Treatment-resistant schizophrenia: effects of smoking on clozapine and health

Schizophrenia is a chronic brain disorder that is a prototypical psychiatric illness that prevents a person from interpreting reality. Schizophrenia is a severe disabling psychiatric condition involving disturbances in speech, thought, perception, appearance, and behavior that must be present for at least 6 months.1 Neurocognitive changes and reality alteration lead to social and functional decline. Schizophrenia usually begins around the age of 21 in men and 27 in women. This population is at high risk for suicide; about a third of people with schizophrenia attempt suicide and 10% die by suicide.1

The medical management of schizophrenia aims to address the positive and negative symptoms of illness, disorganized behavior, and cognition. Treatment includes atypical and typical antipsychotic drugs. Clozapine is an atypical third-line antipsychotic administered to schizophrenic patients who are often refractory to other treatments.2 Balancing the therapeutic window of the drug clozapine and symptom management is a challenge.

Smoking prevalence is high in people diagnosed with schizophrenia and may affect treatment. Stronger cigarettes, starting to smoke at a younger age, and smoking more are thought to decrease negative symptoms of the disease and improve cognition.2 However, tobacco smoke affects the plasma concentration of clozapine. A polycyclic aromatic hydrocarbon found in tobacco smoke induces hepatic cytochrome P450 CYP1A2 enzymes, which is important to understand when prescribing this medication.

Continue reading

The relationship between treatment and smoking is often overlooked and individuals are underdosed or drug levels are too high, which can lead to toxicity. Maintaining a therapeutic level of clozapine is impacted by smoking.

Treatment-resistant schizophrenia

Schizophrenia that is not well managed can present with a number of psychological problems, including:

  • Psychosis
  • Order auditory and/or visual hallucinations
  • Thought poverty, thought blocking, persecutory thoughts (under supervision)
  • Grandiosity (has special powers)
  • Weird (believing in things that don’t exist)
  • Repository (television or radio messages)
  • Somatic complaints (beliefs in a non-existent disease).

Avoidance of eye contact, preoccupation with something in their environment that is not visible to others, self-talk, and internal stimuli become more pronounced. The inability to sleep becomes a concern and can increase the individual’s level of psychosis.

Schizophrenia can be accompanied by other mental illnesses, such as depression or dementia, which can worsen behaviors and lead to agitation, confusion and concerns for the individual’s safety. The differential diagnosis should exclude other medical causes for the presenting symptoms, including delirium, infection, tumor, endocrine and/or metabolic disorders, traumatic brain injury, neurological disease, or intoxication. Additionally, a careful history should rule out substance-induced psychosis secondary to the use of cocaine, methamphetamines, hallucinogens, synthetics, bath salts, or alcohol. A careful medical history should also rule out the use of opioids, prescription drugs, steroids, or over-the-counter anticholinergics.


Schizophrenia is influenced by brain chemistry, genetics, and environmental factors. The pathophysiology represents dysregulation of several pathways to include dopaminergic (Table 1),3 glutamatergic, gamma-aminobutyric acid (GABAergic) and cholinergic neurotransmitters. Abnormal activity at the dopamine (D2) receptor site contributes to most disease-related symptoms.

Table 1. Dopaminergic pathways3

Dopamine pathway Native Role and impact
Nigro-striatal way black stuff Modulates movement.
Mesolimbic pathway Ventral tegmental area (VTA) Reward pathway and influences positive symptoms (delusions and hallucinations).
Mesocortical pathway VTA to the cortex of the brain. The dorsolateral prefrontal cortex is part of the frontal lobe. Motivation, cognition, control and emotional responses.
Tuberoinfundibular route Hypothalamus to pituitary gland Increased prolactin can lead to galactorrhea, amenorrhea, and decreased libido.

Comments are closed.