Understanding Nicotine and Depression

Article Outline

• Abstract
• Symptoms of Nicotine Dependence
• Properties and Effects of Nicotine
• Models for Understanding Nicotine Dependence
  • Neurobiological Model of Nicotine Dependence
  • Associative Learning Model
• Depression and Smoking: Neurobiological Contributions
  • Antidepressant Effect of Nicotine
  • Sensitivity to Stress
• The Treatment of Nicotine Dependence
  • Assessment
  • Nicotine Replacement Therapy
  • Antidepressant Therapy
  • Varencline
  • Strategies to Motivate Change and Prevent Relapse
• Case Study
  • Assessment and Treatment Approaches
• Conclusion
• References
• Copyright

Abstract 

It is likely that nurse practitioners (NPs) will see patients who are chronic smokers and also depressed. Nicotine-dependent smokers are twice as likely to experience major depression compared to nondependent smokers and non-smokers. Biological and cognitive learning models provide an understanding of the relationship between the 2 conditions. Clinicians in primary care settings can select strategies of assessment, treatment, and education to care for patients presenting with these co-occurring conditions.

Keywords:  major depression , nicotine dependence , smoking , smoking expectancies

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Although cigarette smoking between 2002 and 2006 declined in the United States, one quarter of Americans continue to smoke despite the risks to health.¹ Some smokers are unable to regulate the use of cigarettes and become physically and psychologically dependent upon nicotine. The lifetime prevalence of nicotine dependence in the United States is 24% and accounts for nearly half of those individuals who have ever smoked cigarettes daily for one month or more in their lives.², ³

The prevalence of a past-year depression among persons with concurrent substance use rose from 10% in 1991-1992 to 15% in 2001-2002.⁴ Depression is a risk factor for nicotine dependence. Adults 18 years and older who are nicotine dependent are twice as likely as those who are not nicotine dependent to have experienced a major depressive episode (MDE) in the past year (13.8% vs 6%).¹

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Symptoms of Nicotine Dependence 

Nicotine dependence is classified as a maladaptive pattern of substance use, leading to clinically significant impairment or distress. Nicotine is one type of drug and an individual who smokes can be diagnosed as nicotine dependent according to specific criteria (Table 1).⁵ Two hallmark symptoms of dependence are tolerance and withdrawal. Tolerance occurs because nicotine is quickly metabolized and has a short half-life; therefore, receptors can adapt to the drug after continued use by reducing the number of receptors or reducing sensitivity so that higher levels of nicotine are needed to obtain the desired effect.⁶

Table 1. Symptoms of Nicotine Dependence⁵

Source: American Psychiatric Association. Diagnostic and statistical manual of mental disorders, IV-TR 4th ed. Washington, DC: American Psychiatric Association; 2000.

Characteristic withdrawal symptoms such as irritability and anxiety occur when a nicotine-dependent smoker tries to quit and then makes an effort to avoid the distressing symptoms by continuing to smoke.

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Properties and Effects of Nicotine 

Nicotine is quickly absorbed from the lungs, buccal and nasal mucosa, skin, and gastrointestinal tract. Most cigarettes contain between 0.5 and 2.0 mg of nicotine, and 20% of nicotine in a cigarette is inhaled and absorbed into the bloodstream. Nicotine is rapidly metabolized by the hepatic enzyme CYP2A6.

During cigarette smoking, high blood nicotine levels rise within 2 to 3 minutes of initiation and can be maintained for 10 minutes. Nicotine is quickly distributed throughout the body, penetrating the brain, crossing the placental barrier, and appearing in all body fluids, including breast milk. The liver metabolizes about 80% to 90% of the nicotine before it is excreted in the kidneys. The elimination half-life of nicotine in a chronic smoker is about 2 hours, so frequent administration is needed to maintain blood levels. Each cigarette produces a sharp increase in nicotine concentration within the brain to the desired plasma concentration, usually between 20 to 40 nanograms (ng) of nicotine per milliliter (mL) of plasma.⁷

In the early stages of smoking, nicotine causes nausea and vomiting by stimulating the vomiting center in the brain stem and sensory receptors in the stomach. Tolerance to this effect develops quickly. Nicotine reduces the activity of the afferent nerve fibers coming from the muscles to create muscle relaxation. Nicotine also stimulates cognitive functioning, attention, and memory retrieval and decreases appetite, which results in weight loss, but retention of fluid due to the stimulation of the hypothalamus to release anti-diuretic hormone.³¹

Because of nicotine's 2-hour half-life, there is a low residual level of nicotine in the blood and brain after a night's sleep. The smoker wakes each morning in a state of drug withdrawal and the first cigarette brings relief and becomes a powerful reinforcement of smoking behavior. In cigarette smoking, the user can control levels of blood nicotine by regulating the depth and rate of inhalation to achieve the desired effect (relaxation and increased concentration) and avoid unpleasant adverse effects associated with too-high levels (dizzy) or too low (desire to smoke or withdrawal). Higher peak levels of nicotine and more rapid absorption into the bloodstream occur during cigarette smoking as compared to chewing tobacco or chewing nicotine gum.⁷

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Models for Understanding Nicotine Dependence 

Two models of nicotine dependence include the neurobiological model and associative learning model, both of which have important implications for understanding and selecting smoking-cessation strategies. These models also help the practitioner to appreciate how difficult it is for a nicotine-dependent smoker to quit smoking; therefore, there is a need to use both pharmacological and psychological treatment approaches.

Neurobiological Model of Nicotine Dependence 

Neural mechanisms have evolved in the human being to increase the probability that behavior will promote species survival. One primary mechanism is the activation of neural systems that promote a sense of satisfaction and pleasure, referred to as the brain reward system. The administration of drugs can stimulate brain reward mechanisms and, when repeated often enough, the drug becomes rewarding in its own right. There are 2 dopaminergic neuronal systems (DA) in the brain that are involved in psychomotor stimulant reward function. These include the mesolimbic dopamine system, which projects from the ventral tegmentum (VTA) of the forebrain to the nucleus accumbens (NA), or the limbic striatum area; and the mesocortical dopamine system, which projects from the VTA to the frontal lobe (Figure 1).⁸, ⁹ The 2-neuron system forms a dopaminergic loop between the forebrain and the VTA. Nicotine, a psychomotor stimulant, indirectly activates DA neurons projecting to the NA, a center for the experience of reward. The metabolism of nicotine occurs in the shell of the NA, which has projections to the amydala and therefore is involved with both innate and acquired emotional response.¹⁰ This is the basis for reinforcement of expectations or beliefs about nicotine use. Nicotinic acetylcholine receptors (nAChR) on dopaminergic cell bodies are necessary for DA release elicited by nicotine, enabling nicotine agonists to have a rewarding effect.

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• Figure 1. 

  Dopaminergic projections

Associative Learning Model 

Expectations about the effects and outcome of a substance contribute to the continued use of a drug. The associative learning model explains how the repetition of events over time is associated with drug taking. When repeated often enough, the events are rapidly encoded in memory and retrieved quickly, contributing to involuntary and habitual behavior characterized by loss of control. Associative learning involves an environmental cue for a drug (S), a drug stimulus (S*_d), response to a drug (R_d), and an outcome (S*). The model shows how successive pairs of these events provide 3 expectancies that concern drug administration, type of response, and its consequence (Figure 2).¹¹

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• Figure 2. 

  A learning model of a drug-taking situation identifying 4 events: cue for the drug (S), drug stimulus (S*_d), response to the drug (R_d), and an outcome (S*) The model shows how successive pairs of these events provide three expectancies that concern drug administration, type of response, and its consequence.

The first expectancy is represented by the statement (S→ S*_d). A stimulus cue (S), such as an ashtray, precedes the behavior of smoking, the drug stimulus (S*_d); and therefore, the expectation of taking the drug (nicotine) occurs when seeing the ashtray after these events are repeated over time. The second expectancy involves learning that a second pair of events relate the drug stimulus (S*_d) to a particular type of response to the drug (R_d) and is represented by the statement (S*_d) →(R_d). For example, one comes to expect that smoking will reduce distressing feelings and this becomes associated with a reduction in sad mood. A third type of expectancy involves the consequence of the drug represented by the statement (R_d → S*). The response to smoking brings an outcome such as feeling relaxed (R_d) but the outcome can change with the situation (S*). For example, a person may be motivated to smoke because of the expected positive consequence that smoking will help them to feel calm, yet if this individual has problems functioning because of poor breathing and associates smoking with a negative impact upon health, they may be motivated to quit smoking due to the associated negative consequences.

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Depression and Smoking: Neurobiological Contributions 

Two lines of evidence will be discussed in an effort to understand how smoking has a rewarding effect for depressed smokers. The neurobiological mechanisms that contribute to the relationship between nicotine dependence and depression address the following: (a) smoking has antidepressant effects, and (b) smokers are sensitive to stress and depression. Symptoms of a major depression are stated in the Diagnostic and statistical manual of mental disorders (Table 2).⁵ Two-stem questions from The World Health Organization Composite International Diagnostic Interview Short Form (CIDI-SF) have been used to quickly assess for the likelihood of symptoms of major depression occurring anytime in life.¹²

Table 2. Symptoms of Major Depression⁵

Source: American Psychiatric Association. Diagnostic and statistical manual of mental disorders, IV-TR, 4th ed. Washington, DC: American Psychiatric Association; 2000.

Antidepressant Effect of Nicotine 

It has been suggested that a sense of euphoria occurs during cigarette smoking and that this can account for the use of smoking to self-medicate depressed mood.¹³ The sense of well-being is reinforced by dopamine release in the mesolimbic system, involving the shell of the nucleus accumbens (NA) that is associated with the expression of emotion. Nicotine also increases the release of norepinephrine into the neuronal synapse creating an antidepressant effect. Another mechanism that may account for the antidepressant like effect of nicotine is related to compounds in cigarette smoke that contribute to a lowering of monamine oxidase (MAO), an enzyme that metabolizes dopamine, serotonin, and norepinephrine. The inhibition of MAO from cigarette smoking is thought to contribute to increasing mood, given that more dopamine, serotonin, and norepinephrine become available. Inhibited levels of MAO type B enzyme have been found in smokers as compared to former smokers and non-smokers.¹⁴

Sensitivity to Stress 

Review of the effects of nicotine on neural pathways reported by Balfour and Ridley¹⁵ found that people smoke because they are sensitive to stress and experience the reinforcing effects of dopamine associated with relief. Stressful life events have been shown to contribute toward vulnerability to depression. As the exposure to threat increases, the likelihood of the onset of a major depression within 2 months of the stressful event increases, especially in individuals with a less efficient serotonin transporter genotype.¹⁶ Nicotine has an inhibitory effect on serotonin release (5-HT) in some parts of the hippocampus and this effect may attenuate habituation to stress.¹⁵ In addition, the 5-HT receptors that occupy the hippocampus also regulate the release of glucocorticoids during stress and over time a down-regulation of glucocorticoid receptors occur contributing to an increased sensitivity to the rewarding effects of drugs.

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The Treatment of Nicotine Dependence 

Assessment 

The relationship between depression and smoking has been examined in the research according to the presence of depressive symptoms, negative mood, and the diagnosis of major depression. Ruling out the presence or history of major depression in a smoker is important for the following reasons. First, major depression is prevalent among nicotine-dependent smokers. Second, depressive symptoms can occur during quit attempts. Third, all smokers are at greater risk for progressing in smoking behavior from non-dependence to dependence when there has been a history of a major depression or if there is a current untreated major depression.¹⁷ Smokers who are depressed may find that the rewarding effects of reducing mood is a more compelling reason to continue to smoke in contrast to quitting for health reasons.

Any smoker who presents in primary care can easily be screened using tools that are both efficient and effective in diagnosing the likelihood of nicotine dependence and major depression, as given in Table 3. Two questions found to reliable assess for nicotine dependence include asking if the patient has smoked the first cigarette of the day within 30 minutes of waking and if more than 20 cigarettes are smoked per day.¹⁸ Affirmative responses to both questions are needed to assess for withdrawal and tolerance — both hallmarks of dependence. The likelihood of a major depression having occurred can be assessed by using 2-stem questions from the CIDI-SF, as previously stated, and affirmative responses to both stem questions that address low mood and loss of interest for 2 weeks are needed.

Table 3. Quick Screening Tools

Nicotine Replacement Therapy 

Nicotine replacement therapy (NRT) consists of nicotine gum, transdermal nicotine (patch), inhaler, nicotine spray, and nicotine lozenge. NRT facilitates abstinence through 2 primary mechanisms: NRT provides the smoker with a lower dose of nicotine to attenuate withdrawal symptoms and ease in transition to non-smoking statu, and NRT allows the smoker to develop coping strategies to address the behavioral aspects of addiction while physical components are treated.⁷

All forms of NRT such as gum, patch, lozenge, nasal spray, and oral inhalator have been found to be effective when compared to placebo.¹⁹ Treatment with the transdermal patch results in the highest overall abstinence rate, after both initial treatment and after 6 months.²⁰, ²¹ Cost, patient preference, and side effects are considerations when choosing NRT. Common side effects of NRT include irritation of the buccal mucosa, skin, or throat.

Antidepressant Therapy 

The most widely used antidepressant in treating nicotine dependence is bupropion, ie, Wellbutrin and Zyban. Bupropion is a second-generation antidepressant that inhibits the post synaptic reuptake of dopamine and norepinephrine. In a randomized controlled trial of over 800 smokers, cessation rate was highest when the nicotine transdermal patch was used in combination with bupropion compared to bupropion alone (35% versus 30%) at 12 months post treatment.²² In this same study, these results indicated that the combination therapy or bupropion alone was found to be more effective than either the nicotine patch alone or placebo.

Monotherapy with either slow-release bupropion or nortiptyline (another anti-depressant) doubles the odds of successfully quitting smoking at 6 months post treatment.¹⁹ A review of randomized clinical trials indicated that bupropion is effective in lessening the symptoms of depression during quit attempts in nicotine-dependent smokers and is equally effective for smoking cessation in nicotine-dependent smokers who are not depressed.²³

Varencline 

Varencline (Chantix) is an α4β2 nicotinic acetylcholine receptor subtype that works to reinforce the effects of nicotine as measured by dopamine turnover and release in the nucleus accumbens (NA). Varencline binds with the receptor subtype to simulate the release of dopamine to reduce craving and withdrawal while simultaneously blocking the binding and consequent reinforcement effects of smoked nicotine. Although long-term cessation rates after treatment with varencline were found to be higher than treatment with bupropion (21% vs 16%) over a period of 9 to 52 weeks, the clinician needs to review the latest information about varencline because there have been reports that some patients have developed neuropsychiatric symptoms such as agitation, depressed mood, and suicidal ideation.²⁴, ²⁵ Further information regarding treatment for nicotine dependence can be obtained online by locating the American Psychiatric Association Practice Guidelines.²⁶

Strategies to Motivate Change and Prevent Relapse 

The associative learning model of dependence helps to explain the powerful effect that expectations about smoking have in reinforcing habitual behavior. Changing the expectancies or beliefs about smoking is an important cognitive strategy to help create awareness about the consequences of smoking, an important step in the change process. For example, smokers who remain abstinent 3 months after participation in a smoking-cessation program are more likely to express weaker beliefs about smoking such as that smoking reduces depressed feelings, or facilitates socialization, etc, than individuals who hold stronger beliefs in these effects.²⁷

A nicotine-dependent smoker can be helped while quitting to be aware of specific expectations he or she may have about the consequences of smoking. This awareness helps to encourage voluntary thinking in contrast to habitual behavior. Smoking beliefs from The Smoking Consequences Questionnaire for Adults (SCQ-A) are given in Table 4.²⁸ Smokers can take this questionnaire home and circle the likelihood of belief in each consequence of smoking on a scale from 1 to 10 (1 = completely unlikely and 10 = completely likely). On a follow-up visit, the NP can discuss these beliefs and help to correct through education and counseling. Once individuals are aware of beliefs regarding the consequences of smoking, they can then be helped to monitor situations in everyday life that may provoke reinforcement. A useful strategy is to suggest that the patient keep an expectancy chart or journal that documents beliefs, feelings, and coping strategies.

Table 4. Smoking Consequences Questionnaire-Adult (SCQ-A)²⁸

Adapted from Smoking Consequences Questionnaire-Adult, with permission from author.

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Case Study 

K is a 20-year-old college student who works part-time in a large popular pizza restaurant in addition to attending classes. K lives off campus and shares an apartment with other college friends. On campus, she can often be seen smoking outside campus offices, taking a break between classes. K has been smoking cigarettes since age 14 and currently smokes a pack per day and continues to smoke to avoid withdrawal symptoms. She has attempted to quit twice, but each time lit up after experiencing a “lousy” feeling of irritation, anxiety, and craving for a cigarette.

K comes to the college health care clinic seeking a prescription for antidepressant medication. She states she has been worrying about a lot of things and this has made her feel depressed. She has not shown up a few times for class or work lately and states she could fail out of college and lose her job. K told her department chairperson and employer that she was coming to the clinic today to get treatment for depression.

K is vague about her depression. She states she has a “bad attitude” and feels like “sliding through life.” She describes her “bad attitude” as, “I get up in the morning, sit down at the table, and then that's as far as I get sometimes.” K is aware that she also has a problem with smoking because she can't go a day without a cigarette. She admits to sometimes drinking too much beer in order to “feel good” and usually lights up while drinking with friends. K wants to quit smoking but feels that it would be too hard to quit both cigarettes and beer at the same time; in addition, she would lose her friends. She has taken antidepressants before and states, “they really helped me and I cut back on beer.”

Assessment and Treatment Approaches 

K has a 6-year history of cigarette use and is currently smoking, and experiences withdrawal symptoms, a strong indication of nicotine dependence. K smokes 20 or more cigarettes per day and states she also smokes within 30 minutes of waking, indicating the likelihood of nicotine dependence. K states that she is depressed and her use of antidepressants in the past indicate a possible recurrent depression. The 2-stem questions from The World Health Organization CIDI-SF can be used to quickly assess for the likelihood of symptoms of major depression. K is asked if, in the past 2 weeks, she has experienced depressed mood and loss of interest in normal activities for most days. She responds yes, indicating the likelihood of a recurrent major depression.

Once the likelihood of concurrent nicotine dependence and major depression diagnosis has been made, a plan for treatment is needed. A schematic that represents treatment, motivation, and prevention of relapse, based upon evidence-based research, can be referred to as an outline for care (Figure 3).²⁹ Tobacco-dependence treatments appropriate for an individual experiencing both nicotine dependence and depression include the patch plus bupropion slow-release (SR) or bupropion alone. Treatment with bupropion is 150 mg daily for 3 days, followed by 150 mg twice daily and continue for 7 to 12 weeks.¹⁹ The patch dose can begin at 21 mg per day for 4 to 6 weeks, followed by a tapering of 14 mg per day for 2 weeks, then 7 mg per day for 2 weeks.¹⁹

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• Figure 3. 

  Screen for tobacco use status.²⁹

The keeping of an expectancy chart can be used to describe a particular triggering situation that serves as a smoking cue followed by writing down the specific belief about smoking (Table 5). There is a need to help the patient develop and substitute skills such as learning how to regulate feelings in contrast to the use of cigarettes for “self-medicating” purposes. In addition to examining smoking beliefs that serve to reinforce smoking, behavioral therapies such as brief advice by the NP, individual counseling, suggesting physical exercise, and providing telephone quit-line resources increase cessation success when adding this to NRT and antidepressant therapy.¹⁹

Table 5. Sample Expectancy Chart

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Conclusion 

Treatment of nicotine dependence begins with assessment for both nicotine dependence and depression because often, the 2 conditions occur together. Screening tools were recommended followed by pharmacological strategies that will address both nicotine dependence and depression. Associative learning that involves remembering the desired effects as a result of smoking is a powerful reinforcement for dependence. Education about cognitive beliefs regarding these effects is an important strategy because smokers can begin to change beliefs and address habitual behavior.

Smokers who identify the strength of smoking beliefs or expectancies can learn to become critical thinkers about tobacco to resist media messages. Learning how to evaluate who is being targeted by the advertisement, the accuracy of the message, and the personal significance of the message creates strategies to prevent relapse. Additional resources for both providers and the general public that address smoking cessation are given by the Oncology Nursing Society.³⁰

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