Table of contents:

1. Effects of nicotine
2. Smoking and schizophrenia
3. Treatment of nicotine dependence
4. Nicotine replacement therapy (NRT)
5. Bupropion SR
6. Antipsychotics
7. Other drugs
8. Summary

It has been hypothesised that the high prevalence of nicotine dependence among patients with schizophrenia may be due to a common neurobiological vulnerability - there is evidence that certain patients with schizophrenia have abnormal expression of nicotinic receptors. The problem of nicotine dependence is particularly relevant in such patients, as people with schizophrenia live about 10 years less, and the most common causes of death are cardiovascular and pulmonary. Two-thirds of people with schizophrenia die from ischaemic heart disease, compared to one-third of the general population.

Treating nicotine dependence, like other addictions, is not an easy task, nor one that results in spectacular successes. Approximately 4 million people worldwide quit smoking each year, but 75% of them relapse before one year. People with schizophrenia achieve this goal even less frequently.

Since 1996, the APA has recommended routine treatment of tobacco dependence among patients with mental disorders. A proportion of people with schizophrenia are motivated to quit smoking, but in practice patients are rarely offered a break during routine clinic visits. The most common reasons for quitting in this group of people are concern for their own health, the need for self-control and social influences. In one study involving 1 610 patients with schizophrenia, 76% were smokers and only 10% were offered treatment. This low percentage reflects psychiatrists' lack of confidence in the efficacy of such treatment and fear of possible destabilisation of psychotic symptoms.

Effect of nicotine

Nicotine, the primary ingredient in tobacco and the direct cause of addiction, can exert complex effects on numerous neurotransmitter systems, and responses to this substance are individually variable. The substance: reduces anxiety, improves attention, reduces appetite, reduces depression and improves cognitive function.

Nicotine acts through nicotinic acetylcholine receptors located commonly in the brain. These receptors can modulate the dopamine, glutamine, GABA, serotonin, noradrenergic, opioid and cannabinoid systems. Nicotine activates dopamine reward system pathways in the midbrain, which originate in the ventral tegmentum and from there lead to the amygdala, hippocampus, nucleus accumbens, striatum and cortex. Individual differences in the proportions and combinations of nicotinic receptor subtypes in different brain areas and the genotypic diversity of the dopamine system are explanations for individual responses to nicotine.

Smoking and schizophrenia

Various clinical and biological factors have been considered to explain the association between smoking and schizophrenia. It has been suggested that patients smoke in order to:

1. break the monotony that is associated with the illness,
2. gain social contacts,
3. experience some kind of pleasure;
4. in the self-treatment of certain symptoms associated with schizophrenia,
5. self-medication of side effects of neuroleptics.

During clinical observation, it can be seen that the severity of smoking often precedes the onset of symptoms of the illness or signals an exacerbation of psychosis. Studies have also shown that smoking has a greater impact on the negative symptoms of schizophrenia (in relation to the theory of impaired prefrontal cortex activity) - patients who smoke have better scores on neuropsychological and psychophysiological tests. This includes parameters such as:

• attention and vigilance
• spatial organisation
• visual-spatial working memory
• p50 component of auditory evoked potentials
• auditory "sensory gating"
• pPI pre-signal inhibition,
• tracking (leading) eye movements
• spiking (saccadic) eye movements.

Smoking reduces the severity of adverse drug reactions, which has been confirmed mainly for akathisia.

Treatment of nicotine dependence

In the general population, the first-line treatment for nicotine depend ence (according to the FDA) is nicotine replacement therapy (gum, patches, nasal sprays, inhalers and tablets) and bupropion. Varenicline, clonidine and nortriptyline have also been used, although there is no clear evidence of the efficacy of these drugs. The following are being considered: iMAOs (selegiline), SSRIs (fluoxetine), opioid receptor antagonists (naltrexone), dopamine agonist (bromocriptine), antagonist rec. nicotine antagonist (mecamylamine), cannabinoid receptor antagonist (rimonabant), cytochrome p-450 enzyme inhibitor (methoxsalen), nicotine vaccines, and drugs acting on the dopamine D2 receptor and μ opioid receptor genes.

The choice of pharmacological approach in people with schizophrenia may depend on the individual clinical symptoms of addiction or schizophrenia. The aim is complete smoking cessation or partial reduction. Medication may alleviate abstinence symptoms or nicotine craving, and may also act on positive symptoms, negative symptoms, cognitive deficits cause a reduction in extrapyramidal symptoms.

Nicotine replacement therapy (NRT)

A therapy accepted by the FDA as effective and safe for the treatment of nicotine dependence. It prevents withdrawal symptoms and nicotine craving. Additionally in schizophrenia:

1. improves neuropsychological disturbances that are associated with schizophrenia (by affecting nicotinic receptors; this effect may not be permanent due to the tachyphylaxis phenomenon that occurs in some cases),
2. prevents exacerbation of psychotic symptoms associated with nicotine withdrawal,
3. prevents exacerbation of adverse effects of neuroleptics.

Studies conducted between 1991 and 2006 confirmed the efficacy of NRT in this group of patients. NRT was shown to result in a significant reduction in smoking compared to placebo. After 6 months of 10-week NRT, about 40% of patients maintain their smoking reduction and almost 13% quit cigarettes completely. Most of the studies did not confirm changes in positive and negative symptoms of schizophrenia or effects on side effects. However, one study showed that the use of a nicotine nasal spray for four weeks resulted in moderate improvements in attention and working memory. In another, it was observed that nicotine patches induced a dose-dependent reduction in haloperidol side effects, mainly concerning memory functioning. In another, attention was shown to improve after NRT administration in schizophrenics who had never smoked, while it decreased in those who achieved abstinence. In yet another, the incidence of dyskinesias was found to increase during such treatment. The effectiveness of NRT is enhanced by concurrent behavioural-cognitive therapy (CBT).

Bupropion SR

In 1997. The FDA approved bupropion SR for the treatment of nicotine dependence. The drug's efficacy is predicated on its dopamine and norepinephrine reuptake inhibitory properties. It has also been described as a non-competitive nAchR antagonist in the CNS. The main mechanism of action of bupropion is to prevent and attenuate withdrawal symptoms. As the drug acts on the nicotinic receptor, it thereby reduces the reinforcing effects of nicotine. In patients with schizophrenia, bupropion may have an additional therapeutic effect - in some studies it has been shown to improve some symptoms of the illness: it has positive effects on attention, mood and locomotor activity.

The first experience of such treatment is a case report from 1999. a 41-year-old patient treated with clozapine and bupropion at a dose of 150 mg/d not only stopped smoking, but his psychotic symptoms remained under control and clozapine could be reduced from 550 to 300 mg/d. A pilot open-label study with bupropion and group therapy showed a reduction in smoking and a concomitant lack of worsening of neuropsychological symptoms. A follow-up study showed that after 3 months, the group treated with bupropion and CBT achieved a 66% reduction in smoking, while the placebo and CBT group achieved an 11% reduction. There was also an improvement in negative symptoms following the drug, with no worsening of positive and depressive symptoms. In the study with bupropion 300mg/d, abstinence rates were calculated to be 50%, compared with 12.5% for placebo. The drug was more effective in patients taking atypical neuroleptics. Another study not only confirmed the efficacy of bupropion 300mg/d vs placebo, but also showed a trend towards improvement in depressive and negative symptoms, and no effect on extrapyramidal symptoms.

It is therefore an effective drug and appears to be safe - no studies have described a serious side effect of the drug. The efficacy of bupropion in this group of patients may be increased by the concomitant administration of NRT, as demonstrated in one study. It may also be increased by the administration of second-generation neuroleptics. It should be borne in mind that BUP is an inhibitor of the cytochrome p450 isoenzyme 2D6 and interacts with antipsychotics metabolised by this isoenzyme.

Antipsychotics

They have been studied in the context of nicotine dependence because:

1. they improve symptoms of schizophrenia and therefore reduce smoking associated with certain symptoms of this illness,
2. they can improve cognitive function and thus enhance the patient's cooperation in taking medication and participating in psychotherapy,
3. have a direct effect on the reward system by acting on the nicotinic and dopamine systems, thereby reducing withdrawal symptoms and nicotine craving.

Interactions between antipsychotic drugs and nicotine and substances in tobacco smoke, mainly PAHs, should always be considered. Polycyclic aromatic hydrocarbons (PAHs) induce hepatic microsomal enzymes (CYP-1A1, 1A2, 2E1) and thus reduce the concentration of most neuroleptics: olanzapine, clozapine, flufenazine, haloperidol and chlorpromazine. People who smoke therefore require higher doses of neuroleptic. When smoking is discontinued, the concentration of the antipsychotic drug in the blood may be increased, which in turn results in increased side effects. PAHs also affect the metabolism of other drugs, including: imipramine, clomipramine, fluvoxamine, trazodone, alprazolam, lorazepam, oxazepam and diazepam.

The type of neuroleptic itself also influences smoking intensity. In one study, haloperidol use was shown to increase smoking. When some patients were switched from haloperidol to clozapine, there was a 25-35% reduction in smoking. In another study, the classical neuroleptic was changed to clozapine and a reduction in the number of cigarettes smoked per day was observed. Smoking occurred less frequently in the group of patients treated with clozapine than in the group treated with any classical or atypical neuroleptic. In addition, patients treated concurrently with risperidone and clozapine smoked significantly less than those treated with risperidone alone. Olanzapine can also alleviate nicotine craving. At the same time, it causes significant memory impairment and is therefore recommended in combination with NRT. However, antipsychotics that block the 5HT2 receptor, mainly olanzapine, limit the cognitive improvements associated with NRT use.

Other medications

The efficacy of treating nicotine dependence with other drugs, including varenicline, rimonabant and nalterxone, has not yet been studied in schizophrenia patients. SSRI drugs have not been evaluated for this purpose, although there is a possible benefit among certain groups of smokers, such as those with depressive or negative symptoms. Selegiline appears to be effective and safe in the general population, so may be beneficial in schizophrenic patients with negative and extrapyramidal symptoms. Mecamylamine may reduce the reward effect after nicotine, however, at the same time worsening schizophrenic symptoms. Topiramate also requires further research on this topic.

Nicotine dependence in schizophrenia, photo by shutterstock

Summary

Management of a patient with schizophrenia who wishes to quit smoking should begin with education about the effects of smoking and treatment options. The patient's motivation to quit should be assessed and the severity of the addiction assessed. The next step is to select an appropriate form of therapy. First-line treatment, as in the general population, is NRT (up to 40 mg/d) or bupropion SR (150-300 mg/d) or a combination of both. If ineffective, varenicline, clonidine or other drugs may be considered. Concurrent group therapy, especially CBT, motivational therapies, the use of techniques aimed at improving neurocognitive deficits, and social skills training are beneficial. The choice of the right antipsychotic drug is also important.Atypical drugs are not only more effective than classical drugs in treating nicotine dependence, but also have fewer side effects, regardless of smoking status. When the patient wishes to stop smoking, clozapine is the most effective drug. Haloperidol is not recommended - it increases smoking and causes a dose-dependent deterioration of motor function and attention. It is always necessary to monitor the patient's clinical condition during therapy and to make any dose adjustments.