Schizophrenia Treatment

General Treatment Principles

• Choice of agent will be based on STEPS principle which means Safety, Tolerability, Efficacy, Price, Simplicity:
  • Will also consider side-effect profile, prior response history of patient or family member, patient preference and intended route of administration
• Maximize benefits of pharmacological therapy and minimize side effects
• Monotherapy is preferred and polypharmacy should be avoided
• For patients in the first episode of schizophrenia, aim for the lower end of the therapeutic effective dose range of antipsychotics then titrate according to efficacy and tolerability
• Antipsychotics remain the primary treatment for schizophrenia
  • Goal of resumption to baseline and maximal functioning, good quality of life, prevention of recurrence, integration back into the society 
  • Use with caution in the elderly because of increased risk of mortality from sudden cardiac death and cardiovascular accidents
  • Older, first-generation antipsychotics are generally considered to have minimal risk of teratogenicity

Atypical Antipsychotics

• Also called second generation antipsychotics 
• Atypical antipsychotics are now generally preferred over the conventional antipsychotics
• Effects: Have been found to be equivalent or superior to conventional antipsychotics for the treatment of psychotic symptoms and thought disorganization
  • Some may have superior effect on negative symptoms than conventional antipsychotic drugs
  • Most atypical antipsychotics have similar likelihood of causing extrapyramidal symptoms (EPS) as in conventional antipsychotics with lower-potency dopamine D₂ neuroreceptor blockade (eg Chlorpromazine, Thioridazine, Perphenazine)
• All patients are recommended to have regular monitoring of weight, body mass index (BMI), serum lipids and fasting glucose levels
• Atypical antipsychotics have been shown to cause weight gain and metabolic side effects

Amisulpride

• Appears to have benefits against negative symptoms at lower doses and at higher doses tends to be more effective against positive symptoms
• Has favorable side effects profile, but can cause hyperprolactinemia and higher doses increase risk for extrapyramidal symptoms occurrence

Aripiprazole

• Appears to be as effective as Haloperidol in the treatment of schizophrenia
  • May also be used for treatment of acute aggression in schizophrenia
• Extrapyramidal symptoms-related adverse effects have been shown to be comparable to placebo
• May have a higher risk of insomnia compared to conventional antipsychotics, but less risk of raised prolactin and prolongation of the QTc interval than other atypicals

Brexpiprazole

• Has been shown to be effective as conventional antipsychotics with acceptable clinical profile and adverse effects
• Has lower risk for cardiac events than other atypicals

Cariprazine

• A study has shown it to be effective in reducing negative symptoms of schizophrenia compared with Risperidone
• Associated with minimal effects on plasma prolactin level and weight gain
  

Clozapine

• Has been shown to be useful in patients who do not respond to conventional antipsychotics
  • Superior to conventional antipsychotics in terms of symptom reduction and risk of relapse
• Drug of choice in the treatment of chronic and severe aggression in schizophrenia
  • Studies have shown that patients maintained on Clozapine had fewer aggressive episodes and less suicide attempts compared with other antipsychotics
  • Should be considered if there is significant and continuously increased risk of suicide
• In patients who were diagnosed to have both schizophrenia and alcohol use disorder, Clozapine seems to be effective in reducing craving and substance intake
• Avoid use in patients with history of seizure as it may lower seizure threshold
• Licensed for use only in treatment of refractory schizophrenia due to life-threatening side effect
  • Clozapine causes agranulocytosis in approximately 1% of patients
  • Regular and careful monitoring of white blood cell (WBC) count is necessary
• Recommended for use in treatment-resistant schizophrenia patients

Iloperidone

• Studies have shown it to be effective in the acute and maintenance phase of therapy for schizophrenia
• It delays the time to relapse of symptoms of schizophrenia

Lurasidone

• A randomized, double-blind study revealed that Lurasidone is as effective as Olanzapine in improving positive and negative syndrome scale (PANSS) scores in acute psychotic schizophrenic patients
• Long-term treatment with Lurasidone has shown reduced risk of relapse in patients with schizophrenia
• Appears to be associated with minimal effects on body weight and low risk for clinically significant alterations in glucose, lipids or electrocardiogram parameters

Olanzapine

• At least as effective as conventional antipsychotics
  • May also be used for treatment of acute or chronic aggression in schizophrenia
• Generally well tolerated and does not tend to cause extrapyramidal symptoms at therapeutic doses
  • Major side effects are weight gain, hyperlipidemia as part of metabolic syndrome and hyperglycemia

Paliperidone

• Indicated for acute and maintenance treatment of schizophrenia in adults and adolescents (12-17 years of age) and adults with schizoaffective disorder
• It is not extensively metabolized in the liver
• Compared with other atypical antipsychotics, studies showed similar efficacy and lower odds of weight gain and undesirable metabolic side effects
• Major active metabolite of Risperidone

Quetiapine

• At least as effective as conventional antipsychotics in the treatment of schizophrenia
• Very rarely causes extrapyramidal symptoms at any dose
  • Orthostatic hypotension may occur during the initial titration period and at high doses
• May be used for the treatment of acute agitation

Risperidone

• At least as effective as conventional antipsychotics
  • Used as maintenance treatment following acute episode of schizophrenia
  • May also be used for treatment of acute aggression in schizophrenia
• When used at recommended doses (<6 mg/day), it has very low rate of extrapyramidal symptoms
  • Higher doses increase risk of extrapyramidal symptoms
  • Hyperprolactinemia and postural hypotension may also occur

Ziprasidone

• At least as effective as conventional antipsychotics
  • May also be used for treatment of acute aggression in schizophrenia
  • Has been shown to have beneficial effects on symptoms of depression
• Has been associated with prolongation of the QTc interval; dose needs to be adjusted based on therapeutic and side effects

Conventional Antipsychotics

• Eg Haloperidol, Perphenazine, Molindone
• All antipsychotics in this class vary in potency and overall side effects profile, but have similar overall efficacy
• Effects: Patients demonstrate a decrease in positive symptoms, thought disorder, blunted effect, withdrawal retardation and autistic behavior
  • 60% of patients treated for 6 weeks with conventional antipsychotics achieve complete remission or experience only mild symptoms
  • All conventional antipsychotics can cause a broad range of side effects due to their effects on receptors other than the target therapeutic site including extrapyramidal symptoms and tardive dyskinesia

Chlorpromazine

• Is a prototype antipsychotic
• Studies have shown its usefulness in prevention of relapse as well as part of maintenance therapy
• May be used in patients with concomitant psychosis and insomnia

Fluphenazine

• Long-acting preparation used for maintenance therapy
• Has minimal sedative, anticholinergic and weight gain effects

Haloperidol

• Has been shown to be useful in the management of acute aggression in schizophrenia
  • Most commonly used conventional antipsychotic in the emergency room setting
  • May be first-line agent in acute aggression especially if affordability is an issue
  • Cheaper compared with atypical antipsychotics
• Benzodiazepine may also be administered with Haloperidol to enhance the sedative effect

Loxapine

• Has been shown to be useful in the management of psychotic agitation in schizophrenia
• Has an aerosol formulation that is capable of reaching deep lung tissues

Molindone

• Studies have suggested that Molindone may be equally effective as atypical agents
  • A clinical trial, comparing Molindone with Risperidone and Olanzapine in pediatric patients with early-onset schizophrenia and schizoaffective disorder, showed no significant difference in terms of reduction of symptom severity

Perphenazine

• Studies have suggested that Perphenazine may be equally effective as atypical agents
  • A clinical trial, comparing Perphenazine with Risperidone, Olanzapine, Quetiapine and Ziprasidone in adult patients, showed Olanzapine was most effective in terms of rates of discontinuation, but overall efficacy was similar among the drugs; extrapyramidal symptoms were uncommon and metabolic side effects were most seen in Olanzapine use
• For some patients, conventional agents such as Perphenazine may be an appropriate first-line treatment

Route of Administration

Oral

• Typically used for acute and maintenance treatment
• Reaches peak concentration in 2-3 hours which gives a calming effect
  • May take several days-weeks to see the true antipsychotic effects

Short-Acting Intramuscular (IM)

• Quick onset of action is an advantage when calming effects are needed to treat agitation
• Peak concentration is reached in 30-60 minutes after administration

Depot Formulations (Long-acting Injectable)

• Recommended for patients who have trouble taking oral medications reliably, who deny illness or who have poor insight or for those who prefer depot
• Limited number of conventional and atypical antipsychotics are available in this form
• Require 2-4 months to reach steady-state therefore seldom used alone during acute treatment when the dose needs to be adjusted based on therapeutic and side effects

Acute Phase Treatment

Treatment Settings

• Outpatient versus inpatient treatment will depend on assessment of patient’s safety, safety of others and the patient’s level of functioning
• Inpatient treatment is indicated if the patient has a serious threat of harm to self or others, unable to care for self or needs constant supervision

Psychiatric Management

• Goals: Prevent harm, control disturbed behavior, suppress symptoms and return to the best level of functioning
• Build a therapeutic alliance with the patient and the patient’s family
• Educate the patient (to the best of their level of understanding) and the patient’s family/caregiver about the illness
• Establish short- and long-term treatment plans

Psychosocial Interventions

• Goals: Reduce overstimulating or stressful environments, relationships or life events
• Promote reduced disease arousal by giving simple, clear communications and expectations
• Help provide a structured and predictable environment which includes low performance requirements
• Help to establish non-demanding, supportive relationships between the patients and their treatment team

Repetitive Transcranial Magnetic Stimulation (rTMS)

• May be used in patients with principally auditory hallucinations
  • Effective in reducing frequency and intensity of auditory hallucinations, and improved quality of life

Stabilization Phase

Psychiatric Management

• Goals: Minimize stress on the patient and provide support to minimize chances of relapse
• Assist in the patient’s adaptation to life in the community
• Help in maintaining the continued reduction of symptoms and consolidation of remissions
• Continue to educate the patient about the course and outcome of the illness
• Promote adherence to treatment regimen by educating the patient and their families about the chances of relapse with discontinuation of medication

Psychosocial Interventions

• Psychoeducation to promote compliance
• Start on social and community interventions
  • Therapeutic community interventions
  • Rehabilitation eg social skills training, vocational training, cognitive-behavioral therapy (CBT), cognitive remediation therapy (CRT)
  • Self-help groups formed by patients, self-treatment organizations and relative organizations (formed mostly by patient’s parents)

• Individual therapy
  • Supportive and insight-oriented
  • Individualized approach based on clinical condition, coping capabilities and preferences

• Family interventions
  • Involve the family in treatment planning, goal setting and service delivery
  • Provide education, support, guidance and training to assist family members fulfill their role as caregivers
  • Support groups for families should be suggested
  • 10 sessions for a period of 3 months should be considered as the minimum effective dose

• Group therapy
  • Group psychotherapy and support groups help enhance problem solving, goal planning, social interactions and medication side effects