Smoking and Schizophrenia – Neurobiology of Nicotine Dependence | Smoking Cessation Treatments

EPIDEMIOLOGY OF SMOKING IN SCHIZOPHRENIA

More than 50% of patients with schizophrenia are tobacco smokers, consistent across the patient population, from first-episode psychosis to treatment-resistant schizophrenia. [Fond et al 2017]; [Dickerson et al 2018]; [Oluwoye et al 2019]

Compared with people who have not been diagnosed with schizophrenia, there are differences in nicotine dependence behaviours (e.g., puff volume and duration). [Šagud et al. 2018]

• Tobacco smoking is a crucial risk factor for the development of metabolic syndrome [Kang and Song 2015]. This association is stronger for heavy smokers than for low or moderate smokers.
• Nicotine dependence doubles the mortality risk in patients with schizophrenia, notably through its harmful association with coronary heart disease and stroke. [Dickerson et al 2018]; [Hackshaw et al 2018]
• The incidence of lung cancer in patients with schizophrenia is also more than 4x higher than in the general population [McGinty et al. 2012], whilst the mortality risk from lung cancer is 2x higher in patients with schizophrenia compared to the general population. [Tran et al. 2009]

NEUROBIOLOGY OF SMOKING IN SCHIZOPHRENIA

Foetal exposure to nicotine via maternal smoking is linked to an increased risk of schizophrenia in later life. [Niemelä et al. 2016]

Similarly, for those who start smoking before age 13, there is also an increased risk of psychosis in later life. [Mustonen et al 2018]

Together, this indicates that smoking can not only be considered a risk factor for schizophrenia but that there is a shared neurogenetic background.

Furthermore, it has also been proposed that patients with schizophrenia have an enhanced reinforcing effect towards nicotine due to deficits in reward processing and alterations in reward-related circuits that are characteristic of negative symptoms in schizophrenia. [Whitton et al 2015]; [Moran et al 2017]

This may underpin the enhanced susceptibility to tobacco smoking in schizophrenia.

Nicotine addiction and schizophrenia are both polygenic and multifactorial disorders, and research has shown that there are 52 shared genes between the disorders. [Hu et al. 2018]

Neurobiological correlates of Smoking in Schizophrenia: [Lucatch et al., 2018]

Dopaminergic Hypothesis: 

• Nicotine activates β2- Nicotinic acetylcholine receptors (nAChRs) on Ventral tegmental area (VTA) DA neurons facilitating dopamine (DA) release in the Nucleus Accumbens (NAc) and the dorsal striatum. [Schmidt et al, 2019]
• The desensitisation of nAChRs in VTA reduces tonic DA release and increases phasic (burst) firing patterns of DA release associated with reinforcement and reward, moving from liking to wanting (addiction paradigm).
• The desensitisation of nAChRs in the striatum further increases the strength of the reward signal related to reinforcing behaviours due to increases in the concentration difference between tonic and phasic DA release. [Chen et al., 2019]
• Presynaptic striatal hyperdopaminergia is postulated to be involved in the pathogenesis of positive symptoms of schizophrenia. Thus, excessive dopaminergic activity due to nicotine activation by nAChRs can worsen positive symptoms.  [Pistillo et al 2015]
• D1 receptor dysfunction has been linked to cognitive deficits and negative symptoms in schizophrenia. Nicotine enhances dopaminergic transmission in the PFC, stimulating D1 receptors with resultant benefits on cognition and reducing negative symptoms.

Serotonin receptors (5-HT) type 2 and 6:

• Alterations in the serotonin neurotransmitter system are thought to contribute to the pathophysiology of schizophrenia.
• When nicotine binds to nAChRs, it is proposed that 5-HT receptors in brain areas involved in nicotine addiction are also influenced, thus promoting a vulnerability to addiction. [Rose et al. 2007]

Glutamatergic pathways (NMDA, AMPA, and kainate receptors):

• Glutamatergic system dysfunction (i.e., NMDA receptor hypofunction) has been proposed as a mechanism in the pathogenesis of schizophrenia.  [Read more about glutamatergic dysfunction in negative symptoms of schizophrenia]
• Nicotine increases extracellular glutamate levels in the VTA (via action on α7 nAChRs), stimulating NMDA receptors (NMDA-R).

Glutamatergic pathways control DA release and therefore modulate reward-relevant circuitry via two opposing mechanisms: [Schmidt et al., 2019]

1. NMDA-R activation on GABAergic interneurons inhibits DA release.
2. NMDA-R activation on DA neurons leads to a phasic burst-firing DA release. Increasing DA in the prefrontal cortex improves cognition.

• Nicotine-mediated increase in glutamate release does not desensitise during continuous administration of nicotine.
• Chronic nicotine exposure, however, can desensitise the GABAergic inhibitory feedback loop, thus enhancing dopamine activity and the reinforcing effect of nicotine. [D’Souza & Markou 2013]

GABA pathways:

• Nicotine induces GABA release by binding to excitatory nAChRs on presynaptic GABA neurons. This has anti-anxiety effects.
• However, chronic use results in desensitisation of nAChRs which reduces GABA release.  The decreased GABA release decreases GABAergic inhibition of the mesolimbic dopaminergic neurons leading to enhanced DA release. [D’Souza & Markou 2013]
• This enhanced DA release can worsen positive symptoms and anxiety.

Acetylcholine receptors (AChRs)

• Patients with schizophrenia have a reduction in nAChRs expression throughout brain regions central to higher cognitive functioning.
• Presynaptic nAChRs act as a filter on dopamine release probability depending on the activity in dopamine and striatal cholinergic neurons. [Exley & Cragg. 2008].
• The α4β2 nAChRs play a critical role in nicotine reinforcement via activation of the mesolimbic pathway.
• nAChRs interact directly and indirectly with the DA pathway (via GABA interneurons).
• nAChRs are very sensitive to desensitisation with exposure to nicotine, and nAChR occupancy is nearly complete after 1 cigarette. For chronic smokers, this may lead to almost complete high-affinity nAChR occupancy and desensitisation, and that smoking maintains this. [Picciotto et al, 2008]
• Short-term nicotine use is associated with enhanced tonic DA release, while chronic use leads to desensitisation of nAChRs amplifying burst phasic DA release associated with reinforcement. Nicotine acts on excitatory nicotinic acetylcholine receptors (nAChR) to mediate its rewarding effects. [Laviolette & van der Kooy, 2004]

SMOKING CESSATION: BARRIERS AND FACILITATORS

Two main factors are associated with increased tobacco smoking in patients with schizophrenia: the modulation of negative symptoms and the pro-cognitive effects of nicotine. [Wing et al. 2012]

Negative affect

• Research suggests that due to deficits in reward processing, there is a negative correlation between the reinforcement effects of nicotine and the role that negative affect has on increasing nicotine craving.
• Therefore, nicotine may ameliorate anhedonia in those with a blunted reward processing capacity. [Peechatka et al 2015]

Pro-cognitive effects:

• This pro-cognitive effect has only been observed in cases of schizophrenia and not in patients with depression or bipolar disorder. [Morisano et al 2013]
• However, several studies have found that when research is adequately controlled for, then smoking produces deficits in working memory, visual learning, and attention in patients with schizophrenia. [Harris et al 2004]; [Wing et al 2012]; [Reed et al 2016]

More recently, a systematic literature review and meta-analysis identified several additional factors in patients with schizophrenia that can act as barriers (e.g., stress management, liberal inpatient smoking policies, relieving boredom, and prevention of weight gain) or facilitators (e.g., health risk concerns, social pressure) to smoking cessation. [Lum et al. 2018]

Pharmacokinetic considerations: 

Another important consideration is the influence smoking has on the CYP450 system. The isoenzyme CYP1A2 is highly induced by smoking tobacco, and this is the main enzyme involved in the metabolism of the antipsychotics, clozapine and olanzapine.

Thus, smoking cessation has been associated with a 1.55-fold decrease in CYP1A2 activity and can result in drug toxicity. [Dobrinas et al 2011]

On the other hand, smoking can lead to a relapse or worsening of psychotic symptoms due to a reduction of medication levels but also direct effects on DA release. Thus dose adjustments may be needed depending on changes in the patient smoking status.

Impact of Smoking on Clozapine Levels – Management of Smoking Cessation in Clozapine Treatment

CURRENT PHARMACOTHERAPY OPTIONS FOR SMOKING CESSATION IN SCHIZOPHRENIA

Current pharmacotherapeutic options for smoking cessation modulate the nAChRs by both activation and antagonism.

For example: 

• The nicotine patch delivers nicotine with pharmacokinetics that favour the desensitisation of nAChRs.
• Varenicline is a partial agonist of α4/β2 nAChRs and activates α7-type nAChRs.
• Bupropion increases NA and DA but is also a non-competitive antagonist of nAChRs.

Partial agonism or antagonism of nAChRs aids smoking cessation by reducing the firing rate of VTA neurons (phasic bursts), decreasing cue-induced craving while maintaining the filtering effect on DA terminals (tonic DA) that allows other salient reward signals to induce DA release in the NAc. [Picciotto et al, 2008]

Smokers with schizophrenia spectrum disorders should be encouraged to quit smoking. They should receive varenicline, bupropion with or without nicotine replacement therapy, or nicotine replacement therapy, all in combination with behavioural treatment for at least 12 weeks. [Cather et al., 2017]

• Pharmacotherapy appears to play a more central role for smokers with schizophrenia, increasing the odds of quitting by 4–5 times, likely because the quit rate with behavioural treatment alone is so low.
• Varenicline appears to be the most effective treatment for smoking cessation in patients with schizophrenia.
• Both bupropion and varenicline do come with a boxed warning for neuropsychiatric severe adverse events, including but not limited to depression, suicidal ideation, suicide attempt, and completed suicide. Therefore close monitoring is recommended. These side effects should not prevent clinicians from prescribing effective smoking cessation therapies for patients with schizophrenia.
• Controlled trials in smokers with schizophrenia consistently show no greater rate of neuropsychiatric adverse events with pharmacotherapeutic cessation aids than with placebo. [Cather et al., 2017]

1. Nicotine Replacement Therapy NRT : (smokes within 30 mins of waking) [RACGP Smoking Cessation Guidelines]

a. Smoking < 10 /day and starts within 30 mins of waking 

Efficacy and safety

• A Cochrane database review showed that NRT with the transdermal nicotine patch (TNP) had unclear evidence supporting its use in smoking cessation. [Tsoi et al. 2013]
• However, TNP may help reduce the number of cigarettes per day and the relapse rate during maintenance, but the data supporting this is sparse.
• Overall, when NRT (TNP with short-acting forms such as gum, lozenges, and nasal spray) is combined with first-line pharmacologic treatments, the data consistently show a significant increase in rates of smoking cessation.  [Cahill et al. 2014]

2. Bupropion

• Dosing: 150 mg/day for the first three days, then increased to 150 mg BD. The patient should stop smoking in the second week of treatment.

Efficacy and safety: 

• The Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations state that patients with schizophrenia who want to quit or reduce cigarette smoking should be offered treatment with bupropion SR 150 mg BD for 10–12 weeks, with or without nicotine replacement therapy, along with a smoking cessation education or support group. [Kreyenbuhl et al 2010]
• Bupropion monotherapy, or in combination with NRT, is an efficacious treatment option for smoking cessation in patients with schizophrenia. [Evins et al 2007]; [George et al 2008]; [Anthenelli et al 2016]; [Brody et al 2017]
• Bupropion was well tolerated, and no worsening of symptoms (positive, negative, or depressive) in patients with schizophrenia treated with bupropion with or without NRT was identified.

3. Varenicline: 

• Varenicline is a partial α4β2 nAChR agonist and a full agonist of α7- and α3β4 nAChRs.
• Varenicline has the highest efficacy in smoking cessation in patients with and without psychiatric disorders. [Anthenelli et al 2016]; [Russo et al, 2022]
• Partial agonists moderately activate nAChRs releasing normal levels of dopamine to reduce nicotine withdrawal symptoms, but without the strong DA release and reinforcing action induced by nicotine.

Dosing:

• Set a date to stop smoking.
• Start varenicline 1–2 weeks before their quit date.
• Start at 0.5 mg/day (oral) for 3 days followed by 1 mg/day for four days.

Dose titration: [Champix PI]

• Days 1–3: 0.5 mg daily
• Days 4–7: 0.5 mg BD
• Day 8 – end of treatment – continue with 1 mg twice daily from day 8 to the end of a 12-week treatment course.

For patients who successfully stop smoking at the end of 12 weeks, continuing with 1 mg BD for a further 12 weeks is recommended to increase the chance of remaining abstinent at 1 year.

Efficacy and safety: 

• Research on varenicline in combination with behavioural support significantly improves smoking cessation and maintenance of abstinence in patients with schizophrenia or schizoaffective disorder.
• Trials on varenicline show it is well tolerated, with no reports of worsening of positive, negative, or depressive symptoms. [Weiner et al 2011]; [Williams et al 2012]; [Evins et al 2014]; [Ahmed et al, 2018]
• Varenicline increases the odds of quitting by a factor of 4–5 times in smokers with schizophrenia than in other populations of smokers. [Cather et al., 2017]

4. Neuromodulation:

•  rTMS has received FDA clearance as a smoking cessation aid for cigarette smokers.[Zangen et al., 2021]

5. Alpha-1 antagonist and Alpha-2 agonists:

• Prazosin (α1 antagonist) and Clonidine (α2 agonist) may reduce smoking relapse in human smokers by attenuating stress-induced reinstatement of nicotine seeking. [Yamada & Bruijnzeel. 2012] 
• Clonidine is better than placebo in promoting smoking cessation. [Gourlay et al., 2004]
• They are not approved as smoking cessation therapies, and there are no trials in patients with schizophrenia.
• Clinical Application of Prazosin & Clonidine – Role of Alpha (α) Adrenergic Receptors (α1 and α2)

6. E-cigarettes (Vaping)

• Vaping nicotine is an evidence-based option for reducing harm in smokers who are otherwise unable to quit.
• Since 1 October 2021, all nicotine vaping products have been prescription-only medicines across all Australian States and Territories.
• It is legal to possess and use nicotine liquid in Australia if the user has a prescription from a registered medical practitioner.

The RACGP smoking cessation guidelines state: [RACGP Smoking Cessation Guidelines]

For people who have tried to achieve smoking cessation with approved pharmacotherapies but failed, but who are still motivated to quit smoking and have brought up e-cigarette usage with their healthcare practitioner, nicotine containing e-cigarettes may be a reasonable intervention to recommend. 

• The Royal Australasian and New Zealand College of Psychiatrists (RANZCP) also supports nicotine vaping as a harm reduction tool for smokers who are otherwise unable to quit. [RANZCP Position Statement] 

Some of the benefits of vaping in individuals with schizophrenia are: [Mendelsohn, 2021]

• Modest positive effects on attention, working memory and sensory gating.
• Counter negative symptoms such as amotivation, withdrawal and blunted affect.
• Reduce the sedation from antipsychotics.
• Enable a reduction in the dose of some antipsychotic medications, notably clozapine and olanzapine (Vaping nicotine is not associated with CYP1A2 interactions).
• Alleviate boredom, facilitate socialising, improve social interaction and reduce isolation.
• In smoke-free psychiatric facilities, it may help to comfort distressed patients and alleviate boredom, aggression and the risk of injury to staff.
• In contrast to smoking, there is no evidence that passive vaping harms health.
• A high-strength nicotine e-cigarette has the potential to help people with schizophrenia spectrum disorders to quit or reduce smoking. [Pasquale et al, 2021]

CONCLUSION

A complex relationship exists between smoking and schizophrenia that is not explained by the self-medication hypothesis.

Patients with schizophrenia are vulnerable to nicotine addiction due to underlying neurobiological correlates.

Smoking nicotine has positive and negative effects on patients with schizophrenia. Smoking increases the mortality risk in patients with schizophrenia, so psychiatrists must consider proactive intervention to assist patients with harm reduction and smoking cessation.

Several treatment options are available, and previous concerns about significant worsening of neuropsychiatric symptoms are not founded.

Learn More: 

1. Neuropsychiatric Effects of Smoking in Schizophrenia By Prof David Castle
2. Smoking – Research Studies and Risks Associated With Vaping – Prof Colin Mendelsohn
3. Smoking – Health and Economic Costs – Professor Colin Mendelsohn