Schizophrenia

Schizophrenia is a serious mental health disease and one of the most disabling medical conditions. It is characterized by distortions in thinking, perceptions, emotions, speech, self awareness, and behavior. Schizophrenia symptoms may include hallucinations (such as hearing voices or seeing images that are not there) and delusions (fixed, false beliefs or suspicions). The World Health Organization ranks it as one of the top 10 illnesses contributing to the global burden of disease.

People with schizophrenia may also be burdened by additional health conditions such as depression, anxiety disorders, substance use and abuse, and a higher risk of suicide. It is treatable with medicines and psychosocial support, but patients often need assistance with housing, employment and mental health care access. Successful treatment can result in successful work, school and social environment, but people with schizophrenia require lifelong treatment and monitoring.

Schizophrenia is a "psychotic" disorder, but having psychosis does not mean you have schizophrenia. Psychosis is a symptom of other mental disorders, too. Psychosis can be defined as the inability to recognize reality.

• Individuals who have schizophrenia find it difficult to tell the difference between real and unreal experiences, to think logically, to have normal emotional responses to others, and to behave normally in social situations.
• Hallucinations, delusions, extremely disordered thinking and incoherent language, self-neglect and inappropriate behavior can hinder daily functioning, appropriate social interactions, the ability to work.
• Despite the perception of the general population, someone with schizophrenia is usually not aggressive and rarely poses a threat to the safety of others.

Antipsychotic medications are considered the first-line treatment for schizophrenia, which is enhanced with psychosocial support, housing assistance, and employment and educational strategies.

How many people have schizophrenia?

Schizophrenia is thought to affect around 20 million people worldwide, according to World Health Organization (WHO). In the U.S., approximately 3.2 million American adults (about 1.2% of the U.S. population age 18 and older) are affected by schizophrenia.

Causes of schizophrenia

Schizophrenia is a complex illness. A combination of genetics, environment, and altered chemistry may contribute to its development. Some researchers think that the brain may not be able to process information correctly. 

• Genetics: Genetic factors appear to play a role as people who have family members with schizophrenia may be more likely to get the disease themselves. But not all people with schizophrenia have a family member with the disease. If you have a sibling or parent with schizophrenia, you have a 10% risk of having the disease. If you have an identical twin with the this diagnosis, your risk increases to about 50%.
• Environment: Some researchers also believe that events in a person's environment can trigger schizophrenia. For example, problems during intrauterine development and birth may increase the risk for developing schizophrenia later in life. A stressor such as a toxin, infection or a nutritional deficiency may initiate the illness during key periods of brain development.
• Brain chemistry or structures: Hormonal changes or alterations in brain neurotransmitters (chemicals) like dopamine, glutamate, gamma-amino-butyric acid (GABA) or acetylcholine may be involved. Many medications used for treatment of schizophrenia target these neurotransmitters.

Psychological and social factors may also play some role in its prognosis. The level of social support and family engagement appears to influence the course of illness and may be protective against relapse.

Risk factors for schizophrenia

Schizophrenia appears to occur in slightly higher rates among men than in women (ratio of 1.4 to 1, respectively), but women have a later onset.

• Schizophrenia often first appears in men in their late teens or early twenties; for women onset is usually in their late twenties or early thirties.
• Males account for more than half of patients in services; there is also a high proportion of young adults.
• Cases of late onset of the disorder (in individuals aged over 45 years) are known.
• Childhood-onset schizophrenia can also begin after the age of 5 and, in most cases, after relatively normal development; but childhood schizophrenia is rare and can be difficult to differentiate from other pediatric developmental disorders of childhood, such as autism.

Other factors that may increase the risk of schizophrenia include a family history, pregnancy complications that may impact brain development (such as malnutrition, viruses or toxins), or the use of mind-altering drugs in youth.

Symptoms

People with schizophrenia may show a variety of symptoms.

Usually the illness develops slowly over months or even years. At first, the symptoms may not be noticed. For example, people may feel tense, may have trouble sleeping, or have trouble concentrating. They become isolated and withdrawn and they do not make or keep friends.

As the illness progresses, psychotic symptoms develop. The symptoms of schizophrenia fall into three major categories: positive, negative, and cognitive.

Positive Symptoms are psychotic behaviors not normally seen in healthy individuals; patients may "lose touch" with reality.

• delusions - fixed, false beliefs or thoughts with no basis in reality. An example might be thinking that impending harm or death may occur, that one is famous or loved by a celebrity, or beliefs that aliens are inhabiting one's house. These beliefs can be unusual or not.
• hallucinations - hearing (auditory), seeing (visual), feeling (somatic), smelling (olfactory), or tasting (gustatory) things that are not there. Hearing is the most common form of hallucination, occurring in 40% to 80% of people.
• disordered thoughts and speech - thoughts and speech "jump" between completely unrelated topics. The person may talk nonsense or answer questions with seemingly unrelated words (known as "word salad").
• disordered motor behavior - behavior can be childlike or agitated. Not able to follow instructions or set goals. Behaviors can include bizarre postures or excessive, useless movements.

Negative Symptoms are also called deficit symptoms, and encompass a disturbance of a patient's normal emotions and behavior. Negative symptoms can be primary or secondary. Secondary symptoms can be caused by antipsychotic medications or other environmental or mental health issues.

• flat affect - a reduced expression of emotions expressed by decreased facial expressions, tone of voice, eye contact.
• reduced speaking - avoidance of conversation or social withdrawal.
• apathy, lack of motivation - a decreased interest in activities, lack of attention to personal hygiene, lack of emotion.

Cognitive Symptoms are nonspecific and difficult to recognize; patients may notice a change in memory.

• disorganization - disorganized speech, thought, and/or attention
• attention - a trouble focusing on individual tasks
• communications skills - lack of ability to communicate
• memory - difficulty in understanding or remembering information to make decisions

Diagnosis

A diagnosis may involve a physical exam, special tests or images, a psychiatric evaluation, and a review of criteria used by doctors to evaluate your symptoms.

No one symptom is specific for schizophrenia. As outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the diagnosis of "schizophrenia spectrum disorder" involves the presence of at least two of the five symptoms below which are present for a minimum of a one-month period. General symptoms should have been present for at least 6 months. Delusions, hallucinations or disorganized speech must be one of the symptoms:

• delusions
• hallucinations 
• disorganized speech
• highly disorganized or catatonic motor behavior
• negative symptoms

In addition, a decreased level of functioning at work, interpersonal relationships, or self-care must be present for at least six months.

Other diagnoses that would account for the symptoms should be ruled out (such as: prescription or illicit drug use, other medical conditions, or a mood disorder coupled with psychosis).

It is important to differentiate symptoms and rule out other psychotic conditions with similar symptoms to schizophrenia, such as:

• Schizoaffective disorder
• Schizophreniform disorder (symptoms similar to schizophrenia but last less than 6 months)
• Major depressive disorder with psychotic features
• Bipolar disorder with psychotic features
• Substance abuse disorders

Patients with schizophrenia may also exhibit other heath conditions that occur at the same time as schizophrenia, including: panic disorder, anxiety, major depressive disorder and obsessive compulsive disorder.

Substance use and abuse is common in patients with schizophrenia, including alcohol, tobacco, illicit and prescription drugs.

Treatment options for schizophrenia

During an acute episode of schizophrenia, hospitalization is often required to ensure safety and to provide for the person's basic needs such as food, rest, and hygiene. Medications, counseling, and family support are all components of treatment.

Relapse rates are high in patients with schizophrenia and clinical follow-up, and family or community support, when available, are important to the patient's outcome.

When possible, and prior to treatment, patients should first be assessed for ongoing movement disorders, symptoms of metabolic syndrome, and for history of cardiac disease with a possible ECG, especially if using an antipsychotic drug that prolongs the QT interval such as clozapine (Clozaril), thioridazine, iloperidone (Fanapt), or ziprasidone (Geodon).

Drug Treatment

Antipsychotic medications work by changing the balances of chemicals in the brain and are used to control the symptoms of the illness. These are considered first-line agents in schizophrenia and are the central component of the treatment, both for the acute and maintenance phase.

They are usually taken in pill or liquid form, but skin patches and longer-acting injections are also options. Medications are typically continued indefinitely at the lowest possible dose to help prevent a return of symptoms. Antipsychotics are effective in about 75% of patients living with schizophrenia.

These medications are essential but they are also associated with many side effects that may discourage a patient from taking them regularly, in up to half of patients. In general, one agent is not superior over the other with the exception of clozapine for refractory schizophrenia.

Changing to a different antipsychotic may help to manage side effects but may not necessarily boost effectiveness. Long-acting agents may be an option for patients who have trouble with daily treatment. Switching to another agent with a more favorable side effect profile should be considered first if side effects are causing patients to skip treatment.

Antipsychotic agents are not approved for the treatment of dementia-related psychosis due to an increased risk of death.

List of Antipsychotics

Atypical Antipsychotics

Generic Name	Brand Name(s)
aripiprazole, aripiprazole lauroxil	Abilify, Abilify MyCite, Abilify Maintena, Aristada
asenapine	Saphris, Secuado
brexpiprazole	Rexulti
cariprazine	Vraylar
clozapine	Clozaril, Fazaclo
iloperidone	Fanapt
lumateperone	Caplyta
lurasidone	Latuda
olanzapine and samidorphan	Lybalvi
olanzapine	Zyprexa, Zyprexa Zydis
paliperidone	Invega
paliperidone palmitate	Invega Halfyera
pimavanserin	Nuplazid
quetiapine	Seroquel, Seroquel XR
risperidone	Perseris, Risperdal, Risperdal Consta, Risperdal M-Tab
ziprasidone	Geodon

Atypical antipsychotics, also called second generation antipsychotics, are the newer generation of antipsychotic treatment, although they have been available since the 1990s. They bind to a variety of receptor types, including serotonin, dopamine, adrenergic, cholinergic (muscarinic), and histamine receptors. Side effects of the individual agents are often associated with receptor types, and may help to direct prescribing.

Atypical antipsychotics are usually preferred over the older first generation (or typical) antipsychotics because they are less likely to produce movement disorders known as extrapyramidal side effects (EPS), which includes dystonia, akathisia, pseudoparkinsonism, and potentially irreversible tardive dyskinesia. However, metabolic effects including a significant risk of weight gain, type 2 diabetes, and elevated cholesterol (lipid) levels are more common with certain second generation agents.

Clozapine (Clozaril, Fazaclo) may have more benefit in treatment-resistant patients and in patients at risk of suicide or movement disorders, including tardive dyskinesia. Clozapine can lead to a risk of a serious side effect known as neutropenia, which is a low level of white blood cells that may increase your risk for severe infections and death. For safety, all patients, pharmacies and healthcare providers are enrolled in a special program called the Clozapine REMS Program to make sure the benefit of this drug outweighs any risks.

First Generation Antipsychotics

Generic Name	Brand Name(s)
chlorpromazine	Thorazine*
fluphenazine	Prolixin*
haloperidol	Haldol*
loxapine	Loxitane*
mesoridazine*	Serentil*
molindone*	Moban*
perphenazine	Trilafon*
prochlorperazine	Compro Suppositories
thioridazine	Mellaril*
thiothixene	Navane*
trifluoperazine	Stelazine*

^{*generic and/or brand discontinued in US}

First generation antipsychotics reduce dopaminergic neurotransmission by blocking D2 receptors, and differ in level of side effects compared to first generation agents. First generation agents are classified as the phenothiazines, the thioxanthenes, and miscellaneous agents such as haloperidol and loxapine.

First generation antipsychotics are more commonly linked with extrapyramidal symptoms (movement disorders). Second generation antipsychotics have a somewhat better safety profile regarding side effects overall, and, in general, are the preferred first-line drugs for this reason.

Latest Treatments for Schizophrenia

Paliperidone palmitate (Invega Hafyera)

In Sept. 2021, 6-month paliperidone palmitate (Invega Hafyera) from Janssen was approved to treat schizophrenia in adults. It is a twice-yearly injectable (dosed every 6 months) and is given as an intramuscular gluteal (upper buttocks area) injection by a healthcare provider.

• Before starting Invega Hafyera, patients must be adequately treated with Invega Sustenna (1-month paliperidone palmitate) for at least four months, or Invega Trinza (3-month paliperidone palmitate) for at least one 3-month injection cycle.
• It is given as an intramuscular gluteal injection by a healthcare provider. Dosing is based on the patient's previous once-a-month or every-three month product.
• The most common side effects include upper respiratory tract infection, injection site reaction, weight increased, headache, and parkinsonism (may include shuffling gait, tremors, restlessness, slowed movements, stiffness).

Olanzapine and samidorphan (Lybalvi)

In June 2021, the FDA approved the oral combination tablet olanzapine and samidorphan (Lybalvi) from Alkermes. It is a combination of olanzapine and a novel μ-opioid receptor antagonist samidorphan for the treatment of schizophrenia and bipolar I disorder. 

• It is taken once per day with or without food.
• The samidorphan contained in Lybalvi blocks the effects of opioids. Lybalvi is contraindicated in patients who are using opioids and in patients who are undergoing acute opioid withdrawal.
• In clinical studies, Lybalvi demonstrated antipsychotic efficacy, safety and tolerability, including statistically significantly less weight gain than olanzapine used alone.
• Common side effects include an increase in weight, somnolence (drowsiness), dry mouth, and headache.

Lumateperone (Caplyta)

In December 2019, first-in-class atypical antipsychotic lumateperone (Caplyta) was FDA-approved for the treatment of schizophrenia in adults. It is thought to work by blocking serotonin 5-HT2A receptors and postsynaptic dopamine D2 receptors.

• The recommended dosage of Caplyta capsules is 42 mg once daily with food. The dose does not need to be titrated.
• The efficacy of Caplyta was demonstrated in two placebo-controlled trials showing a statistically significant outcome on the Positive and Negative Syndrome Scale (PANSS) total score.
• In combined data from short term studies, mean changes from baseline in weight gain, fasting glucose, triglycerides and total cholesterol were similar between Caplyta and placebo. The incidence of extrapyramidal symptoms was 6.7% for Caplyta and 6.3% for placebo.
• Most common adverse reactions in clinical trials (incidence > 5% and at least twice of placebo) were somnolence / sedation and dry mouth.

Asenapine (Secaudo)

In October 2019, the FDA approved asenapine (Secuado), a transdermal atypical antipsychotic formulation. Secuado was the first treatment approved in skin patch form to treat adults with schizophrenia.

• The sublingual form of asenapine (brand name: Saphris) is already an approved treatment for schizophrenia and bipolar I disorder.
• In Phase 3, placebo-controlled studies in 616 adults with schizophrenia, Secuado achieved the primary endpoint of statistically significant improvement in the change of the total Positive and Negative Syndrome Scale (PANSS) when compared to placebo after 6 weeks.
• Commonly observed side effects (incidence ≥5%) were extrapyramidal (movement) disorder, application site reaction, and weight gain.
• The recommended starting dose of Secuado is the 3.8 mg per 24 hours patch. A new patch is applied daily.

Risperidone (Perseris)

In August 2018 the FDA approved risperidone injection (Perseris) from Indivior, a once-monthly subcutaneous depot injection used for schizophrenia in adults. Risperidone is a well-established atypical antipsychotic treatment.

• In Phase 3, placebo-controlled, 8-week studies, Perseris showed an improvement in the Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impression Severity of Illness (CGI-S), both at day 57 of treatment.
• Clinically relevant levels were reached after the first injection of Perseris without use of a loading dose or any supplemental oral risperidone.
• The most common side effects included increased weight, sedation/somnolence, musculoskeletal pain, and injection site reactions.

Aripiprazole (Abilify MyCite) 

Keeping patients on their medications is an ongoing challenge in with schizophrenia. In November 2017, the FDA approved aripiprazole (Abilify MyCite) from Otsuka, an atypical antipsychotic with an embedded tracking sensor for schizophrenia, bipolar I disorder, and depression in adults.

• The Abilify tablet formulation is embedded with the ingestible Proteus sensor that allows patients, and, if given access, doctors and caregivers, to digitally track ingestion of the medication on a smartphone or web-based portal.
• The system sends a message from the pill’s sensor to a wearable patch on the patient, which then transmits to the device.

Side effects with antipsychotics

The choice of an antipsychotic is often determined based on the side effect profile and tolerability in the patient. Antipsychotics are commonly linked with side effects that can lead to treatment discontinuation and poor outcomes. Common side effects include:

• weight gain
• elevated blood sugar, type 2 diabetes
• elevated cholesterol and triglycerides
• extrapyramidal symptoms (movement disorders): acute dystonic reactions, akinesia, akathisia (restlessness), Parkinson-like symptoms, tremor, tardive dyskinesia (abnormal, repetitive facial movements)
• prolactin elevation (hyperprolactinemia)
• sedation
• anticholinergic side effects
• orthostatic hypotension
• QTc prolongation
• seizures
• male or female sexual dysfunction
• increased risk of heat stroke
• neuroleptic malignant syndrome
• psychiatric side effects such as confusion, disorientation, delirium, psychosis
• neutropenia/agranulocytosis (high risk with clozapine)
• photosensitivity, elevated risk for sunburn

Nonpharmacologic treatment

While drug treatment is the backbone of treatment for schizophrenia, nonpharmacologic, psychosocial treatments can lower hospitalizations, boost medication adherence, maintain clinic follow-up, and help prevent relapse. Individual, group, and cognitive behavioral therapy have all been used. Family support and education can also play a beneficial role.

Supportive and problem-focused forms of psychotherapy may be helpful for many individuals. Behavioral techniques, such as social skills training, can be used in a therapeutic setting or in the patient's natural environment to promote social and occupational functioning.

Family interventions that combine support and education about schizophrenia can help families cope and reduce relapse. Patients who lack family and social support may be helped by intensive case management programs that emphasize active outreach and link to a range of community support services.

Community rehabilitation services may include:

• Case management
• Self-help groups
• Drop-in community centers
• Housing support
• Employment programs
• Counseling and talk therapy
• 24-hour crisis services

How to help someone with schizophrenia

The role of a caretaker for someone with schizophrenia can be difficult. Remember that schizophrenia is a biological illness and treatment can have a positive effect. Work with the doctor if you are a caretaker, and also remember to take time to find services to support your role, too. Here are other suggestions:

• Initiate treatment at a doctor's office
• Encourage ongoing treatment
• Help with transportation to clinic visits, if and when able
• Learn how to monitor symptoms and report side effects when suspected
• Be respectful but do not tolerate dangerous or inappropriate behavior; seek help from a medical professional in these cases
• Locate support groups in your local area.

Patients - call your doctor if:

• Voices are telling you to hurt yourself
• You are unable to care for yourself
• You are feeling hopeless and overwhelmed
• You feel like you cannot leave the house
• You are seeing things that aren't really there.