Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics.

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 has 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.

Changes in Expression of DNA-Methyltransferase and Cannabinoid Receptor mRNAs in Blood Lymphocytes After Acute Cannabis Smoking.

Background: Cannabis use is a component risk factor for the manifestation of schizophrenia. The biological effects of cannabis include effects on epigenetic systems, immunological parameters, in addition to changes in cannabinoid receptors 1 and 2, that may be associated with this risk. However, there has been limited study of the effects of smoked cannabis on these biological effects in human peripheral blood cells. We analyzed the effects of two concentrations of tetrahydrocannabinol (THC) vs. placebo in lymphocytes of a subset of participants who enrolled in a double-blind study of the effects of cannabis on driving performance (outcome not the focus of this study). Methods: Twenty four participants who regularly use cannabis participated in an experiment in which they smoked cannabis cigarettes (5.9 or 13.4% THC) or placebo (0.02%) ad libitum. Blood samples were drawn at baseline and several times after smoking. Lymphocytes were separated and stored at -80°C for further analysis. Samples were analyzed for mRNA content for cannabinoid receptors 1 (CB1) and 2 (CB2), methylation and demethylating enzymes (DNMT, TET), glucocorticoid receptor (NRC3) and immunological markers (IL1B, TNFα) by qPCR using TaqMan probes. The results were correlated with THC whole blood levels during the course of the day, as well as THCCOOH baseline levels. Statistical analyses used analysis of variance and covariance and t-tests, or non-parametric equivalents for those values which were not normally distributed. Results: There were no differences in background baseline characteristics of the participants except that the higher concentration THC group was older than the low concentration and placebo groups, and the low concentration THC group had higher baseline CB2 mRNA levels. Both the 5.9 and 13.4% THC groups showed increased THC blood levels that then decreased toward baseline within the first hour. However, there were no significant differences between THC blood levels between the 5.9 and 13.4% groups at any time point. At the 4-h time point after drug administration the 13.4% THC group had higher CB2 (P = 0.021) and DNMT3A (P = 0.027) mRNA levels than the placebo group. DNMT1 mRNA levels showed a trend in the same direction (P = 0.056). The higher 13.4% THC group had significantly increased CB2 mRNA levels than the 5.9% concentration group at several post drug administration time points and showed trends for difference in effects for between 5.9 and 13.4% THC groups for other mRNAs. TET3 mRNA levels were higher in the 13.4% THC group at 55 min post-cannabis ingestion. When the high and lower concentration THC groups were combined, none of the differences in mRNA levels from placebo remained statistically significant. Changes in THC blood levels were not related to changes in mRNA levels. Conclusion: Over the time course of this study, CB2 mRNA increased in blood lymphocytes in the high concentration THC group but were not accompanied by changes in immunological markers. The changes in DNMT and TET mRNAs suggest potential epigenetic effects of THC in human lymphocytes. Increases in DNMT methylating enzymes have been linked to some of the pathophysiological processes in schizophrenia and, therefore, should be further explored in a larger sample population, as one of the potential mechanisms linking cannabis use as a trigger for schizophrenia in vulnerable individuals. Since the two THC groups did not differ in post-smoking blood THC concentrations, the relationship between lymphocytic changes and the THC content of the cigarettes remains to be determined.

Lithium-induced renal insufficiency: a longitudinal study of creatinine increases in intellectually disabled adults.

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.

Serendipity strikes again: scopolamine as an antidepressant agent in bipolar depressed patients.

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.

Lithium effect on renal glomerular function in individuals with intellectual disability.

OBJECTIVE: The current study evaluated the effects of chronic administration of lithium on renal functioning in an intellectually disabled population. METHODS: 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. RESULTS: 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. CONCLUSIONS: Chronic administration of lithium led to clinically significant increases in serum creatinine levels and decreases in creatinine clearance in lithium-treated intellectually disabled individuals.

Bipolar disorder- and major depression-relevant abstracts from the 2009 9th World Congress of Biological Psychiatry Meeting.

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.

Antipsychotic withdrawal-induced relapse predicts future relapses in institutionalized adults with severe intellectual disability.

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-relevant abstracts of posters from the 2008 CINP congress.

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.

Interpersonal Maneuvers of Manic Patients.

(Reprinted with the permission American Journal of Psychiatry 1974; 131: 250-255).

Relapse of aggressive and disruptive behavior in mentally retarded adults following antipsychotic drug withdrawal predicts psychotropic drug use a decade later.

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.

Anticholinesterase (DFP) toxicity antagonism by chronic donepezil: a potential nerve agent treatment.

Animal studies exploring the antagonism of irreversible cholinesterase inhibitors (i.e. nerve agents) such as soman and sarin have shown that pretreatment with the reversible centrally acting cholinesterase inhibitor, physostigmine, alone or in conjunction with the centrally acting anticholinergic drug, scopolamine, antagonizes the lethality and toxicity of these agents. This study evaluated the effects of pretreatment with the oral cholinesterase inhibitor and anti-Alzheimer's agent, donepezil (Aricept) on the hypokinetic, hypothermic and diarrhea-inducing effects of the irreversible long-acting cholinesterase inhibitor, diisopropylfluorophosphate (DFP) in adult Sprague-Dawley rats. Donepezil (2 mg/kg), given acutely (30 min pretreatment) or chronically (10 daily treatments), significantly antagonized the hypothermia, hypoactivity and diarrhea induced by DFP (1.25 mg/kg) administration. The effects were most prominent 4 and 6 h after the injection of DFP and some protection was observed even when the last treatment of the chronic donepezil protocol was given 24 h before the DFP injection. Although these phenomena are not the same as lethality, they may be parallel phenomena, and our results may have therapeutic implications for the treatment of nerve agent toxicity.

The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited.

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.

Basal and post-dexamethasone cortisol and prolactin concentrations in depressed and non-depressed patients with chronic pain syndromes.

To assess the behavior of two putative neuroendocrine markers of depression in chronic pain, the authors determined plasma cortisol and prolactin concentrations before and after dexamethasone in 52 hospitalized male chronic pain patients. Their psychiatric diagnoses by Research Diagnostic Criteria (RDC) were: major depression (N = 24; 44.2%), minor depression (N = 10; 19.2%), another RDC diagnosis (N = 7; 13.5%) and not mentally ill (N = 12; 21.6%). Failure to suppress cortisol after dexamethasone (a positive DST) occurred in 43.5% of those with major depression, 20% of those with minor depression, 42.8% of those with other psychiatric diagnoses and in 8.3% of patients without a psychiatric disorder. The frequency of non-suppression was significantly different only for patients with major depression compared to those without diagnosable psychiatric disorder. Mean basal cortisol concentrations at 08.00, 16.00 and 23.00 h did not differ among psychiatric diagnostic groups of pain patients, or between these groups and healthy volunteers. Levels of prolactin, but not cortisol, were significantly correlated with the severity of mood disturbances. These findings suggest strategies using multiple endocrine markers to distinguish pain from depression should be explored.

Olanzapine for self-injurious, aggressive, and disruptive behaviors in intellectually disabled adults: a retrospective, open-label, naturalistic trial.

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 <.05). A numerical decrease in the dosage of concurrent conventional antipsychotic medications occurred over the course of the first 6 months of olanzapine therapy, and a statistically significant (p <.005) decrease from the start of olanzapine therapy occurred in those subjects who received olanzapine for longer than 6 months (mean = 20.3 months). A significant increase in weight occurred in the subject group during the first 6 months of olanzapine treatment (p <.006), and sedation and constipation were the other common side effects noted. CONCLUSIONS: Olanzapine was found to be effective in the treatment of challenging behaviors in the intellectually disabled and in part could be substituted for administration of conventional antipsychotic drugs.

Relationship of Myers Briggs type indicator personality characteristics to suicidality in affective disorder patients.

The current study characterized the Myers Briggs Type Indicator (MBTI) personality profiles of 64 suicidal and 30 non-suicidal psychiatric inpatients with affective disorder diagnoses. The MBTI divides individuals categorically into eight personality preferences (Extroverted and Introverted, Sensing and Intuitive, Thinking and Feeling, and Judging and Perceiving). Compared to the group of non-suicidal affective disorder patients, suicidal affective disorder patients were significantly more Introverted and Perceiving using ANCOVA analyses, and significantly more Introverted alone using Chi Square analyses.

Preference for higher sucrose concentrations in cocaine abusing-dependent patients.

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 (0.83 M). 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.

Antagonism of anticholinesterase (DFP) toxicity by donepezil plus scopolamine: a preliminary study.

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.

Myers Briggs Type indicator personality profiles in unipolar depressed patients.

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 Judging 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.