Himanshu P. Upadhyaya

The Role of Cystine-Glutamate Exchange in Nicotine Dependence in Rats and Humans

BACKGROUND The present study determined if, akin to cocaine, nicotine self-administration in rats induces adaptations in the expression of glutamate transporters and cystine-glutamate exchangers in brain nuclei implicated in reinforcement and if treating cigarette smokers with a drug that restores cystine-glutamate exchange affects the number of cigarettes smoked. METHODS Rats self-administered nicotine intravenously for 12 hours/day or received nicotine through osmotic minipumps for 21 days. Somatic signs of withdrawal were measured and immunoblotting was performed 12 hours after the last nicotine exposure to determine if the catalytic subunit of the cystine-glutamate exchanger, xCT, or the glial glutamate transporter, GLT-1, were altered in the ventral tegmental area (VTA), nucleus accumbens, prefrontal cortex, or amygdala. For the smoking reduction study in humans, nicotine-dependent smokers were treated for 4 weeks with N-acetylcysteine (2400 mg daily) to promote cystine-glutamate exchange or placebo. Participants provided weekly ratings of withdrawal symptoms, craving, and carbon monoxide (CO) measurements and logged daily cigarette and alcohol use. RESULTS Rats receiving nicotine via self-administration or minipumps displayed somatic signs of withdrawal, but only nicotine self-administering rats showed decreased xCT expression in the nucleus accumbens and VTA and decreased GLT-1 expression in the nucleus accumbens. Human smokers treated with N-acetylcysteine reported a reduction in cigarettes smoked, and there was no effect of N-acetylcysteine on estimates of CO levels, craving, or withdrawal. CONCLUSIONS These results indicate that the cystine-glutamate exchanger and the glial glutamate transporter are downregulated after nicotine self-administration, and augmenting exchanger activity with N-acetylcysteine reduced the number of cigarettes smoked in nicotine-dependent individuals.

Cigarette Smoking and Psychiatric Comorbidity in Children and Adolescents

OBJECTIVE To review the current state of knowledge of psychiatric comorbidity in adolescent cigarette smokers. METHOD assisted literature search was conducted and seminal articles were cross-referenced for comprehensiveness of the search. For each disorder, a synopsis of knowledge in adults is provided and compared with the knowledge in adolescents. RESULTS Psychiatric comorbidity is common in adolescent cigarette smokers, especially disruptive behavior disorders (such as oppositional defiant disorder, conduct disorder, and attention-deficit/hyperactivity disorder), major depressive disorders, and drug and alcohol use disorders. Anxiety disorders are modestly associated with cigarette smoking. Both early onset (<13 years) cigarette smoking and conduct problems seem to be robust markers of increased psychopathology, including substance abuse, later in life. In spite of the high comorbidity, very few adolescents have nicotine dependence diagnosed or receive smoking cessation treatment in child and adolescent psychiatric treatment settings. CONCLUSIONS There is increasing evidence for high rates of psychiatric comorbidity in adolescent cigarette smokers. Cigarette smoking in adolescence appears to be a strong marker of future psychopathology. Child and adolescent psychiatry treatment programs may be a good setting for prevention efforts and treatment, which should focus on both nicotine dependence and psychiatric disorders.

Menstrual Cycle Phase Effects on Nicotine Withdrawal and Cigarette Craving: A Review

Evidence suggests that women are less likely to quit smoking than are men. This may reflect differences in nicotine dependence and, more specifically perhaps, nicotine withdrawal and craving. However, there is conflicting research on gender differences on the experience of withdrawal and craving. Menstrual cycle effects may moderate this relationship. Given hormonal changes during the menstrual cycle, abstinence-related symptoms such as withdrawal and craving may vary as a function of menstrual phase as well. This qualitative review summarizes the modest but expanding body of research in this area. One of the challenges inherent in interpreting this literature is the difficulty in distinguishing withdrawal symptomatology from premenstrual symptomatology. Methodological variation, including limited sample size and possible selection bias, in which several studies finding null effects excluded women with severe premenstrual dysphoric disorder, may explain some of the inconsistent findings across studies. Nonetheless, some of the 13 studies included in this review found heightened experiences of withdrawal or craving within the latter days of the menstrual cycle (i.e., the luteal phase). Further research is necessary to replicate these findings, but they may suggest the need for focused cessation treatment during the luteal phase or quit attempts that are well timed relative to specific menstrual phases.

Cigarette smoking associated with attention deficit hyperactivity disorder.

OBJECTIVE To evaluate the association between attention deficit hyperactivity disorder (ADHD) and severity of physical dependence on nicotine in a controlled study of adolescents and young adults with ADHD. STUDY DESIGN In controlled longitudinal family studies of ADHD, we examined self-reports on the modified Fagerström Tolerance Questionnaire (mFTQ) for degrees of physical dependence on nicotine. RESULTS We obtained mFTQ data from 80 ADHD probands and 86 control probands (mean age, 19.2 years). The smokers with ADHD had significantly higher scores on the mFTQ, indicative of more severe physical dependence on nicotine. Similarly, in current smokers, a positive linear relationship was found between mFTQ score and both inattentive and hyperactive ADHD symptoms. Environmental factors, such as current parental smoking, peer smoking, and living with a smoker, all increased the risk for smoking in those with ADHD compared with controls. CONCLUSION Male and female smokers with ADHD manifest more severe physical dependence on smoking compared with controls. Important environmental factors appear to add to the risk of smoking associated with ADHD.

Gender Differences in Craving and Cue Reactivity to Smoking and Negative Affect/Stress Cues

There is evidence that women may be less successful when attempting to quit smoking than men. One potential contributory cause of this gender difference is differential craving and stress reactivity to smoking- and negative affect/stress-related cues. The present human laboratory study investigated the effects of gender on reactivity to smoking and negative affect/stress cues by exposing nicotine dependent women (n = 37) and men (n = 53) smokers to two active cue types, each with an associated control cue: (1) in vivo smoking cues and in vivo neutral control cues, and (2) imagery-based negative affect/stress script and a neutral/relaxing control script. Both before and after each cue/script, participants provided subjective reports of smoking-related craving and affective reactions. Heart rate (HR) and skin conductance (SC) responses were also measured. Results indicated that participants reported greater craving and SC in response to smoking versus neutral cues and greater subjective stress in response to the negative affect/stress versus neutral/relaxing script. With respect to gender differences, women evidenced greater craving, stress and arousal ratings and lower valence ratings (greater negative emotion) in response to the negative affect/stressful script. While there were no gender differences in responses to smoking cues, women trended towards higher arousal ratings. Implications of the findings for treatment and tobacco-related morbidity and mortality are discussed.

PTSD and the HPA axis: differences in response to the cold pressor task among individuals with child vs. adult trauma.

Hypothalamic pituitary adrenal (HPA) axis and subjective stress response to a cold-water immersion task, the cold pressor task (CPT), in individuals (N=89) with post-traumatic stress disorder (PTSD) were examined. All tests were conducted at 08:00h after an overnight hospital stay. Plasma adrenocorticotrophin hormone (ACTH), cortisol, and subjective stress were examined at baseline and five post-task time points in controls (n=31), subjects with PTSD as a result of an index trauma during childhood (i.e. before age 18; n=25), and subjects with PTSD as a result of an index trauma as an adult (n=33). Approximately, 50% of individuals in both trauma groups were alcohol dependent, and the impact of this comorbidity was also examined. Subjects with PTSD, regardless of age of index trauma, had a less robust ACTH response as compared to controls. Regardless of the presence or absence of comorbid alcohol dependence, subjects with childhood trauma had lower cortisol at baseline and at all post-task measurement points and did not demonstrate the decrease in cortisol over the course of the 2h monitoring period seen in subjects with adult index trauma and controls. The findings reveal differences in the neuroendocrine response to the CPT in individuals with PTSD compared to control subjects, and differences in PTSD subjects when examined by age of index trauma.

Menstrual Phase Effects on Smoking Cessation: A Pilot Feasibility Study

BACKGROUND AND OBJECTIVES A growing body of research suggests that nicotine withdrawal and cigarette craving may vary across the menstrual cycle and that the luteal phase of the cycle may be associated with increases in each. This potential relationship suggests that careful timing of quit attempts during the menstrual cycle may improve initial success at abstinence, although there are no direct tests of this approach yet published. Our objectives were to preliminarily test the effect of timing of quit attempts for smoking cessation relative to menstrual cycle and to identify methodological procedures that could guide subsequent, larger clinical trials. METHODS In this pilot study, we randomized female smokers aged 18-40 who were not currently using hormonal contraception to quit smoking during either the follicular (n = 25) or luteal phase (n = 19) of their menstrual cycle. Participants were provided with two sessions of smoking cessation counseling (90 minutes total). All participants were provided with a transdermal nicotine patch contingent on maintenance of abstinence throughout the course of the 6-week study. RESULTS Among participants who initiated treatment, received the patch, and made a quit attempt (n = 35), carbon monoxide-verified repeated point prevalence abstinence 2 weeks after the target quit date was higher in the follicular than the luteal group (32% vs. 19%, respectively; OR = 2.0, 95% CI = 0.4-9.8). Within the overall study population, this difference was slightly lower (24% vs. 16%; OR = 1.7, 95% CI = 0.4-7.8). CONCLUSIONS Timing quit attempts based on menstrual phase is feasible. Insights gained from this study and the recommendations made herein may inform future research on this important clinical question.

Bupropion SR and contingency management for adolescent smoking cessation

There is a significant need for evidence-based treatments for adolescent smoking cessation. Prior research, although limited, has suggested potential roles for bupropion sustained-release (SR) and contingency management (CM), but no previous studies have assessed their combined effect. In a double-blind, placebo-controlled design, 134 adolescent smokers were randomized to receive a 6-week course of bupropion SR + CM, bupropion SR + non-CM, placebo + CM, or placebo + non-CM, with final follow-up at 12 weeks. The primary outcome was 7-day cotinine-verified point prevalence abstinence, allowing for a 2-week grace period. Combined bupropion SR + CM treatment yielded significantly superior abstinence rates during active treatment when compared with placebo + non-CM treatment. In addition, combined treatment showed greater efficacy at multiple time points than did either bupropion SR + non-CM or placebo + CM treatment. Combined bupropion SR and CM appears efficacious, at least in the short-term, for adolescent smoking cessation and may be superior to either intervention alone.

Cue reactivity in young marijuana smokers: A preliminary investigation.

To develop and evaluate the feasibility of a cue reactivity paradigm for young marijuana smokers, the authors set up a laboratory procedure involving neutral and marijuana-related imagery, video, and in vivo cues. Fifteen adolescents and young adults with cannabis use disorders completed the procedure, which included continuous measurement of skin conductance and heart rate. Participants also completed questionnaires regarding marijuana craving before, during, and after cue presentations. Higher levels of craving and skin conductance were observed during marijuana cue presentations. The procedure appears to elicit cue reactivity among adolescents and young adults with cannabis use disorders and should be further evaluated and refined with a larger sample. Implications for future studies are discussed.

Underdiagnosis of Attention-Deficit/Hyperactivity Disorder in Adult Patients: A Review of the Literature

Objective: To raise awareness of attention-deficit/hyperactivity disorder (ADHD) as an underdiagnosed, undertreated, often comorbid, and debilitating condition in adults. Data Sources: PubMed was searched using combinations of keywords, including ADHD, adult, diagnosis, identify, prevalence, and comorbid, to find articles published between 1976 and 2013. Study Selection: In total, 99 articles were selected for inclusion on the basis of their relevance to the objective and importance to and representation of ADHD research, including international guidelines for adults with ADHD. Results: In a large proportion of children with ADHD, symptoms persist into adulthood. However, although adults with ADHD often experience chaotic lifestyles, with impaired educational and vocational achievement and higher risks of substance abuse and imprisonment, many remain undiagnosed and/or untreated. ADHD is usually accompanied by other psychiatric comorbidities (such as major depressive disorder, anxiety disorder, and alcohol abuse). Indeed, adults with ADHD are more likely to present to a psychiatric clinic for treatment of their comorbid disorders than for ADHD, and their ADHD symptoms are often mistaken for those of their comorbidities. Untreated ADHD in adults with psychiatric comorbidities leads to poor clinical and functional outcomes for the patient even if comorbidities are treated. Effective treatment of adults’ ADHD improves symptoms, emotional lability, and patient functioning, often leading to favorable outcomes (eg, safer driving, reduced criminality). A few medications have now been approved for use in adults with ADHD, while a multimodal approach involving psychotherapy has also shown promising results. Conclusions General psychiatrists should familiarize themselves with the symptoms of ADHD in adults in order to diagnose and manage ADHD and comorbidities appropriately in these patients.