculum for psychopharmacology residency programs. The curriculum consists of 1) overview, 2) learning and educational objectives, 3) what and how to teach, 4) how to evaluate, 5) how to organize a psychopharmacology program, and 6) an investigative psychiatry curriculum. There are 31 lecture outlines and hard copies of 1,500 slides, comprising basic and advanced courses. A 1-year follow-up evaluation of users’ experience found that 62% rated the curriculum, to varying degrees, as improving the teaching of psychopharmacology in their programs.

The purpose of this study is to profile the personalities of patients with social phobia. Sixteen patients with social phobia were compared with a normative population of 55,971, and with 24 hospitalized Major Depressive Disorder inpatients, using the Myers Briggs Type Indicator. The Myers Briggs Type Indicator, a popular personality survey, divides individuals into eight categories: Extroverts versus Introverts, Sensors versus Intuitives, Thinkers versus Feelers, and Judgers versus Perceivers. Social phobia patients were significantly more often Introverts (93.7%) than were subjects in the normative population (46.2%). In addition, using continuous scores, the social phobia patients scored as significantly more introverted than did the patients with Major Depressive Disorder, who also scored as Introverted. Introversion is a major component of social phobia, and this observation may have both etiological and therapeutic significance.

A group of bipolar and a group of unipolar depressed pa-tients filled out the MBTI, the TPQ, the Beck Depression Inventory,and the CAGE questionnaire. The two groups were compared witheach other as to responses on the above surveys, and subgroups ofbipolar depressed and bipolar patients with manic symptoms were alsocompared.

Epidemiological studies indicate a high incidence of cigarette smoking among depressed individuals. Moreover, individuals with a history of depression have a much harder time giving up smoking. It has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. Although some animal and human studies suggest that nicotine may act as an antidepressant, further verification of this hypothesis and involvement of nicotinic cholinergic system in depressive symptoms is required. Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression. These rats, selectively bred for their hyperresponsiveness to cholinergic stimulation, show an exaggerated immobility in the forced swim test compared to their control Flinders Resistant Line (FRL) rats. Acute or chronic (14 days) administration of nicotine (0.4 mg/kg s.c.) significantly improved the performance of the FSL but not the FRL rats in the swim test. The effects of nicotine on swim test were dissociable from its effects on locomotor activity. Moreover, the FSL rats had significantly higher [3H]cytisine binding (selective for the alpha4beta2 nicotinic receptor subtype) but not [125I]alpha-bungarotoxin binding (selective for the alpha7 subtype) in the frontal cortex, striatum, midbrain and colliculi compared to FRL rats. These data strongly implicate the involvement of central nicotinic receptors in the depressive characteristics of the FSL rats, and suggest that nicotinic agonists may have therapeutic benefits in depressive disorders.

The author has reviewed bipolar disorder-relevant abstracts from the July 2008 Munich CINP (Collegium Internationale Neuro-Psychopharmacologicum) meeting. Seven abstracts are summarized, focusing on the psychopharmacologic treatment of bipolar depression, the neuropsychological effects of psychotropic drugs used to treat bipolar disorder, and the relationship of mood stabilizers and antidepressants to emotional instability over time.

Animal studies have shown a positive association between the consumption of high concentrations of sweet solutions and subsequent alcohol intake. In a previous clinical study, it was shown that a preference for a high (0.83 M) concentration of sucrose (sweet liking) is characteristic of alcoholics, compared with controls. The present study was designed to determine whether personality variables, reported to be associated with subtypes of alcoholism, differentiate sweet liking alcoholics from sweet liking controls. Fifty-two male controls and 26 alcoholic patients were tested for sweet preference and administered the Tridimensional Personality Questionnaire. Sweet liking alcoholics scored significantly higher on the Tridimensional Personality Questionnaire Novelty Seeking and Harm Avoidance scales and related subscales when compared with sweet liking controls. Further analysis showed that preferred sucrose concentration, Harm Avoidance score, and Novelty Seeking predicted alcoholic versus nonalcoholic group status at 65% sensitivity and 94% specificity, with a correct classification in 85% subjects. We hypothesize that sweet liking may identify a specific alcoholism subtype also characterized by high novelty seeking and high harm avoidance. These findings may have theoretical biological significance and practical clinical implications.

This review discusses several depression-relevant abstracts of posters and talks presented at the 2005 American College of Neuropsychopharmacology Annual Meeting and the 2006 Collegium Internationale Neuro-Psychopharmacologicum Meeting. Described are several novel psychopharmacologic treatments for major depressive disorder, some predictors of efficacy, and information relevant to understanding the activation of the hypothalamicpituitary-adrenal axis in depression.

The Chinese herbal medicine, NPI-028, has been used for centuries in China to counteract alcohol intoxication. The present study used a number of different experimental conditions to determine whether NPI-028 and its derivatives might selectively influence alcohol intake in rodents that naturally exhibit high alcohol intakes. It was determined that intraperitoneal (i.p.) injections of NPI-028 (0.5, 0.75, and 1.0 g/kg) suppressed alcohol intake by up to 30% in both alcohol-preferring P and Fawn-Hooded (FH) rats during a continuous access schedule. These injections did not significantly affect food or water intakes, nor did the highest dose of NPI-028 (1 g/kg) alter blood ethanol levels after an i.p. injection of 2.5 g/kg of ethanol. In P rats, it was found that NPI-028 was orally active with the dose of 1.5 g/kg having a greater effect on ethanol intake than the 1.0 g/kg dose; once again, food and water intakes were not significantly altered. In FH rats maintained on a limited access schedule (1 hr/day), alcohol intake was completely abolished by 1.5 g/kg of NPI-028. Chronic i.p. administration of NPI-028 (0.75 g/kg) for four consecutive days in FH rats maintained on a continuous access schedule did not lead to any diminution of its alcohol-suppressant effects. Thus, NPI-028 has significant effects on alcohol intake without much effect on water and food intake, and tolerance does not readily develop to these effects. The i.p. administration of a partially purified extract (NPI-031) of NPI-028, obtained by countercurrent chromatography, also dose-dependently suppressed ethanol intake in FH rats, but the highest dose 200 mg/kg) also significantly decreased food intake. Finally, the i.p. administration of puerarin (NPI-31G), an isoflavone isolated from NPI-031 by countercurrent chromatography, significantly reduced ethanol intake in FH rats without affecting food or water intake. Therefore, NPI-028 and one of its pure components, NPI-031G, selectively reduced ethanol intake in alcohol-preferring rats.

It was previously reported that selection for differences in the hypothermic effects to the selective 5-HT-1A agonist, 8-OH-DPAT, occurred rapidly, with very substantial differences present by the fourth generation. The present communication summarizes the findings from the next five generations of selection and from behavioral and other functional studies on these rats. The rats which were more sensitive to 8-OH-DPAT (High DPAT Sensitive-HDS) exhibited decreases in temperature of 4 degrees C or more and the distribution did not overlap with that of the rats which were less sensitive to 8-OH-DPAT (Low DPAT Sensitive-LDS) which exhibited decreases in temperature of 1.5 degrees C or less. The randomly bred control group (Random DPAT Sensitive-RDS) exhibited intermediate temperature decreases (means of 1.6-1.8 degrees C), with time overlap with the distributions of the selected groups. Pretreatment with pindolol, a 5-HT-1A antagonist, reduced the hypothermic response to 8-OH-DPAT, but pretreatment with ritanserin, a 5-HT-7 and 5-HT-2A/C antagonist, had no effect, confirming that the hypothermic response to 8-OH-DPAT is mediated predominantly by 5-HT-1A receptors. The HDS rats were less mobile in a forced swim test and drank more saccharin solution in a two-bottle choice paradigm than the LDS or RDS rats over several generations. In contrast, there were no consistent differences among the groups for open field activity or performance in an elevated plus maze. There were no differences among the groups for voluntary alcohol intake, but the HDS rats exhibited greater suppression of alcohol and saccharin intake after injection of 8-OH-DPAT (0.125 mg kg-1). The HDS rats were also found to have a higher number of 5-HT-1A binding sites in cortical regions than the LDS or RDS rats, but there were no 5-HT-1A binding site differences in the raphe nuclei. These findings clearly show that consistent behavioral differences do occur in the 8-OH-DPAT-selected lines of rats, but only for behaviors related to possible depression or reward, not anxiety. The pattern of binding results suggests that these behavioral correlates of 8-OH-DPAT selection may be related to changes in cortical 5-HT-1A receptors rather than raphe autoreceptors.

Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression because they resemble depressed humans in that they have elevated REM sleep, reduced activity, and increased immobility and anhedonia after exposure to stressors. The present paper reviews experiments on the drug treatment of FSL and control Flinders Resistant Line (FRL) rats related to their utility as an animal model of depression, and presents new information. FSL rats exhibited exaggerated immobility in the forced swim test which is counteracted by the tricyclic antidepressants imipramine and desipramine and the serotonin reuptake blocker sertraline; the low immobility exhibited by the FRL rats is generally unaffected by these compounds. In contrast to these "therapeutic" effects of well recognized antidepressants, lithium and bright light treatment did not alter the exaggerated immobility of FSL rats. Novel data indicated that neither FSL nor FRL rats exhibited alterations in swim test immobility following chronic administration of the psychomotor stimulant amphetamine (2 mg/kg) and the anticholinergic scopolamine (2 mg/kg), which typically reduce immobility after acute administration. However, it was found that the calcium channel blockers verapamil (5 and 15 mg/kg) and nicardipine (10 mg/kg) did reduce the exaggerated immobility in FSL rats following chronic administration, suggesting that these compounds need to be evaluated further in humans. Previous studies have indicated no differences between FSL and FRL rats evaluated in the elevated plus maze, either at baseline or after the administration of diazepam, suggesting that the FSL rat may not differ from controls in anxiety-related behavior. Another recently published study showed that the FSL rat also did not differ from normal Sprague-Dawley rats in startle tests, indicating that the FSL rats do not exhibit behaviors shown in animal models of schizophrenia. These findings confirm the utility of FSL rats as an animal model of depression because the FSL rats do not appear to exhibit behaviors analogous to anxiety or schizophrenia and because they respond "therapeutically" to antidepressants and not psychomotor stimulants.

Complement proteins and fragments participate in the induction and modulation of specific and nonspecific immune reactions. We have examined the effect of 4 weeks of chronic mild stress (CMS) on complement sheep red blood cell hemolytic activity measured in CH50 units in two selectively bred lines of rats, the Flinders resistant line (FRL) and the Flinders sensitive line (FSL), that differ in cholinergic sensitivity and behavioral characteristics. Additionally, CMS-induced hedonic deficit (decreased preference for 0.02% saccharin over water) and serum corticosterone levels were compared in FRL and FSL rats. CMS caused a significantly (p < 0.01) greater decline in CH50 responses in FSL (−15%) than in FRL (−7%) rats. This was accompanied by a significant (p < 0.01) suppression of saccharin preference over a 24 h period in both FRL and FSL rats. Both lines showed a similar, more than 2-fold (p < 0.01) increase in corticosterone levels following CMS. These results further confirm that CMS induces a depressive-like state in rats as well as the validity of the FSL rat as a genetic model of depression. They also indicate that the effect of stress on the immune system can be monitored by measuring the complement CH50 response.

The recent literature on the involvement of cholinergic muscarinic mechanisms and adrenergic/cholinergic balance in affective disorders is reviewed and integrated with the older literature. There is strong evidence supporting the presence of exaggerated responses (behavioral, neuroendocrine, sleep) to cholinergic agents in affective disorder patients relative to normal controls and certain other psychiatric patients. There is also some, albeit less, conclusive evidence that these exaggerated responses may occur in euthymic individuals with a history of affective disorders, or in children at risk for development of affective disorders. Despite these promising results, suggesting a role for acetylcholine in the genetics of the affective disorders, further work in biochemistry and genetics is needed to link specific muscarinic receptors or other cholinergic variables to affective illness.

The effects of acute and chronic stressors on saccharin intake and preference in the hypercholinergic Flinders Sensitive Line (FSL) rat, a putative genetic animal model of depression, were studied and compared to the control Flinders Resistant Line (FRL) rats. Overall, the FRL rats drank significantly less saccharin and water than the FSL rats when compared over a wide range of saccharin concentrations (0.01-5%) under baseline conditions. A 0.02% saccharin concentration was used in subsequent experiments. We observed a significant suppression of saccharin intake/preference at 1 h following a single 5-min exposure to cold swim stress only in FSL rats. There was a tendency to increase saccharin intake in both lines at 1 h following a scrambled foot shock stress. These effects of acute stressors disappeared upon retesting for saccharin consumption/preference 23 h after the stress. Chronic 4-week exposure to unpredictable mild stressors significantly (p < 0.01) decreased saccharin consumption in the FSL rats, but not in the FRL rats. The FSL rats also exhibited a significantly greater decrease in saccharin preference (-24% vs. prestress baseline, as compared to -7% in FRL controls, p < 0.05). In conclusion, FSL rats appear more prone than the FRL rats to chronic, as well as immediate acute, stress-induced anhedonic effects. This outcome further supports the notion that the FSL rat is a useful model of a genetic predisposition to depressive-like reactions.

Fourteen women with PMS and ten without PMS were evaluated with a battery of neuropsychological tests during the follicular and late luteal phases of two consecutive menstrual cycles. Classification was determined with NIMH diagnostic criteria and prospective record keeping. The results indicated that (1) the PMS women had significant difficulty in learning new material and this problem was not phase-dependent, (2) both groups performed better on a test of frontal lobe function during the follicular phase, and (3) mood did not account for any of the differences in cognitive functioning.

The author has reviewed selected bipolar disorder- and major depression-relevant abstracts from the 2009 9th World Congress of Biological Psychiatry Meeting in Paris. The seven selected abstracts, which represent a small percentage of the presentations made at the meeting, explore the relationship between bipolar and unipolar diagnoses and suicidal behavior, the differentiation of bipolar I and bipolar II disorder, and some novel non-industry-supported treatments of bipolar and unipolar depression.

The present document is the second of three parts in a review that focuses on recent data from clinical and animal research concerning the biochemical bases of depressive disorders, diagnosis, and treatment. Various receptor/transmitter theories of depressive disorders are discussed in this section. Specifically, data supporting noradrenergic, serotonergic, cholinergic, dopaminergic, GABAergic, and peptidergic theories, as well as interactions between noradrenergic and serotonergic, or cholinergic and catecholaminergic systems are presented. Problems with the data and future directions for research are also discussed. A previous publication, Part I of this review, dealt with the classification of depressive disorders and research techniques for studying the biochemical mechanisms of these disorders. A future publication, Part III of this review, discusses treatments for depression and some of the controversies in this field.

In order to determine the effect of an anticholinergic agent on mood and sleep, scopolamine (0.4 mg IM) was administered before bedtime for three consecutive nights to 10 depressed patients (8 with a history of alcohol abuse) and 10 normal comparison subjects. The patients had a small, statistically significant antidepressant response on the second morning of treatment. Scopolamine inhibited rapid eye movement (REM) sleep and prolonged REM latency equally in depressed patients and the normal comparison group. Partial tolerance to the REM inhibiting effect of scopolamine developed between the first and third night of treatment. A REM rebound occurred during recovery nights. These results are consistent with concepts relating central cholinergic mechanisms to the control of REM sleep. Compared with controls, patients showed a greater increase in Stage 2 and Stage 2% and a lesser and increase in Delta (Stage 3 and 4) sleep % and Stage 4% on the first night of treatment. Further, well-controlled studies are needed to determine whether anticholinergic drugs possess clinically significant antidepressant effects.

This clinical trials review is derived from the presentations made at the Third International Conference on Bipolar Disorder, held June 17-19, 1999 in Pittsburgh, PA, published as abstracts in Bipolar Disorders: An International Journal of Psychiatry and Neurosciences, Edited by Jair C. Soares, and Samuel Gershon. In this review, abstracts reporting on the efficacy of "third generation" anti-epileptic agents, including topiramate, lamotrigine, diphenylhydantoin, gabapentin, and the new generation antipsychotic agent, olanzapine in treating bipolar disorders are reviewed.

Affective aggression was studied in pairs of Flinders Sensitive Line hypercholinergic rats (FSL) and Flinders Resistant Line (FRL) rats in shock-induced and apomorphine-induced fighting tests. FSL rats were significantly more aggressive in both tests. They had higher pain threshold, assessed by the jump-flinch method, than FRL rats. It is concluded that genetically developed cholinergic system supersensitivity has resulted in enhanced responsiveness to stimuli eliciting affective aggression.

1. Calcium channel blockers have been proposed, in addition to inhibiting the influx of Ca++ into the cells, to possess a wide variety of pharmacological effects, including interference with certain neurotransmitters involved in mood, mental disorders and alcohol craving. Further, it has been documented that certain neurotransmitters are involved in alcohol craving both in animals and humans. 2. To investigate the effects of Ca(++)-channel antagonist on alcohol preference, verapamil in three doses (5, 10 and 15 mg/kg) was injected (S.C.) twice daily over a period of one day in alcohol-preferring (P) and alcohol non-preferring (NP) rats at 9:00 a.m. and 4:00 p.m. 3. Water, alcohol and food intake were monitored. 4. Our results show that verapamil in doses of 10 and 15 mg/kg significantly (p less than 0.02 and 0.01, respectively) reduced the intake of ethanol and increased the intake of water by P rats. However, injection of an equal volume of saline did not change the pattern of alcohol intake. 5. These results suggest that a (++(+)-channel blocker such as verapamil, could, at least partially, attenuate alcohol preference in alcohol preferring rats. It is possible that verapamil exerts an inhibitory effect on alcohol preference by interfering with Ca++ channels, blocking serotonin uptake or through another mechanism(s).

For more than a century, acetylcholine has been postulated to be a factor in the regulation and etiology of affect. In 1889, Willoughby (1) reported a case in which pilocarpine, now known to be a muscarinic cholinergic agonist, was used to alleviate acute mania. Subsequently, in the late 1940s, 1950s, and early 1960s, a number of authors observed the anergic, inhibitory, anxiety-enhancing and mood-depressing effects of centrally acting cholinesterase inhibitors, compounds that inhibit the breakdown of acetylcholine. The mood altering effects of these compounds, used as insecticides in the agriculture industry and as nerve agents by the military, were described naturalistically and as tested in experimental settings. The observations by Grob et al. (2), Gershon et al. (3,4), Bowers et al. (5), and Rowntree et al. (6) led to a series of reports suggesting that increases in central acetylcholine led to depression, anxiety, and anergia. In the early 1970s, based on the above studies and on animal data reported by Domino and Olds (7), Stark and Boyd (8), and Carlton (9), Janowsky et al. (10) developed an adrenergic-cholinergic balance hypothesis of manic depression. This hypothesis proposed that depression represents an overabundance of central acetylcholine, relative to central adrenergic neurochemicals, and that mania represents the converse. Part of the work of Janowsky et al. (10,11) involved infusing the short acting reversible central cholinesterase inhibitor physostigmine on one occasion and the noncentrally acting cholinesterase inhibitor, neostigmine on another. Comparing behavioral effects, Janowsky and colleagues used this paradigm in manics, depressives, schizophrenics, and normals and observed decreased manic and increased depressive symptoms only in their physostigmine treated subjects (11,12). This work was replicated during the 1970s and early 1980s by a variety of investigators. In the late 1970s Sitaram et al. (13) observed that shortening of the cholinergic-sensitive sleep parameter, rapid eye movement (REM) latency, by cholinomimetic drugs was exaggerated in affective disorder patients, suggesting cholinergic supersensitivity in these patients, a finding subsequently replicated in a number of studies. In the late 1970s and early 1980s, Davis and Davis (14) and Risch et al. (15) began a series of experiments in which they evaluated the effect of cholinergic influences on stress-sensitive neurohormones including ACTH, beta-endorphin

BACKGROUND: Mental retardation is frequently associated with aggression toward self and others. Antipsychotic medications are frequently used as a major treatment of such aggression. However, national and state policies and guidelines are weighted toward stopping or decreasing the doses of these medications whenever possible, although exceptions are permitted. The purpose of this study was to determine if relapse during or after antipsychotic drug withdrawal in mentally retarded adults predicts continuing antipsychotic drug use an average of a decade later. METHOD: We report here on a 6- to 13-year (average 10-year) follow-up of 151 institutionalized mentally retarded adults. During the period 1990-1997, the subjects had been prescribed antipsychotic medications to treat maladaptive behaviors, primarily consisting of aggression, disruptive/destructive behaviors, or a combination of these. We compared subjects' psychotropic medication profiles in 2003 as they related to outcome during the earlier period. Our goal was to determine if rapid relapse (a clinically significant increase in maladaptive target symptoms, beginning 3 months or less after antipsychotic drug termination or dosage reduction, that was reversed by antipsychotic drug reinstitution or dosage increases) during or after routine withdrawal of an antipsychotic predicted psychotropic drug use in 2003. RESULTS: For those individuals successfully withdrawn from antipsychotic medications, 66.3% (55/83) were still psychotropic drug free in 2003. For those who rapidly relapsed during the period 1990-1997 following antipsychotic drug withdrawal or dosage decreases, only 9.0% (5/55) were psychotropic medication free in 2003. CONCLUSION: These observations support policies and guidelines indicating that attempts to stop treatment with antipsychotic medications in mentally retarded individuals are worthwhile. However, the results also indicate that eventual discontinuation of antipsychotic medications in institutionalized mentally retarded adults who have previously relapsed upon such withdrawal is unlikely to be successful. Rigid adherence to drug withdrawal policies and guidelines in such individuals should be reconsidered. Language: en

Studies in animals exploring the antagonism of the cholinesterase inhibitors soman and sarin have shown that pretreatment with low doses of the centrally acting cholinesterase inhibitor, physostigmine, alone or in conjunction with the centrally acting anticholinergic agent, scopolamine, is effective against their lethality and toxicity. The current study evaluated the effects of pretreatment with the oral anticholinesterase agent, donepezil (Aricept, 2.0 mg/kg), used to treat Alzheimer's disease, with and without scopolamine in decreasing the hypothermic, hypokinetic, and diarrhea-inducing effects of the irreversible long-acting cholinesterase inhibitor diisopropyl fluorophosphate (DFP, 1.0 mg/kg) in adult Flinders sensitive line (FSL) male rats. Donepezil alone and donepezil plus scopolamine (0.1 mg/kg) to a greater extent antagonized the decrease in temperature, hypoactivity, and induction of diarrhea due to DFP observed at 4 h after its administration. However, donepezil alone induced hypothermia at 1 and 2 h after treatment. Therefore, these preliminary findings are encouraging, but many additional studies are needed to establish the effectiveness of donepezil as a prophylactic agent against irreversible cholinesterase inhibition by DFP.

Background: The effectiveness of olanzapine in treating challenging behaviors in the intellectually disabled and its ability to substitute for conventional antipsychotic drugs were evaluated. Method: A total of 20 institutionalized adults with a mean age of 42.7 years (range, 18-55 years) with intellectual disability and aggression, self-injurious behavior, destructive/disruptive behavior, or combinations of these behaviors were studied. These individuals were receiving multiple psychotropic medications at baseline and were given additional treatment with the atypical antipsychotic agent olanzapine. The mean dose of olanzapine was 9.1 mg/day (range, 2.5-22.5 mg/day). Effectiveness was determined by retrospective review of the summaries of quarterly neuropsychiatric behavioral reviews and retrospective review of longitudinal behavioral graphs of target symptoms. Data were collected from 1995 to 2000. Results: A significant decrease in global challenging behaviors and specific target behaviors (i.e., aggression, self-injurious behaviors, destructive/ disruptive behaviors) occurred (p