Glutamatergic, GABAergic, and cholinergic neurotransmitters also influence schizophrenia.  Glutamate is an excitatory neurotransmitter that is released by nerve cells sending signals between cells and playing a role in memory and learning. GABA is an inhibitory neurotransmitter that contributes to vision, motor control, cortical functions and regulation of anxiety. Cholinergic neurotransmitters use acetylcholine, a chemical that motor neurons release in order to activate muscles. They are often referred to as neuromodulators.4 Deficits in acetylcholine can affect REM sleep. The interplay of neurotransmitters and change in the balance of dopamine can lead to the psychosis in schizophrenia and other symptoms.4,5  

Three distinct symptoms characterized schizophrenia: positive, negative, and cognitive. Positive symptoms (delusions and hallucinations) improve with typical or atypical antipsychotic medications. Negative symptoms such as social withdrawal, lack of motivation, cognitive impairment, impaired social interactions, attention deficits, and changes in executive functioning present more challenges.3 Common negative symptoms include a diminished emotional expression, avolition that decreases goal – directed behavior, anhedonia and alogia. The prefrontal cortex (PFC) suggests hypofunction that accounts for cognitive impairment.

Genetics play a role in schizophrenia. If both parents have schizophrenia the likelihood of their children having schizophrenia is 40%.1,6 Environmental factors have also been thought to influence the etiology of schizophrenia, such as obstetric complications like low birth weight, pre-eclampsia, and hypoxia. Exposure to infections may compromise neurodevelopment with the thought that the mother’s immune response to the infection is producing cytokines.7

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The Role of Cigarette Smoking

Cigarette smoking is often referred to as a means of self-medication to mask or relieve the symptoms of schizophrenia. In the United States, approximately 25% to 30% percent of the overall population are smokers, while the incidence of smoking among patients with schizophrenia is almost 90%.8 Patients with chronic schizophrenia will spend 27% of their income on cigarettes and smoke 20 to 40 cigarettes per day.8

The life expectancy of patients with schizophrenia is between 15 and 20 years less than people without schizophrenia.1,6 Cardiovascular disease is the leading single cause of death in people with schizophrenia.9 Causal factors include lifestyle, lack of physical activity, poor diet, substance use, and smoking.

Nicotine imitates the neurotransmitter acetylcholine, which binds to a specific acetylcholine receptor known as the nicotinic receptor. Both acetylcholine and nicotine cause ion channels to open and excite the cells, and over time, the cells to close preventing the passage of neurotransmitters.5 The inhalation of nicotine causes an up-regulation and increases the availability of the nicotinic acetylcholine receptors throughout the brain. Chronic smokers maintain a high concentration of nicotine and deactivate the receptor. When smokers have periods when they are not consuming nicotine, such are during sleeping hours, the concentration of nicotine drops opening the cholinergic pathways to the brain. The lack of nicotine may lead to agitation leading to smoking another cigarette.

Nicotine-Clozapine Conundrum

Clozapine is an atypical antipsychotic used for treatment of resistant schizophrenia and to reduce recurrent suicidal behaviors.3 Treatment-resistant schizophrenia is reported in 20% to 30% of all patients diagnosed with the mental illness.10 Clozapine is commonly used with patients who demonstrate violent, aggressive behavior accompanied by psychosis.

Clozapine was first used and approved in Europe in the 1960s.11 In 1976, however, a Finnish study reported that 8 out of 17 fatalities were due to agranulocytosis caused by the drug and the drug was removed from use in the United States.12 In 1990, the United States re-instated clozapine but with a mandated blood test monitoring program.11White blood counts and absolute neutrophil counts (ANC) must be monitored and maintained at safe levels.13

Two landmark studies, the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) and CUtLASS (Cost Utility of the Latest Anti-psychotic Drugs in Schizophrenia Study),14 established clozapine as a treatment option of patient who have failed 2 or more antipsychotic medications.10

Clozapine is metabolized by the liver by way of the cytochrome P450 system by stimulating the CYP1A2 enzyme.4,9 Absorption is complete through oral administration and oral bioavailability is around 60% to 70% due to first-pass metabolism.3The estimate half-life is 14 hours.4

The presence ofCYP1A2 enzyme may increase or decrease the metabolism of clozapine. Smoking increases the metabolism of clonidine through the CYP1A2, which may require the dose to be doubled to have the same plasma concentration compared to a non-smoker.6  Patients with schizophrenia who smoke often have higher hospitalization rates and more symptoms, like hallucinations and delusions during acute episodes. When hospitalized and the dose of the medication is routinely increased the symptoms will subside. (Table 2)

It has been suggested that there is a relationship between the class of antipsychotic and smoking. Patient taking typical antipsychotics, such as haloperidol, chlorpromazine, and thioridazine tend to smoke more than patients taking atypical antipsychotics, such as clozapine, risperidone and olanzapine.4 Patients who switch from a typical to an atypical antipsychotic will decrease their level of smoking.4