Schizophrenia is a chronic brain disorder that is a prototypical psychiatric illness preventing 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 impairment of reality result in social and functional decline. Schizophrenia typically begins around 21 years of age in men and 27 years of age in women. This population is at high risk for suicide; approximately one-third of people with schizophrenia attempt suicide and 10% will die by suicide.1

Medical management of schizophrenia is aimed at addressing positive and negative symptoms of the disease, disorganized behavior, and cognition. Treatment includes atypical and typical antipsychotic medications. Clozapine is a third-line atypical antipsychotic administered to patients with schizophrenia who are often refractory to other treatment.2 Balancing the therapeutic window of the drug clozapine and the management of the symptoms is challenging.

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

The relationship between treatment and smoking is often overlooked and individuals are either under-dosed or drug levels are too high potentially leading to toxicity. Maintaining a therapeutic level of clozapine is impacted by smoking.

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Treatment-Resistant Schizophrenia

Schizophrenia that is not well managed may present with a number of psychological issues, including:

  • Psychosis
  • Command auditory and/or visual hallucinations
  • Poverty of thought, thought blocking, persecutory thoughts (being monitored)
  • Grandiosity (possess special powers)
  • Bizarre (believe in things that are not there)
  • Referential (messages from the television or radio)
  • Somatic complaints (beliefs in non-existing illness).

Avoidance of eye contact, preoccupation with something in their environment that is not visible to others, talking to themselves, and internal stimulations becomes more pronounced. Inability to sleep becomes a concern and can increase the individual’s level of psychosis.

Schizophrenia may be accompanied by other mental illnesses, such as depression or dementia that may worsen the behaviors and induce restlessness, confusion, and concerns for the individual’s safety. The differential diagnosis must rule out other medical causes of the presenting symptoms, including delirium, infection, tumor, endocrine and/or metabolic disorders, traumatic brain injury, neurologic disease, or intoxication. In addition, a careful history should rule out substance-induced psychosis secondary to the use of cocaine, methamphetamines, hallucinogens, synthetics, bath salts, or alcohol. A careful medication history should also rule out the use of opioids, prescribed medications, steroids, or over the counter anticholinergics. 


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

Table 1. The Dopaminergic Pathways3

Dopaminergic PathwayOriginatesRole and Impact
Nigrostriatal pathwaySubstantia nigraModulates movement.
Mesolimbic pathwayVentral tegmental area (VTA)Reward pathway and influences positive symptoms (delusions and hallucinations).
Mesocortical pathwayVTA to the cortex of the brain. The dorsolateral prefrontal cortex is part of the frontal lobe.Motivation, cognition, control and emotional responses.
Tuberoinfundibular pathwayHypothalamus to the pituitary glandIncrease in prolactin can lead to galactorrhea, amenorrhea and reduced libido.