Doctors sometimes recommend combination therapies when monotherapy for schizophrenia has failed or when additional symptoms require treatment.

Schizophrenia is a serious mental health condition that affects a person’s thought process, perception, and behavior.

In this article, Dr. Yalda Safai answers some common questions about antipsychotic drugs, including their effects, benefits, and risks.

Schizophrenia is the result of a dysregulation of dopamine in the brain.

When there is too much dopamine, people may experience episodes of psychosis, which can include:

  • Hallucinations: Most commonly, people experience auditory hallucinations, but they may sometimes experience visual, olfactory, and tactile hallucinations.
  • Delusions: A person may have a set of false fixed beliefs. For example, a person experiencing paranoid delusions may believe that people around them are trying to conspire against them or hurt them.
  • Disordered thoughts: A person may have a disorganized and illogical thought process, which can also affect their speech. People experiencing an episode of psychosis may often jump from topic to topic in a conversation or speak incoherent and illogical sentences.

Schizophrenia also has negative symptoms, which are deficits in typical behavior. These include:

  • blunted affect
  • withdrawal
  • lack of motivation
  • poverty of speech, or an unwillingness to talk

Some of these negative symptoms resemble major depression in many ways.

Antipsychotic medications work by regulating the amount of dopamine in the brain to alleviate some of the symptoms above. They are available in pill, liquid, and injectable formulations.

Other therapies focus on helping individuals:

  • manage their symptoms
  • improve day-to-day functioning
  • achieve educational or career goals

People living with schizophrenia may need different types of therapies to support a fulfilling life.

If treatment with one antipsychotic medication is not successful, it is common for people with schizophrenia to receive two or more antipsychotics. They may take these medications along with antidepressants or mood stabilizers to target other symptoms.

This is called combination therapy. It is most effective when the first treatment drug has shown some favorable effects but residual psychotic symptoms remain.

While some research has shown benefits from combination therapy, the research on the topic is still limited and the use of combination therapy is somewhat controversial.

Adding medications also means dealing with more side effects. Each medication comes with its own side effect profile. The rule is to try monotherapy first and, if that fails, move on to combination therapy.

Other types of nonpharmacological combination therapies involve adding psychosocial therapies to medications. Some of the most popular psychosocial therapies are:

  • cognitive behavioral therapy
  • social skills training
  • supported employment
  • cognitive remediation interventions

Combination therapy can happen in different ways.

The first method is to add a second antipsychotic to a person’s medication regimen when their condition has only partially responded to one medication. This could involve adding a second oral medication to the first oral medication or adding an injectable form of an antipsychotic that is different from the first antipsychotic medication.

The second method is to add a mood stabilizer, antidepressant, or anti-anxiety medication to an antipsychotic medication regimen to treat mood symptoms or negative symptoms of schizophrenia.

In either scenario, a person’s doctor will recommend combination therapy only if symptoms have not responded to one medication alone.

Combination therapies are the second choice when monotherapy has failed. Doctors usually reserve combination therapies for those they have deemed “partial responders” or whose condition is “treatment resistant.”

If a person has experienced only a partial response to the first medication, their condition may warrant the addition of a second antipsychotic.

Healthcare professionals define treatment-resistant schizophrenia as moderate to severe symptoms with poor functioning over a period of at least adequate trials of two antipsychotic drugs. In this case, combination therapies might also be beneficial.

Each medication comes with side effects, some of which are medically serious.

Common side effects of antipsychotics include:

  • weight gain
  • metabolic disorders, such as increased lipid levels, increased glucose levels, and diabetes mellitus
  • hyperprolactinemia, or a high blood level of the hormone prolactin
  • akathisia, or restlessness
  • heart problems
  • agranulocytosis, or low white blood cell count
  • extrapyramidal signs (EPS), which include muscle stiffness

More serious possible side effects include tardive dyskinesia — irreversible uncontrolled movement of the limbs after chronic antipsychotic use — and neuroleptic malignant syndrome, a life threatening emergent condition. Antipsychotic drugs also carry an increased risk of cardiovascular events and death in older adults with dementia.

Combination therapies could have an additive effect from each of these side effects. Healthcare professionals should weigh the benefits and risks before deciding on combination therapies.

Antipsychotic drugs can resolve some of the symptoms of schizophrenia, such as hallucinations, within hours. However, they usually take up to 4 full weeks to produce their full effect.

Each person is slightly different and might respond differently to treatment.

If a person’s condition has not responded to a certain medication after 4 weeks, it is likely that the individual will not respond to that medication and that their condition warrants a change in the medication regimen.

There is still much controversy and limited data on the effectiveness of combination therapies. However, due to limited advancement in the field of psychopharmacology, healthcare professionals need to use the options they have at their disposal when treating people whose conditions do not respond to medications.

Before starting combination therapy, a healthcare professional should weigh the benefits and risks. Only when the benefits outweigh the risks should they recommend combination therapy.

For cases of schizophrenia that are difficult to treat, it is important to integrate pharmacological, psychological, and psychosocial interventions. Individuals and their doctors should not rely on medications alone.

Yalda Safai, MD, MPH, is a psychiatrist in New York City. She completed her undergraduate degree from University of California Los Angeles and went on to do a dual MD, MPH program. She completed a Master’s in Public Health along with her medical degree in order to pursue a career in global mental health. She did her training at New York Medical College. She has been a contributor to multiple news outlets including ABC News, Good Morning America, Fox News, NewsNation, and Dr. Phil.