Friday, December 8, 2023
Psychiatric disorder and substance abuse comorbidity is highly prevalent in the community and also in the clinical population. Several large epidemiologic surveys over the past 2 decades have consistently reported that individuals with psychiatric disorders have higher rates of substance use disorders, and those who have substance use disorders have higher rates of psychiatric disorders.[1-3] For example, the Epidemiological Catchment Area Survey has found a lifetime rate of 13.5 % for alcohol use disorders among the general population. The rate of alcohol use disorders increased to 16.5 for major depression, 21% for dysthymic disorder, 24% for obsessive-compulsive disorder, 29% for panic disorder, 34% for individuals with schizophrenia, and the highest rates among the major psychiatric disorders were found for bipolar II (39%) and bipolar I (46%) disorders.[1] The more recent surveys of nationally representative samples, the National Comorbidity Survey[2] and the National Institute on Alcohol Abuse and Alcoholism's National Epidemiologic Survey on Alcohol and Related Conditions (NESARD),[3] the largest survey to date, have reported similar findings for lifetime[2] and 12-month[3] rates.
Comorbid psychiatric and substance abuse disorders present with significant clinical challenges and have a negative impact on treatment adherence, treatment response, course, and outcome; they lead to increased service utilization, morbidity, and mortality. Efforts at improving treatment interventions are ongoing, however, and the treatment needs for this population remain largely unmet. Furthermore, tobacco smoking and nicotine dependence, a major comorbid substance use disorder among individuals with psychiatric disorder, have received much less attention by the mental health and the substance use treatment communities. Some of these issues were discussed at the American Psychiatric 2005 Annual Meeting in Atlanta, Georgia.
Treatment of comorbid psychiatric and substance use disorders pose multiple challenges. These comorbidities represent a wide array of conditions that are likely to begin in adolescence and co-occur over the life span. "Dual diagnosis" patients are more likely to be over-represented in treatment settings, as individuals suffering from more than 1e disorder are more likely to seek care. Clinicians caring for this population are faced with multiple challenges; a key concern is the selection of effective treatment. Evidence-based treatment for most psychiatric and substance use comorbidities is a developing field, and we still have limited options to guide treatment selections. Francis Levin, MD[4] Associate Professor of Psychiatry Columbia University/College of Physicians and Surgeons/New York State Psychiatric Institute, reviewed these issues at the APA meeting.
Dr. Levin's review focused on pharmacologic treatment approaches of common comorbid psychiatric disorders among individuals with substance use disorders. These included comorbid depressive disorder, bipolar disorder, anxiety disorders, and attention deficit/hyperactivity disorder (ADHD).
Optimizing treatment of psychiatric disorders is essential to improving the outcome of the substance use disorder. It has been long documented that high psychiatric severity predicts poor substance use treatment outcome.[5] Several studies have shown that psychiatric disorders may worsen treatment outcome of substance use disorders. For example, depressed patients tend to do worse in treatment.[6,7] Also, patients with depressive disorders are more likely to relapse to alcohol use earlier than those without major depression.[8] Rapid relapse subsequent to substance use treatment has also been documented among adolescents with major depression.[9] Patients suffering from posttraumatic stress disorder (PTSD) have poor treatment response.[10] Similarly, substance abusers with ADHD do worse in treatment, are less successful in attaining treatment goals, and are less likely to graduate from therapeutic communities.[11]
Furthermore, the presence of a comorbid condition increases the overall symptom burden. Individuals with mania and alcoholism were found to have significantly higher incidence of symptoms of impulsivity, mood lability, violent behavior, and other drugs of abuse compared with those with mania but without alcoholism.[12] Female patients with bipolar alcoholism reported heightened burden of depressive symptoms as well.[13] The presence of substance abuse disorder also increases the risk of suicidal behavior among patients with severe psychiatric disorders, such as those with major depression, bipolar disorder, and schizoaffective disorders.[14] Moreover, a longitudinal study found that individuals with prior history of alcohol dependence had a 4-fold increase in the incidence of current major depressive disorder.[15]
Treatment of these patients requires combined attention to both psychiatric and substance use disorders. Addressing only 1 disorder usually leads to treatment failures, poor response, and treatment dropout, resulting in worsened prognosis.[4] Treatment also generally requires a combination of counseling and pharmacotherapy. Several nonpharmacologic interventions may be used in these patients. These include the Minnesota model, motivational enhancement therapy, relapse prevention, contingency management, and integrative case management.[4] Despite the high frequencies of these comorbid conditions, well-controlled pharmacologic trials are still scarce. Comorbidity of major depression with substance use disorders is the most studied to date. Fewer studies are available for comorbidity with anxiety disorders, and fewer still have been conducted in comorbid bipolar disorder or comorbid ADHD.
This form of comorbidity is highly prevalent as both major depressive disorder and substance use disorders are among the most frequent psychiatric disorders in the community.[1] As described by Dr. Levin, more studies have been conducted evaluating different pharmacologic agents for this form of comorbidity. Dr. Levin presented the results of a recent meta-analysis on treatment of comorbid depression and substance use disorder.[16] Fourteen well-controlled, randomized, double-blind, placebo-controlled studies were analyzed.[16] The majority of these studies addressed alcohol dependence; other studies focused on cocaine dependence alone or cocaine dependence among methadone maintenance patients. Four studies evaluated the efficacy of the antidepressant imipramine, 4 studies evaluated the efficacy of sertraline, 3 studies evaluated the efficacy of fluoxetine, and 3 studies focused on 1 medication each (desipramine, nefazodone, and viloxazine). Methodologic differences between these studies were noted. For example, some studies had periods of enforced abstinence prior to making the diagnosis of major depression, while others did not. Also, there were large variations in placebo-response rate among these studies. Studies with higher placebo rate were less likely to find a medication effect. On the other hand, most of these studies used common, standardized measures for depression and alcohol/drug use outcomes. The pooled data from all of these studies included fewer than 850 subjects. The results of this meta-analysis showed that there was a modest overall beneficial effect for the depressive symptoms among these patients. Improvement in substance use correlated with improved depression regardless of medication response. In those studies that had a large effect size in improving depression, there was also an effect on substance use. It was also noted that there were high placebo-response rates in those studies that included nonabstinent populations or when a history of long-standing depression was not ensured. These latter findings may indicate higher rates of drug-induced depression in those samples and emphasize the importance of ascertaining the primary nature of the major depressive disorder prior to initiating pharmacotherapy.
Thus, although a number of clinical trials have been completed in comorbid depression and substance use disorders, pharmacologic approaches that are clearly effective for both the depression and the substance use disorders are still lacking. Treatment of depression in substance-abusing patients may be best accomplished by utilizing agents that are best tolerated, with a safe adverse event profile, and that are less likely to interact with abused substances.
Dr. Levin explained that there is little empirical evidence to guide treatment for comorbid bipolar disorders and substance abuse. This population presents the additional challenge of a particularly serious lack of treatment adherence. A number of open-label pilot studies with different compounds have reported conflicting results. Results from open-label studies are subject to multiplicity of confounds. Only 3 controlled trials have been published to date. A double-blind pilot study of 25 adolescents reported an advantage of lithium carbonate over placebo on the urine-positive screen (mostly marijuana) and also on mood symptoms.[17] Adolescent-onset bipolar disorder may be a significant risk factor for the development of substance use disorder[18]; thus, effective treatment of adolescent-onset bipolar disorder should be particularly beneficial in the prevention of substance use among these patients. To date, there has been no replication of this study.
The efficacy of carbamazepine in cocaine dependence was evaluated in a sample of 139 adult subjects over a 12-week period. Of the total sample, 57 subjects had a history of affective disorders; almost half of them had bipolar spectrum disorder. In these subjects, carbamazepine was better than placebo in reducing cocaine use as measured by self-report and urine drug screen, and there was a nonsignificant trend toward time to relapse to first cocaine use.[19]
Only 1 randomized clinical trial has been published to date with a group of adult subjects presenting in an acute bipolar episode (depressed, mixed, or manic) and active alcohol dependence. This 24-week double-blind, placebo-controlled trial evaluated the efficacy of valproate compared with placebo in patients who were stabilized on lithium carbonate and received weekly individual dual diagnosis counseling. Valproate was significantly better than placebo at reducing the percentage of heavy drinking days and time to relapse to sustained heavy drinking. Higher valproate blood levels correlated with improved alcohol outcome. Manic and depressive symptoms improved equally in both groups.[20] It is clear that more evidence-based treatment approaches need to be evaluated for this form of comorbidity. Other potentially useful agents, such as newer anticonvulsants or novel antipsychotics, have not been tested yet in this population.
Anxiety disorders include disorders that may present different challenges when co-occurring with substance use disorder. For example, diagnostic difficulties may be quite high when considering the diagnosis of generalized anxiety disorder in the context of substance use, as most substance intoxication or withdrawal states may mimic the symptoms of generalized anxiety disorders.
However, in terms of pharmacologic treatment, generalized anxiety disorder and comorbid alcoholism has received the most attention. Dr. Levin explained that 3 double-blind, placebo-controlled studies evaluating buspirone have been published to date.[21-23] Buspirone was found to decrease anxiety symptoms in 2 of these studies,[21,23] especially in those subjects who reported severe anxiety at baseline.[23] One study reported decreased desire to drink and improved functioning as well.[21] Another study reported a significant advantage of buspirone over placebo with regard to subjects' retention, time to first heavy drinking day during the acute treatment phase, and reports of number of drinking days at 6-month follow-up.[23] No differences between buspirone and placebo with regard to either anxiety or alcohol outcome were found by the third trial.[22]
Thus, there are conflicting reports on the efficacy of buspirone in alcoholism with co-occurring generalized anxiety disorder. Subgroups of patients with alcoholism and comorbid severe initial anxiety symptoms may benefit from this medication; however, there have been no follow-up trials assessing the efficacy of buspirone in subgroups of alcohol-dependent patients. The advantage of buspirone, explained Dr. Levin, is that buspirone has no abuse potential. It also has a low side-effect profile and is easy to discontinue. However, it has slow onset and often requires an increase to the higher therapeutic dose. Also, there seems to be low level of acceptance by patients.
Only 1 published randomized, double-blind, placebo-controlled pilot study has evaluated the efficacy of paroxetine in patients with comorbid social anxiety and alcohol use disorders. Fifteen subjects were randomized to paroxetine (flexible dose, up to 60 mg/day) vs placebo and followed for 8 weeks. There was a significant advantage of paroxetine over placebo with regard to improvement in social anxiety symptoms and improvement rated on the clinical global impression scale for alcohol use. However, the 2 groups did not differ with regard to the quantity/frequency of reported alcohol use.[24]
Only 1 randomized clinical trial has been published to date describing comorbid PTSD and alcohol dependence.[25] This double-blind, placebo-controlled trial of 94 individuals evaluated sertraline (150/mg day) vs placebo over a 12 week-period. A differential response to sertraline vs placebo was found. Subjects with less severe alcohol dependence and early-onset PTSD who were randomized to sertraline reported significantly fewer drinks per drinking day than those randomized to placebo. By contrast, subjects with more severe alcohol dependence and late-onset PTSD and who were randomized to sertraline reported significantly worse outcome with regard to the number of drinks per drinking day than those randomized to placebo.
The results of this study highlight the heterogeneity of treatment response among different subgroups of alcohol-dependent subjects and the intricacy of psychiatric and alcoholism interaction in terms of mediation of treatment response. Responders to sertraline in this group had a longstanding history of PTSD while their alcoholism was less severe. This may support the observation that optimizing treatment of the primary psychopathology would lead to improvement in alcohol outcome.
Dr. Levin explained that individuals with ADHD have an earlier age of onset of substance use disorders, and substance dependence is less likely to remit than in those without ADHD. Also, a number of clinical epidemiologic studies have reported high prevalence of ADHD in clinical samples of treatment-seeking substance abuse populations, with rates ranging from 15% to 24%.[4] A number of case reports and open trials using a variety of medications have been published, but only a few randomized, controlled trials have been reported to date.
One randomized, double blind, placebo-controlled study evaluated the efficacy of pemoline (75 to 112.5 mg/day) in 69 adolescents (aged 13-19) with ADHD, substance use disorders, and conduct disorder (CD), over a 12-week period. There was an advantage of pemoline over placebo in decreasing ADHD symptoms. However, pemoline was not better than placebo with regard to substance use or CD outcome.[26] Another 12-week, double-blind, placebo-controlled trial of methylphenidate (MPH) in 48 individuals with comorbid ADHD and cocaine dependence reported an advantage of MPH over placebo with regard to proportion of subjects with clinical global impression rating of 1 or 2. However, there were no differences between the 2 groups with regard to other outcomes, including several measures of cocaine use. There was also no worsening in cocaine use for subjects participating in the study.[27] The efficacy of sustained-release MPH was evaluated in a recent 14-week, double-blind, placebo-controlled trial in 90 adult subjects with comorbid cocaine dependence and ADHD.[4] There was no difference between the 2 groups with regard to ADHD symptoms. On the other hand, there was a reduction in cocaine use for patients treated with MPH.[4]
Dr. Levin discussed that there was not a simple answer for the question of whether stimulants should be used in patients with substance use disorders. Other medications with no abuse potential may be tried first. Atomoxetine is the only nonstimulant medication approved by the United States Food and Drug Administration (FDA) for the treatment of ADHD and is a reasonable first choice. Those with current or past substance abuse should be involved in ongoing substance use treatment programs and should attempt to establish a period of abstinence. Also, a careful history of amphetamine or other stimulant abuse should be determined. Furthermore the patient's reliability should be carefully assessed. Also, the presence, availability, and willingness of a family member or close associate without a substance abuse problem should be sought for involvement in the treatment plan. The treatment team should ensure that the patient and family members are adequately informed about the potential risks of stimulant therapy. Long-acting preparations should be used, with emphasis on medications taken on a regular basis rather than on an as-needed basis.
Cannabis abuse is a significant problem among individuals with psychotic disorders. The comorbidity and treatment of cannabis use disorder with psychosis was discussed by Alan I. Green, MD,[28] Professor and Chairman, Department of Psychiatry, Dartmouth Medical School.
Epidemiologic surveys have documented that 47% of patients with schizophrenia have substance use disorders. Alcohol, cannabis, cocaine, and nicotine are the primary substances of abuse in schizophrenia. The rate of cannabis use disorders among first-episode patients is substantial, with some studies reporting rates up to 50%.[29] Longitudinal studies have indicated that up to 63% of first-episode schizophrenia patients have used cannabis prior to psychosis and 53% have concurrent cannabis use with the development of psychosis.
Several hypotheses are advanced to explain the high association between substance use disorders and schizophrenia. This may include a potential causal link between cannabis use and the development of schizophrenia, and whether cannabis increases the vulnerability to schizophrenia. Studies have shown an earlier age of onset of schizophrenia in cannabis users.[30] Also individuals with schizophrenia may be prone to use cannabis as a form of self-medication. Patients with schizophrenia may have mesocorticolimbic dopamine system dysfunction leading to reward deficit that could predispose them to cannabis and other substance abuse.
The association of cannabis with schizophrenia leads to many negative consequences, including earlier onset of schizophrenia, increased relapse, treatment noncompliance, poorer overall response to antipsychotic medication, more hospitalizations, increased risk for violence, and increased medical costs.[28] Despite these negative consequences, treatment of cannabis abuse has been generally underemphasized in the psychiatric treatment setting, and cannabis abuse is not addressed unless it clearly interferes with treatment. It is important to address cannabis use in this population, as cannabis abuse is associated with earlier age of onset and delays treatment of psychosis. Certain psychosocial treatments such as contingency management appear to be helpful in decreasing cannabis use among these patients. Treatment programs that integrate attention to both disorders, including pharmacotherapy and substance abuse psychosocial services, may best address the need for these patients.
Studies of pharmacotherapy for comorbid cannabis use in patients with schizophrenia have shown that typical antipsychotics are of limited value in controlling the substance abuse. Comorbid patients have shown poor response to these medications, with increased incidence of extrapyramidal side effects and minimal improvements in negative symptoms. Patients receiving typical antipsychotics have shown a high rate of substance use, and one study reported an increase in the rate of smoking in patients treated with haloperidol.
Among the atypical, or novel antipsychotic drugs, clozapine appears to be the most promising so far for schizophrenic patients with comorbid substance abuse. Initial case report studies and retrospective surveys have indicated decrease in substance abuse, cocaine cravings, and smoking among schizophrenic patients. A naturalistic prospective study[31] of 151 treatment-refractory dual-diagnosis patients, including 36 treated with clozapine, showed that 79% of clozapine treated patients had remission of their alcohol abuse compared with only 33% of those treated with typical antipsychotics. In that same sample, 6/9 (67%) of those who used cannabis improved on clozapine compared with 12/37 (32%) for those treated with typical neuroleptics.
There is scant evidence for other novel antipsychotics. One study reported decrease in cocaine craving in patients with schizophrenia and cocaine use while on risperidone. On the other hand, a 1-year follow-up for patients treated with either risperidone or clozapine showed abstinence rate of 54% (n = 24) in those treated with clozapine and 12.5% (n = 8) of those treated with risperidone.[32] One open-label study reported improved substance use outcome for patients treated with olanzapine, and one open-label study reported a decrease in stimulant craving for patients treated with quetiapine. The potential role of adjunctive medications to help decreasing alcohol and other substance was also discussed.[28] There are no published randomized controlled trials to date in this population. The need for effective interventions to treat cannabis and other substance abuse among patients with schizophrenia is highlighted by the early development of cannabis abuse among these patients and its impact on delaying treatment interventions and the overall negative outcome.
Jack R. Cornelius, MD, MPH,[33] Professor of Psychiatry, University of Pittsburgh, discussed the role of fluoxetine in the treatment of adolescents with cannabis and alcohol use disorders. He reviewed the only available acute treatment and long-term follow-up pilot study for this comorbidity. Studies evaluating the efficacy of psychotropic medications in comorbid major depression and cannabis or other substance dependence are still few and mostly conducted in adult populations. There are no such studies published to date for adolescents or young adults.
It is hypothesized that low serotonergic functioning underlies major depressive disorder, suicidal behavior, and alcohol and substance use disorders. Thus, medications that enhance serotonergic functions, such as the serotonin reuptake inhibitors, may be helpful for these conditions.[34] In a double-blind, placebo-controlled study of 51 adult patients with severe major depression and comorbid alcohol dependence, fluoxetine (20-40 mg/day) was found to decrease alcohol use and depressive symptoms compared with placebo.[34] Fluoxetine was also found to have an advantage over placebo in decreasing the number of cannabis use days, and on cumulative number of marijuana cigarettes smoked among patients in that study who also were marijuana abusers. The number of days of cannabis use was 5 times higher in the placebo group than in the fluoxetine-treated group.[35]
Marijuana is the most frequent drug of abuse among treatment-seeking adolescents, and comorbidity with major depression is estimated at 15%. Relapse apparently occurs rapidly in adolescents. A study of 59 patients reported that two thirds relapsed within 6 months, with median time to relapse occurring within 2 months of discharge from treatment. The most cited reasons for relapse include social pressure, withdrawal, and negative affect. Major depressive disorder was also found to be a predictor of relapse to alcohol use among adolescents.[36]
Limited pharmacologic treatment options are available for adolescents with comorbid major depression and cannabis or any other substance abuse. There are no published randomized, placebo-controlled trials to date in this population. Fluoxetine is the only antidepressant approved by the FDA to be used in adolescents.[37] Dr. Cornelius reviewed the only long-term pilot study of the efficacy of fluoxetine on alcohol and cannabis use in adolescents (ages 13-19 years) with comorbid major depression and alcohol use disorders, half of whom also had cannabis dependence.[38] During the acute treatment phase, patients were given fluoxetine up to 20 mg and evaluated 8 times over a 3-month period. There was significant improvement during the acute treatment phase. Depressive symptoms remitted (average Hamilton Rating Scale score decreased from 25.6 at baseline to 6.4) over the study period. There was also significant decrease in the quantity (6.7 to 3.7 drinks per drinking day) and frequency (2.6 to 1.5 drinking day per week) of drinking and a significant decrease in the number of DSM-IV criteria for cannabis dependence (from 5 to 2). Of the 13 subjects, 10 were followed long term in naturalistic treatment for 1, 3, and 5 years.
Follow-up at 1, 3, and 5 years showed that the number of adolescents who did not meet any alcohol use diagnoses substantially increased, from 0 (at baseline, 9 had alcohol dependence, and 1 had an alcohol abuse diagnosis) to 5, 6, and 6, respectively. Five subjects had cannabis dependence at baseline, which decreased to 4 at 1 year, 3 at 3 years, and 0 at 5 years. On the other hand, those who were free from major depressive disorders at follow-up were 3 at 1 year, 2 at 3 years, and 4 at 5 years. Thus, there was more noticeable improvement for the alcohol and cannabis use disorders than the major depressive disorder. Furthermore, despite periodic depressive symptoms, these patients had particularly good functional outcome. At the time of the last follow-up, 3 were enrolled in graduate school, 6 were fully employed, and 2 had part-time employment.
Overall, the acute study showed that fluoxetine was helpful in decreasing depressive symptoms as well as alcohol and cannabis use. There was no associated increase in reports of suicidal behavior in these patients. The long-term (5-year follow-up) outcome in this sample of adolescents with comorbid major depression and alcohol and marijuana use disorders appears to be good for the alcohol and cannabis use, while the major depressive disorder outcome may be less favorable.
In summary, there is still little empirically based information to guide clinicians in the treatment of most comorbid psychiatric and substance use disorders, and more research is needed in this area. Medication of choice should have safe adverse-events profile, should be long-acting, and should be associated with less abuse liability.
Tobacco smoking among patients with psychiatric disorders is a significant public health problem, with major toll on morbidity and mortality among this population. Mental health professionals and psychiatrists in general have been, to a large extent, absent in addressing this problem. Douglas Ziedonis, MD, MPH,[39] Professor & Director, Division of Addiction Psychiatry, UMDNJ Robert Wood Johnson Medical School, in his presentation entitled "Psychiatrists Should Take a Lead in Addressing Tobacco: Clinical, Program, & System Perspectives," discussed the important role that psychiatrists and mental health professionals should assume in addressing this problem.
Psychiatric patients have a very high rate of tobacco smoking. Individuals with a current psychiatric disorder consume a staggering 44% of all cigarettes consumed in the United States. This has an estimated cost of $256 billion.[39] Three quarters of patients in substance use treatment and in mental health programs smoke cigarettes. Complications of cigarette smoking are major causes of morbidity and mortality among these patients. Public health interventions over the past 40 years have been very effective in reducing smoking for most of the general population except for those with mental illness. There is an immediate need to provide more treatment and to do more research to enhance our understanding of factors related to nicotine dependence to provide more effective treatment.
Dr. Zeidonis discussed that barriers to addressing smoking are present at multiple levels. These include provider, patient, and family resistance; concerns about exacerbation of psychiatric symptoms with smoking cessation, and concerns about interactions with psychotropic medications. Further barriers to treatment implementation include lack of staff training, and the fact that tobacco treatment medications are usually not covered by health insurance and patients are unable to afford the cost of over-the-counter preparations. Stigma, rationalization, minimization of the problem, and misinformation or lack of information about the health implications of nicotine dependence are additional major barriers to addressing smoking in this population.
Dr. Zeidonis suggested change must be implemented at multiple levels by addressing clinical, program, and system issues. For example, at the clinical levels there is a need to implement effective screening, assessment, and treatment strategies. Staff training and quality improvement strategies could be implemented at the programmatic levels, and collaboration and networking may be undertaken at the system levels to create prevention and treatment programs. It is important to identify the barriers for change and also identify the innovations in the field.
It is important that all psychiatrists, not just specialists, be involved in addressing nicotine dependence among individuals with mental disorders. Recommended steps for implementing change at the program levels include raising awareness of the need to address tobacco use among this population, acknowledging the challenge, establishing a leadership group and commitment to change, and creating a plan for change and an implementation timeline. Steps also include staff training, promoting integrating tobacco treatment into mental health and addiction setting, and providing treatment and recovery assistance for interested nicotine dependent staff. Tobacco issues should be incorporated into the patient education curriculum. Further steps include providing on site Nicotine Anonymous meetings and establishing ongoing communication with other self-help recovery groups and other professional and referral resources, and developing tobacco policies.
One effective approach to treatment is to employ motivation-based intervention strategies with focus on recovery and wellness. This approach allows the health professional to meet the patient where he or she is and is more effective in reducing resistance. There are a number of programs around the country that address smoking among psychiatric patients with specific disorders such as PTSD, depression, schizophrenia, and other addictions. Addressing tobacco addiction in mental health and addiction treatment settings with emphasis on both prevention and treatment is overdue. Motivation-based approaches and effective nicotine treatments are available; however, program and system changes are critical to the broad-based success of a model program.
The neurobiological links between smoking and mental disorders, along with some emerging treatment implications, were discussed by Nora D. Volkow, MD,[40] Director, National Institute on Drug Abuse. Dr Volkow emphasized that cigarette smoking is implicated in at least 400,000 deaths annually, and smoking is the single largest preventable source of morbidity and mortality in the United States. Twenty three percent of American adults are smokers, and smoking typically begins in adolescence.
Nicotine dependence is a drug addiction. Nicotine has similar effects on the dopamine pathway in the brain to those of other drugs such as amphetamines, or natural rewards such as food and sex. Nicotine causes increase in dopamine and activation of the reward pathways, leading to behavioral reinforcement and addiction. Nicotinic receptors regulate dopamine release in the central nervous system. Nicotinic acetylcholine receptors (nAChRs), especially subunits (alpha4beta2 and alpha7), have the highest concentration in the central nervous system.[41] Experimental studies with beta2 subunit "knockout" mice showed that the beta2-containing neuronal nicotinic acetylcholine receptor is involved in mediating the reinforcing properties of nicotine.[42] Cigarette smoking leads to widespread effects on nicotinic receptors in the brain. Studies have demonstrated that more than 50% of nicotine receptors are occupied at nicotine levels achieved by smokers when smoking a cigarette.
Addictive disorders often coexist with mental disorders. While smoking rate in the general population is 23%, much higher figures have been reported for individuals with psychiatric disorders, including 90% in alcoholism, 90% in other addictions, 85% in schizophrenia, and 80% in depression. Thus, individuals with mental disorders are at increased risk for nicotine and other addictive disorders.
Drug abuse, alcoholism, and other addictions mainly develop during adolescence and childhood. There may be differential vulnerability to drug abuse of the adolescent brain. There is experimental evidence demonstrating that the adolescent brain responds differently to nicotine than the adult brain. Pre-adolescents and animals treated with nicotine display increase in nicotine self-administration, and also have demonstrated a significant increase in nicotine receptors, including the beta2 subunits linked to the reinforcing properties of nicotine.
Furthermore, there may be complex interactions between nicotine use and some psychiatric conditions. Patients with schizophrenia have fewer alpha7 nicotinic receptors in the hippocampus.[43] Nicotine normalizes a sensory gating abnormality P50 inhibitory deficit, found in most schizophrenics and 50% of their first-degree relatives,[44] and nicotine appears to improve concentration among individuals with schizophrenia. A large follow-up study found that smokers were at greater risk to develop schizophrenia, with adjusted relative risk of 1.94 (CI 1.05-3.58). The number of cigarettes smoked was significantly associated with the development of schizophrenia, and increased risk for hospitalization for schizophrenia increased with increased number of cigarettes smoked.[45]
Neurobiological links were also reported for the relationship between depression and smoking. Studies have shown that smokers have a 30% to 40% reduction in their brain monoamine oxidase (MAO). MAO inhibitors are effective antidepressants, and depressed patients may therefore be prone to smoking as smoking is likely to reduce depressive symptoms.[46,47] Individuals with depression have more difficulty quitting smoking. For example, women with depression have increased depression symptoms subsequent to smoking cessation and experience greater difficulty maintaining early abstinence than nondepressed women.[48]
A number of treatments are currently available for nicotine dependence, including nicotine replacement therapy, bupropion, and MAO inhibitors. MAO B inhibition may also be helpful in smoking cessation.[49] Future directions in treatment may include a number of options such as the use of vaccines, cannabinoid antagonists such as rimonabant, and inhibitors of nicotine metabolism such as methoxsalen.
In conclusion, it is likely that clinicians will confront the challenges posed by dual-diagnosis patients, given the large number of these patients using the healthcare system. As the results of clinical studies are translated into clinical practice, perhaps the future will provide some consensus on best treatments for the highly complex condition of comorbid substance abuse and psychiatric disorder.
