Escalating doses of transdermal nicotine in heavy smokers: effects on smoking behavior and craving.

Fixed-dose nicotine replacement therapy (NRT) is efficacious for smoking cessation in the general population of smokers. However, it is less effective in populations with psychiatric comorbidities and/or severe tobacco dependence where the percent nicotine replacement is suboptimal. The objective of this pilot study was to determine the effectiveness of nicotine patch dose titration in response to continued smoking in heavily dependent smokers with psychiatric comorbidity. In a single-arm, open-label study adult smokers (mean cigarettes per day, 25.4 ± 13.4; range, 14-43; n = 12) willing to quit were treated with escalating doses of transdermal nicotine and brief counseling intervention if they continued to smoke over a 9-week treatment period. Plasma nicotine and cotinine, along with expired carbon monoxide levels, and the subjective effects of smoking, urge to smoke, demand elasticity, and mood symptoms were also assessed. The mean NRT dose was 32.7 (SD, 16.4) mg/d (range, 7-56 mg/d). Smokers reported significant reductions in both cigarettes per day (mean decrease, 18.4 ± 11.5) confirmed by expired carbon monoxide (mean decrease, 13.5 ± 13.0) with no significant changes in plasma nicotine concentrations during the course of NRT dose titration. There were significant effects on the subjective effects of smoking and measures of smoking behavior. Most commonly reported adverse events were respiratory infections, skin irritation at patch site, nausea, and sleep disturbances, which were generally mild and transient. Titrating doses of NRT to effect with brief intervention hold promise as an effective clinical strategy to assist heavily dependent psychiatrically ill smokers to change their smoking behavior.

Varenicline and cytisine: two nicotinic acetylcholine receptor ligands reduce ethanol intake in University of Chile bibulous rats.

RATIONALE: Neuronal nicotinic acetylcholine receptors (nAChRs) are pharmacological targets that have recently been implicated in the reinforcing effects of many drugs of abuse, including ethanol. Varenicline and cytisine are nAChR partial agonists in clinical use as smoking cessation aids. However, their efficacies to reduce alcohol consumption have not been fully studied. OBJECTIVES: This study aims to compare the effects of varenicline and cytisine on ethanol consumption by rats bred for many generations as high ethanol drinkers (UChB). RESULTS: Repeated dosing (0.5 or 1.0 mg/kg/day i.p.) of varenicline or cytisine, for three consecutive days, to male UChB rats pre-exposed to 10 % (v/v) ethanol and water 24 h/day for 4 weeks, significantly reduced alcohol intake and preference of ethanol over water during 1- and 24-h ethanol access periods. This effect was specific for ethanol intake and was not observed for 0.2 % saccharin or water consumption. Varenicline appears to be more effective than cytisine, probably due to its more favorable pharmacokinetic and pharmacodynamic properties. Long-term use of both nAChRs ligands for more than 8-10 days induced tolerance to their effects on ethanol consumption. CONCLUSIONS: This preclinical study in UChB rats demonstrated that both varenicline and cytisine reduce alcohol intake, with varenicline producing a greater and longer-lasting reduction than cytisine. However, dose adjustment will have to be considered as a possible way to counter tolerance arising after continued use.

Effects of stress and alcohol cues in men with and without problem gambling and alcohol use disorder.

BACKGROUND: Relapse is a serious challenge in problem gambling (PG), as it is in substance addiction. Stress and cues are implicated in relapse in both conditions. However, experimental research on motivational effects of stress in PG subjects is scant. This study examined subjective-motivational, cognitive and physiological effects of stress and alcohol cues in subjects with PG, alcohol use disorder (AD), co-occurring PG and AD (CO), and healthy controls (HC). METHODS: Fifty-two (12/clinical group; 16 HC) physically healthy men received stress in the form of 10-min uncontrollable noise (U-Noise vs. controllable noise; C-Noise) and cues (355 ml non-alcoholic 'placebo' beer; P-Beer vs. soft drink) under Separate or Combined conditions on two test sessions. Visual analogue scales assessed subjective effects. Emotional Stroop and Go/No-Go 'Shift' tasks assessed inhibitory control. Systolic blood pressure (SBP) indexed physiological reactivity. RESULTS: U-Noise and C-Noise increased desire for alcohol in all groups. U-Noise selectively inhibited desire to gamble in PG subjects. Both U-Noise and C-Noise inhibited desire to gamble in CO subjects. Neither manipulation reliably altered cognitive performance. Compared to Neutral words, Alcohol words impaired Stroop color-naming in all groups except PG, which displayed relatively faster color-naming of Alcohol words (facilitation). U-Noise increased SBP relative to C-Noise in AD and HC groups. U-Noise plus P-Beer and U-Noise per se decreased SBP in PG and CO groups, respectively. CONCLUSIONS: Noise stress has opposite motivational and physiological effects in men with problem gambling vs. alcohol use disorder. A homeostatic process may explain the impact of stress in problem gamblers.

Stress and alcohol cues exert conjoint effects on go and stop signal responding in male problem drinkers.

Stress, cues, and pharmacological priming are linked with relapse to addictive behavior. Increased salience and decreased inhibitory control are thought to mediate the effects of relapse-related stimuli. However, the functional relationship between these two processes is unclear. To address this issue, a modified Stop Signal Task was employed, which used Alcohol, Neutral, and Non-Words as Go stimuli, and lexical decision as the Go response. Subjects were 38 male problem drinkers (mean Alcohol Dependence Scale (ADS) score: 18.0). Uncontrollable noise (∼ 10 min at 110 dB) was the stressor; nonalcoholic placebo beer (P-Beer) was the cue manipulation, and alcohol (0.7 g/kg), the pharmacological prime. Half the sample received alcohol, and half P-Beer. Stress and beverage (test drink vs soft drink) were manipulated within subjects on two sessions, with half the sample receiving active manipulations together and half receiving them separately. Go response time (RT) and Stop Signal RT (SSRT) were slower to Alcohol than Neutral words. Stress augmented this bias. Alcohol and P-Beer impaired overall SSRT. Stress impaired neither overall SSRT nor Go RT. SSRT to Neutral words and Non-Words correlated inversely with Go RT to Alcohol and Neutral words, and Non-Words. ADS correlated directly with SSRT to Alcohol words. A resource allocation account was proposed, whereby diversion of limited resources to salient cues effectively yoked otherwise independent Go and Stop processes. Disturbances of prefrontal norepinephrine and dopamine were cited as possibly accounting for these effects. Treatments that optimize prefrontal catecholamine transmission may deter relapse by reducing disinhibitory effects of salient eliciting stimuli.

Cocaine and amphetamine regulated transcript (CART) gene in the comorbidity of schizophrenia with alcohol use disorders and nicotine dependence.

Studies have shown a genetic susceptibility to develop schizophrenia, alcohol use disorders and nicotine dependence. Brain areas related to reward and reinforcement show high expression of the cocaine and amphetamine regulated transcript (CART). Nicotine and alcohol are also able to modulate CART expression in the hypothalamic areas. In this study, we evaluated whether CART variants would influence the predisposition of schizophrenia subjects to alcohol use disorders and nicotine dependence. Clinical and genetic data were obtained from 190 unrelated Caucasian schizophrenia subjects collected at the Centre for Addiction and Mental Health. We found no association of CART variants with alcohol use disorders or nicotine dependence. We found a trend for allelic association of rs11575893 with the heaviness of smoking behaviour (p=0.057). Our results indicate that genetic variants in the CART gene may not play a major role in the vulnerability of schizophrenia subjects to concurrent alcohol use disorders and nicotine dependence. Additional association studies in independent samples can evaluate whether CART gene is playing a role in the schizophrenia comorbidity with alcohol use disorders and nicotine dependence.

Comorbidity between bipolar disorder and alcohol use disorder: association of dopamine and serotonin gene polymorphisms.

Bipolar disorder is a chronic mental illness with high prevalence of co-occurring alcohol use disorder. Linkage studies have revealed several candidate genes in the dopaminergic and serotonergic pathways which may be associated with both bipolar and alcohol use disorders. We investigated the relationship between polymorphisms in candidate genes and alcohol use disorder comorbidity in bipolar patients. We performed a retrospective study of a genomic database consisting of 278 bipolar disorder patients. Diagnosis of bipolar disorder was according to the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). RFLP analysis of single nucleotide polymorphisms were performed in dopamine (DRD1, DRD2 and DRD3) and serotonin receptor and transporter genes (5HTTLPR, 5HT1B, 5HT2A, 5HT2C). There were 179 (64%) females in the database. Seventy-one (25.5%) of the bipolar patients were diagnosed as comorbid alcohol use disorder. Chi-square analysis indicated that in female bipolar patients, there was a significant difference in genotype frequency between the bipolar patients with comorbid alcohol use disorder and non-comorbid bipolar patients for the Ser23Cys (rs6318) polymorphism of the 5HT2C gene. Overall, the results indicate a possible association between 5HT2C and alcohol use disorder comorbidity.

Dopaminergic activity in depressed smokers: a positron emission tomography study.

Tobacco dependence is highly prevalent in depressed patients. We assessed changes in [(11)C]-raclopride binding potential (BP) using positron emission tomography (PET) before and after the oral administration of d-amphetamine in healthy controls and unmedicated patients with current depression with and without current tobacco dependence. Over a single study day 2 [(11)C]-raclopride positron emission tomography scans were taken in 38 subjects: at baseline and 2 h following oral d-amphetamine 30 mg. Twenty controls (9 smokers, 11 nonsmokers) and 18 subjects with current major depressive episode (8 smokers, 10 non-smokers). Striatal [(11)C]-raclopride binding potential was measured before and after d-amphetamine administration. Depressed smokers had a lower baseline [(11)C]-raclopride binding potential compared with both control non-smokers (P < 0.007) and depressed non-smokers (P < 0.001). There was a main effect of smoking status on amphetamine-induced change in [(11)C]-raclopride binding potential (P < 0.02), but no main effect of depression. This may be due to a floor effect because of the low BP at baseline. Depressed subjects reported significant increase of positive mood after d-amphetamine administration compared with controls (depressed smokers vs. control smokers: P < 0.05; depressed non-smokers vs. controls: P < 0.055). Tobacco dependence appears to decrease d-amphetamine-induced changes in [(11)C]-raclopride binding potential as measured by positron emission tomography. Comorbid major depression and tobacco dependence exacerbates this effect, suggesting an altered dopamine system in comorbid patients.

Apathy associated with Alzheimer disease: use of dextroamphetamine challenge.

OBJECTIVE: To assess the role of the dopaminergic brain reward system (BRS) in apathy associated with Alzheimer disease (AD). DESIGN: BRS function was probed in 20 AD patients using dextroamphetamine (d-amph) challenge. After baseline behavioral testing, patients were given a single 10 mg dose of d-amph. The time course of the subjective response to d-amph was assessed at hourly intervals for 4 hours. SETTING: Three outpatient dementia clinics associated with a university-affiliated hospital. PARTICIPANTS: Twenty AD patients aged 77 +/- 8 years with Neuropsychiatric Inventory (NPI) apathy scores of 3.4 +/- 3.5 and Mini-Mental State Examination scores of 20.4 +/- 5.1. MEASUREMENTS: Patients were classified as apathetic based on an NPI apathy subscore of > or =4. Apathy severity was assessed using the Apathy Evaluation Scale (AES). The subjective and behavioral responses to d-amph were assessed using computerized versions of the Addiction Research Centre Inventory (ARCI), Profile of Mood States and Connor's Continuous Performance Task. RESULTS: Repeated measures ANOVA revealed a significant interaction between the presence of apathy and the peak subjective response to d-amph on the ARCI, such that while nonapathetic AD patients were responsive to the rewarding effects of d-amph, apathetic patients were not (F(1,17) = 4.93, p = 0.04). Continuous AES scores were predicted by peak ARCI positive effects scores and baseline overall behavioral disturbances (NPI total) in a backward linear regression analysis using the entire study sample (F(2,17) = 10.00, p = 0.01, R(2) = 0.49). CONCLUSIONS: Apathy in AD is associated with a blunted subjective response to d-amph, which may be indicative of dysfunction in the BRS.

Methylphenidate for the treatment of apathy in Alzheimer disease: prediction of response using dextroamphetamine challenge.

Apathy is a common behavioral symptom of Alzheimer's disease (AD), being present in up to 70% of patients. Apathy in AD and non-AD populations has been associated with dysfunction in the dopaminergic brain reward system, suggesting that pharmacotherapeutic targeting of this system may be an effective treatment for apathy in AD. We therefore performed a randomized, double-blind, placebo-controlled crossover trial of methylphenidate in a sample of 13 apathetic AD patients (6 men, 7 women; age mean 77.9 years [SD, 7.8 years]; Mini Mental Status Examination score, 19.9 [SD, 4.7]). Patients were treated with methylphenidate (10 mg PO twice a day) or an identical placebo in two 2-week phases separated by a 1-week placebo washout. All patients participated in a dextroamphetamine challenge test (one 10-mg oral dose) before treatment with methylphenidate to gauge the functional integrity of the dopamine brain reward system. Overall, patients demonstrated greater improvement with methylphenidate compared with placebo according to Apathy Evaluation Scale total change scores (end of treatment - baseline: Wilcoxon Z = -2.00; P = 0.047). However, a significantly greater proportion of patients experienced at least 1 adverse event with methylphenidate compared with placebo (3 vs 1; chi = 4.33, P = 0.038). Two patients experienced serious adverse events with methylphenidate, consisting of delusions, agitation, anger, irritability, and insomnia, which resolved upon discontinuation of the medication. Response to methylphenidate was associated with increases in inattention on a continuous performance task after dextroamphetamine challenge. Psychostimulants may be effective in treating features of apathy in AD, and dopaminergic changes may predict response.

Effects of 2-week treatment with temazepam and diphenhydramine in elderly insomniacs: a randomized, placebo-controlled trial.

A randomized, controlled, crossover clinical study compared 14-night treatment with 15 mg temazepam, 50 mg diphenhydramine, and placebo in elderly individuals with insomnia (mean age, 73.9 years; range, 70-89 years). Primary outcome measures were subjective assessments of sleep recorded on sleep diaries. Secondary measures were the morning-after psychomotor impairment, using the digit symbol substitution task and the manual tracking task, and the morning-after memory impairment, using a free-recall procedure. Results showed sleep improvements with 15 mg temazepam compared with placebo-sleep quality (mean score, 3.3 +/- 0.9 vs 2.9 +/- 0.8; P = 0.03), total sleep time (6.9 +/- 1.0 hours vs 6.3 +/-1.3 hours; P = 0.02), number of awakenings (1.5 +/- 1.3 vs 2.0 +/- 1.2; P < 0.001), and sleep-onset latency (25 +/- 22 minutes vs 37 +/- 25 minutes; P = 0.03). Improvements were seen with diphenhydramine treatment compared with placebo on the number of awakenings only (mean, 1.7 +/- 1.1 vs 2.0 +/- 1.2; P < 0.05). Numbers of adverse events reported were similar after all treatments, although there was 1 fall during temazepam treatment. Findings indicate that temazepam is more effective than diphenhydramine when compared with placebo at the doses tested, although this advantage is mitigated by the risk of falls associated with temazepam use. The choice of agent to use in the elderly must consider these relative benefits and risks.

Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe.

CONTEXT: The pathophysiology of major depressive disorder (MDD) includes disturbances in several neuroanatomical substrates and neurotransmitter systems. The challenge is to elucidate the brain mechanisms of MDD behavioral symptoms, chiefly those of anhedonia. OBJECTIVES: To visualize the neuroanatomical substrates implicated in altered reward processing in MDD, using functional magnetic resonance imaging in combination with a dopaminergic probe (a 30-mg dose of oral dextroamphetamine sulfate) to stimulate the brain reward system; and to test the hypothesis that a hypersensitive response to dextroamphetamine in MDD involves the prefrontal cortex and the striatum. DESIGN AND INTERVENTIONS: Among subjects with MDD and healthy control subjects, functional magnetic resonance imaging data were collected before and after single-blind administration of dextroamphetamine. SETTING: Subjects were recruited through local newspaper advertisements and by word of mouth. PARTICIPANTS: Twelve depressed subjects (mean age, 34.83 years; male-female ratio, 6:6) met criteria for MDD according to the DSM-IV, were not taking antidepressants, and had no comorbid Axis I disorders. Twelve control subjects (mean age, 29.33 years; male-female ratio, 5:7) were healthy volunteers without a history of Axis I disorders. MAIN OUTCOME MEASURES: Functional magnetic resonance imaging blood oxygen level-dependent activation was measured during a controlled task, and dextroamphetamine-induced subjective effects were assessed using the Addiction Research Center Inventory. RESULTS: Subjects with MDD had a hypersensitive response to the rewarding effects of dextroamphetamine (2-fold increase; t(21) = 2.74, P = .01), with altered brain activation in the ventrolateral prefrontal cortex and the orbitofrontal cortex and the caudate and putamen (F(1,44) = 11.93, P = .001). CONCLUSION: Dopamine-related neuroanatomical substrates are involved in altered reward processing in MDD, shedding light on the neurobiology of the anhedonic symptoms in MDD and suggesting these substrates as future therapeutic targets.

Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits.

OBJECTIVES: To quantify and compare potential benefits (subjective reports of sleep variables) and risks (adverse events and morning-after psychomotor impairment) of short term treatment with sedative hypnotics in older people with insomnia. DATA SOURCES: Medline, Embase, the Cochrane clinical trials database, PubMed, and PsychLit, 1966 to 2003; bibliographies of published reviews and meta-analyses; manufacturers of newer sedative hypnotics (zaleplon, zolpidem, zopiclone) regarding unpublished studies. SELECTION CRITERIA: Randomised controlled trials of any pharmacological treatment for insomnia for at least five consecutive nights in people aged 60 or over with insomnia and otherwise free of psychiatric or psychological disorders. RESULTS: 24 studies (involving 2417 participants) with extractable data met inclusion and exclusion criteria. Sleep quality improved (effect size 0.14, P < 0.05), total sleep time increased (mean 25.2 minutes, P < 0.001), and the number of night time awakenings decreased (0.63, P < 0.001) with sedative use compared with placebo. Adverse events were more common with sedatives than with placebo: adverse cognitive events were 4.78 times more common (95% confidence interval 1.47 to 15.47, P < 0.01); adverse psychomotor events were 2.61 times more common (1.12 to 6.09, P > 0.05), and reports of daytime fatigue were 3.82 times more common (1.88 to 7.80, P < 0.001) in people using any sedative compared with placebo. CONCLUSIONS: Improvements in sleep with sedative use are statistically significant, but the magnitude of effect is small. The increased risk of adverse events is statistically significant and potentially clinically relevant in older people at risk of falls and cognitive impairment. In people over 60, the benefits of these drugs may not justify the increased risk, particularly if the patient has additional risk factors for cognitive or psychomotor adverse events.

Oral D-amphetamine causes prolonged displacement of [11C]raclopride as measured by PET.

Parenterally administered D-amphetamine has been used as a challenge drug to release dopamine, which in turns inhibits [11C]raclopride binding to dopaminergic D2 receptors as measured using positron emission tomography (PET) techniques. The primary objective of this study was to determine whether orally administered D-amphetamine would inhibit [11C]raclopride binding in a manner similar to that produced by intravenously administered D-amphetamine. The secondary objective was to assess the timeline of these effects. Twelve healthy human volunteers participated in this study. Subjects were scanned at baseline and 2 h after D-amphetamine administration (n = 5); at baseline, 2 and 6 h postdrug (n = 4); or at baseline, 2 and 24 h postdrug (n = 3). Orally administered D-amphetamine caused a significant decrease in [11C]raclopride binding at 2 h (13% +/- 5%). Receptor availability was still decreased at 6 h (18% +/- 6%), even though physiological effects had completely returned to baseline. [11C]Raclopride binding returned to baseline at 24 h. The percentage of [11C]raclopride displacement was not correlated with plasma D-amphetamine concentrations. In conclusion, orally administered D-amphetamine caused a reliable and prolonged [11C]raclopride displacement, the magnitude of which is similar to that observed after intravenous administration. Possible mechanisms for the observed prolonged displacement may include persistence of intrasynaptic dopamine and/or receptor internalization.

Acute pharmacological effects of temazepam, diphenhydramine, and valerian in healthy elderly subjects.

Elderly insomniacs are often treated pharmacologically with benzodiazepines, antihistamines, or natural products. A double-blind, randomized, crossover, placebo-controlled study was performed to assess the comparative pharmacodynamics of single doses of temazepam (15 and 30 mg), diphenhydramine (50 and 75 mg), and valerian (400 and 800 mg) in 14 healthy elderly volunteers (mean age, 71.6 years; range, 65-89). Assessments were made at 0, 0.5, 1, 2, 3, 4, 6, and 8 hours postdosing with use of validated measures of subjective sedation and mood (visual analogue scales, Tufts University Benzodiazepine scale) and psychomotor performance (manual tracking and digit symbol substitution tests). Temazepam had dose-dependent effects on sedation and psychomotor ability with a distinct time course. Temazepam 30 mg had the most detrimental effect on psychomotor ability (p < 0.001 compared with all other treatments). Temazepam 30 mg and both doses of diphenhydramine elicited significantly greater sedation than placebo (p < 0.05, all), and temazepam had the greatest effect. There was no difference in sedation scores between 50 and 75 mg diphenhydramine. Sedative effects were slightly lesser with 15 mg temazepam and were not significant in comparison with placebo. Psychomotor impairment was evident after administration of 75 mg diphenhydramine in comparison with placebo on the manual tracking test (p < 0.05); this was less than the impairment with 30 mg temazepam (p < 0.001) but similar to that with 15 mg temazepam (NS). No psychomotor impairment was detected with 50 mg diphenhydramine. Valerian was not different from placebo on any measure of psychomotor performance or sedation.

Comparative abuse liability and pharmacological effects of meprobamate, triazolam, and butabarbital.

Implementation of regulations to control the prescribing of benzodiazepines in New York State in 1989 resulted in a 55% decrease in benzodiazepine prescribing, with a concomitant increase in the rates of prescribing older sedative-hypnotic compounds such as butabarbital (30% increase) and meprobamate (125% increase). In a double-blind, crossover, placebo-controlled study, we compared the behavioral and pharmacological effects of triazolam, meprobamate, and butabarbital in 14 recreational drug users. Placebo and three doses each of triazolam, meprobamate, and butabarbital were administered to each subject in a random order. Objective tests (motor performance, concentration) and subjective response questionnaires measured drug effects. Triazolam, meprobamate, and butabarbital showed comparable negative dose-response slopes on the objective measures. On the basis of these objective data, equivalent doses for the three compounds were determined to be as follows: 0.5 mg triazolam = 2,400 mg meprobamate = 400 mg butabarbital. Subjective effects data on equivalent doses show that butabarbital produced the highest peak score on Cole/ARCI Abuse Potential, ARCI Pentobarbital Chlorpromazine Alcohol Group (PCAG), and "drug strength" scales. Triazolam and butabarbital produced equivalent results on ARCI Morphine Benzedrine Group (MBG), Cole/ARCI Euphoria, and "drug liking" scales. Meprobamate was indistinguishable from placebo on euphoria and abuse potential scales. Behavioral economics analysis indicated a price crossover point two times higher for butabarbital (400 mg) than for any other drug condition. These data indicate a comparative abuse liability of butabarbital > triazolam > or = meprobamate, suggesting that the prescribing restrictions on benzodiazepines had little net benefit on abuse risk in the population and may have increased the risk of overdose morbidity and mortality.

Brain reward system activity in major depression and comorbid nicotine dependence.

Major depressive disorder (MDD) and nicotine dependence are highly comorbid. MDD patients may use nicotine to ameliorate depressive symptoms. The pathophysiology of the comorbidity of these two disorders is unknown. We hypothesized that a dysfunctional dopaminergic brain reward system (BRS) might be a neurobiological link between MDD and nicotine dependence and that smoking modulates the activity of the BRS by enhancing dopaminergic activity and relieving some depressive symptoms. Eighteen nicotine-dependent, nonmedicated subjects with Diagnostic and Statistical Manual of Mental Disorders (4th edition) diagnosis of MDD and 16 nicotine-dependent, control subjects participated in a double-blind, placebo-controlled, randomized parallel study. A single 30-mg oral dose of d-amphetamine (d-amph) was used to release dopamine and probe the activity of the BRS. The d-amph-mediated physiological and rewarding effects were assessed at baseline and post-treatment using standardized and validated questionnaires. Our results show that d-amph significantly increased blood pressure (p < 0.001). Subjective rewarding d-amph effects increased in both groups. Negative subjective effects were reported while on placebo during nonsmoking sessions. A significant correlation between depression severity (Hamilton depression scale) and d-amph rewarding effects was found in MDD smoker subjects (Addiction Research Center Inventory composite: r = 0.89, p < 0.000; profile of mood states composite: r = 0.71, p < 0.003; and visual analog scales composite: r = 0.78, p < 0.005). These data show that smoking did not modify the response to d-amph in MDD or control subjects, but decreased overall negative mood state during placebo sessions. Severity of depression was significantly correlated with increased rewarding effects of d-amph. Thus, although the BRS may be dysfunctional in MDD subjects, chronic nicotine use does not modify response to d-amph.

Probing brain reward system function in major depressive disorder: altered response to dextroamphetamine.

BACKGROUND: The state of the brain reward system in major depressive disorder was assessed with dextroamphetamine, which probes the release of dopamine within the mesocorticolimbic system, a major component of the brain reward system, and produces measurable behavioral changes, including rewarding effects (eg, euphoria). We hypothesized that depressed individuals would exhibit an altered response to dextroamphetamine due to an underlying brain reward system dysfunction reflected by anhedonic symptoms. METHODS: In a double-blind, placebo-controlled, randomized, parallel study, the behavioral and physiological effects of a single 30-mg dose of oral dextroamphetamine sulfate were measured. Forty patients with a diagnosis of DSM-IV major depressive disorder who were not taking antidepressant medications (22 assigned to dextroamphetamine and 18 to placebo) were compared with 36 control subjects (18 assigned to dextroamphetamine and 18 to placebo) using validated self-report drug effect measurement tools (eg, the Addiction Research Center Inventory), heart rate, and blood pressure. RESULTS: Multiple regression analysis showed that severity of depression as measured by the Hamilton Rating Scale for Depression correlated highly with the rewarding effects of dextroamphetamine in the depressed group (model R(2) = 0.63; interaction P =.04). A subsequent analysis categorizing the depressed group into patients with severe symptoms (Hamilton score >23) and those with moderate symptoms revealed a significant interaction between drug and depression (P =.02). Patients with severe symptoms reported rewarding effects 3.4-fold greater than controls. CONCLUSIONS: The results suggest the presence of a hypersensitive response is present in the brain reward system of depressed patients, which may reflect a hypofunctional state and may provide a novel pathophysiologic and therapeutic target for future studies.

Nicotine patches and the subjective effects of cigarette smoking: a pilot study.

Twenty-five per cent of the North American population smoke cigarettes regularly. Twelve smokers (aged 19 to 55 years, Fagerström test score 3 to 10) participated in a double-blind, placebo controlled, counterbalanced study to determine the extent to which subjective effects of smoking are altered by nicotine delivered by transdermal patches. Subjects wore a placebo or 21 mg nicotine patch while abstaining from smoking for 48 h. Nicotine-mediated objective and subjective effects were measured at baseline, and after smoking a regular and a low yield cigarette at four different study sessions. Subjective effects were assessed using validated computerized questionnaires such as the Profile of Mood States and Visual Analogue Scales. Nonsmoking compliance was determined by measuring expired air carbon monoxide and saliva cotinine concentrations. Significant within-session differences were found in subjective effects at baseline and after smoking. No differences in subjective effects were found between patch treatments before smoking. Nicotine withdrawal symptoms such as craving, irritability, tension, frustration, anxiety and restlessness were significantly increased in both patch conditions after 48 h of smoking abstinence. Smoking markedly ameliorated nicotine withdrawal symptoms. Systolic blood pressure increased after smoking in both patch conditions (P=0.01). Visual Analogue Scale scores for cravings, nicotine effects, good effects and 'high' consistently increased after smoking during either patch condition. Thus, wearing a nicotine patch did not seem to modify the subjective effects of smoking compared with placebo in this preliminary study.