Drugs used to manage schizophrenia

Schizophrenia is a disorder of the mind that is debilitating and chronic. The prevalence of this disorder is about 1% of the population and seems to affect all areas of the globe equally. It is not well understood what causes the disorder. Some combination of genetic and environmental factors contributes toward the development of this disease, which is characterized by an alteration of brain structure and chemistry mainly involved in dopamine and glutamate pathways.

Symptoms include hallucinations, delusions and disorganized thoughts and behaviors that cause an individual to withdraw socially and exhibit psychosis such that they are unable to differentiate the hallucinations and delusions from reality. As with most diseases, schizophrenia can range in severity. Some individuals exhibit mild symptoms and are able to live relatively normal lives while others exhibit severe symptoms requiring hospitalization and specialized care.

Symptom onset typically begins in early adulthood. Diagnosis is made based upon the symptoms exhibited instead of on lab tests. The Diagnostic and Statistical Manual of Mental Disorders, 5^th Edition (DSM-5) lists the criteria by which a schizophrenia diagnosis is made. DSM-5 lists both positive and negative symptoms of the disease, which are included below.

Positive Symptoms

• Hallucinations – sensing things that are not real (hearing voices, seeing things)
• Delusions – believing things that are not real (the doctor is poisoning me through my medications)
• Disorganized thoughts/behaviors – incoherent speech, purposeless behavior, difficulty communicating thoughts (jumbling words together meaninglessly or stopping in the middle of a sentence)

Negative Symptoms

• Loss of interest in everyday activities
• Lack of emotion
• Poor hygiene
• Social withdrawal
• Loss of motivation
• Lack of speech

Schizophrenia is believed to be a disorder involving abnormalities in brain chemistry. Patients with schizophrenia have elevated dopamine levels within certain parts of their brain and also altered glutamate levels. The role of glutamate is not well understood, so treatment primarily involves blockade of dopamine receptors. Newer agents also block other receptors including serotonin, but as the pathophysiology of the disease is not fully understood, it is unclear how alteration of other neurotransmitter pathways exert therapeutic effects. Drugs are effective at treating positive symptoms of the disorder, but often are poor at treating the negative symptoms. If negative symptoms do respond to treatment, they typically take longer to correct compared with positive symptoms.

First Generation Antipsychotics (FGAs) such as chlorpromazine, thioridazine, perphenazine, thiothixene, and haloperidol work primarily by blocking dopamine (D₂) receptors and also block serotonin (5-Hydroxytryptamine) receptors in the brain to a lesser extent. Most first generation antipsychotics carry a risk of extra-pyramidal symptoms (EPS), sedation, orthostatic hypotension, tachycardia and anticholinergic effects. Other side effects include weight gain and sexual dysfunction. In addition, thioridazine and haloperidol carry risks of QT prolongation.

Second Generation Antipsychotics (SGAs) such as clozapine and aripiprazole work by blocking D₂ and serotonin receptors; however, some agents have additional mechanisms of action. Aripiprazole, brexpiprazole and cariprazine are D₂ and serotonin 5-HT_1A receptor partial agonists. Brexpiprazole also acts as a serotonin 5-HT_2A antagonist. SGAs have multiple unwanted effects including metabolic side effects (hyperglycemia, weight gain and lipid abnormalities) and increased prolactin levels (risperidone and paliperidone) causing gynecomastia, irregular menstrual cycles, and sexual dysfunction. QT prolongation is a concern with ziprasidone, quetiapine and risperidone. Clozapine is one of the most effective agents for treatment resistant schizophrenia, but carries a host of black box warnings for seizures, agranulocytosis, myocarditis and metabolic abnormalities. As a result of clozapine’s side effects, absolute neutrophil count and white blood cell count must be monitored at baseline before initiation of the medication, periodically thereafter as long as the patient remains on therapy, and for 4 weeks after therapy is discontinued. SGAs typically have a lower risk of EPS compared to FGAs, but they can still occur, especially at higher doses.

Some antipsychotic agents carry an increased risk of cerebrovascular effects (e.g. stroke) when used to treat dementia-related psychosis in elderly patients. 

Schizophrenia/psychosis is a concern in patients with Parkinson’s disease because agents used to treat Parkinson’s disease typically increase dopamine levels. Almost half of patients with Parkinson’s disease will experience hallucinations or delusions at some point during their treatment. Treating psychosis in these patients can be difficult because antipsychotics that antagonize dopamine receptors can worsen movement disorders in these patients. As a result, quetiapine is typically used because it carries the least risk of EPS among all antipsychotics. Additionally, pimavanserin can be used in this patient population because it treats psychosis by altering serotonin levels and does not affect dopamine levels, minimizing the risk of EPS and disrupting Parkinson therapy.

Medication adherence is poor among schizophrenia patients. Delusions can lead these patients to believe that the medication prescribed is actually poison; medication side effects can be difficult to tolerate, and disorganized thought patterns can lead to the belief that the medication is unnecessary, causing patients to stop taking prescribed therapies. To aid with adherence, some medications are available in formulations aimed to improve medication adherence. Long acting depot injections are popular and are available for several FGAs and SGAs; effects last between 2 weeks and 3 months per injection. Also, orally disintegrating tablets are popular methods in improving adherence; these tablets dissolve as soon as they reach the mouth and prevent “cheeking” of medications (storing medication in the cheeks and spitting out when medical professionals exit the room).

Finally, antipsychotics, especially FGAs, cause a variety of EPS ranging from akathisia (restless movements of extremities accompanied by anxiety), parkinsonism and tardive dyskinesias (TD). Akathisia is treated utilizing central anticholinergics such as diphenhydramine. It can also be treated with propranolol. Parkinsonism looks like Parkinson’s disease with tremors, rigidity and abnormal gait. It is caused by imbalance of dopamine levels in the basal ganglia and can be treated with central-acting anticholinergics, and more importantly the fine titration of the antipsychotic drugs. TD involves abnormal involuntary movements of the tongue, lips, face, trunk or eyes. If TD develops, the FGA must be discontinued and replaced with an SGA with low EPS risk such as quetiapine or clozapine. TD can be irreversible and the risk of it becoming irreversible affects the duration of the treatment.