The goals of schizophrenia treatment differ according to the phase of illness. Early intervention is a key to more a favorable prognosis for patients since the duration of untreated psychosis is associated with worst treatment response, poor symptom control, and worse overall functional outcome for patients with schizophrenia¹.

Remission and recovery are the ultimate goals for patients with schizophrenia, although these concepts may mean different things in different stages of the disease. Remission of psychotic symptoms within the first year of treatment occurs in 70%-80% of individuals⁶ and remains stable with ongoing comprehensive treatment⁷. However, there is a high percentage of relapse (80%) that is largely attributable to discontinuation of antipsychotic medication rather than to the effects of the disease process^8,9. Recovery, which is defined as sustained symptom remission with social and vocational improvement is realized by 15% of patients¹⁰.

Antipsychotic medications have been the foundation of treatment in schizophrenia since the discovery of chlorpromazine over 60 years ago.

All antipsychotics act to block dopamine pathway receptors¹². The early agents, which are classified as first-generation (or typical) antipsychotics, all predominantly act by blocking dopamine D₂ receptors. Studies have demonstrated that antipsychotic effects are associated with striatal D₂ receptor occupancy of 65%–70%, while D₂ occupancy greater than 80% significantly increases the risk of extrapyramidal symptoms. Later agents, which are classified as second-generation (or atypical) antipsychotics, have diverse pharmacology, but most have lower affinity for dopamine D₂ and higher affinity for other neuroreceptors, (particularly serotonin [5-HT] 2_A)than the first-generation agents have^13,14. Other sites of action for the second-generation agents include dopamine receptors other than D₂ (D₁,D₃,D₄), serotonin receptors (5-HT_1A, 5-HT_2C, 5-HT₆,5-HT₇), and muscarinic, cholinergic, and histamine receptors.

Antipsychotics are more effective than placebo in treating total psychopathology in schizophrenia¹⁵. Although the first-generation agents  vary in potency and pharmacological properties, they are similarly effective in treating positive symptoms and preventing their recurrence¹³. Nevertheless, due to severe side effects, they are not the first choice in the treatment of schizophrenia any more. Second-generation antipsychotics are the agents of choice². They are at least as effective as first-generation agents, although superior efficacy versus typicals is debated^14,16. In one meta-analysis, only 4 of the 9 atypical antipsychotics that were evaluated were better than the typical agents in overall efficacy; the others were not more efficacious, not even on negative symptoms¹⁷. Other meta-analyses^18–20 and effectiveness studies^21,22 have also found no clear evidence that atypical antipsychotics were more effective than typical agents in treating overall schizophrenia psychopathology.

Increasingly, atypical antipsychotic drugs with more diverse mechanisms of action are being used for the treatment of schizophrenia in recognition of some efficacy (eg, negative, cognitive, and mood symptoms) and side effect advantages, as well as an appreciation that D2 receptor stimulation is not the only means to treat psychosis.

There are a number of safety and tolerability issues associated with existing treatments²³. The most frequently reported or observed antipsychotic side effects identified in a meta-analysis were sexual dysfunction, metabolic problems, and weight gain, with a longer duration of treatment associated with more severe long-term side effects such as diabetes and metabolic syndrome²⁴.

All of the first generation antipsychotics can produce extrapyramidal symptoms at therapeutic doses, including parkinsonism, dystonia, akathisia and tardive dyskinesia, and increase serum prolactin concentration in the usual clinical dose range¹³. Although the second-generation agents as a class have lower incidences of extrapyramidal symptoms and tardive dyskinesia than the first generation agents, individual second-generation agents are associated with a greater likelihood of other adverse events that were less of an issue with the first generation agents. Issues such as increased risk of weight gain, diabetes mellitus, prolonged QTc interval, and possible secondary cardiovascular complications are more likely with some second-generation agents^13,24.

Psychosocial treatments can help improve functioning, including self-care, independent living skills, quality of social relationships, and the capacity to work or go to school. Although treatment of schizophrenia requires pharmacotherapy to be maximally effective, various psychosocial therapies are useful adjuncts to drug treatment¹³. Psychosocial interventions in schizophrenia target specific domains including core psychopathology (eg, symptoms, cognitive impairment), psychosocial functioning (eg, role functioning, social relationships, self-care), and comorbid conditions (eg, substance abuse, posttraumatic stress disorder, physical health conditions)²⁵.

Recommended non-pharmacologic practices comprise assertive community treatment, supported employment, cognitive behavioral therapy, family-based services, token economy, skills training, psychosocial interventions for alcohol and substance use disorders, and psychosocial interventions for weight management²⁶. Additional areas of interest for intervention that do not currently meet the criteria for an evidence-based practice include cognitive adaptive therapy, first-episode psychosis intervention, interventions targeting older individuals, peer support services, physical disease management, prodromal stage intervention, social cognition training, supported education, and supported housing^25,26. Some of these interventions are specifically tailored to patient age or stage of illness and may prove to be particularly helpful to patients across the course of the disorder.

Although antipsychotics are the bedrock of treatment for patients with schizophrenia, not all agents effectively treat all patients with schizophrenia or all symptoms of schizophrenia. For example, approximately 20% to 30% of patients do not respond to antipsychotic therapy. Additionally, 40% of patients have prominent negative symptoms and 80% of patients have clinically relevant cognitive impairment that are generally not responsive to treatment. This suggests that schizophrenia is associated with significant unmet medical needs, functional impairments, and a high burden of illness despite treatment with antipsychotics^13,27,28. Lack of compliance with medications is one of major roadblocks to treatment success in schizophrenia. Non-adherence is common, with consequences including inadequate symptom control, relapse, hospitalization, and increased health care resource utilization and cost²⁹. Patients who discontinue antipsychotics may be 2- to 5-times more likely to relapse than other patients^8,30,31. Although the reasons for non-adherence to medication are complex (eg, patient attitudes towards drugs and illness, adverse effects, caregiver involvement³², lack of insight in to their illness)³³, the inability to remain on medication greatly jeopardizes the opportunity for remission and improved functioning in patients with schizophrenia.

Reference: Adapted from Llorca, P. M. Partial compliance in schizophrenia and the impact on patient outcomes. Psychiatry Res. 161, 235–247 (2008)³⁴