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Depression is a serious mental health disorder that can affect anyone, regardless of their age, gender, or background.

It’s estimated that over 300 million people worldwide suffer from depression, and it’s the leading cause of disability worldwide. 

For many, standard antidepressant medications are effective at treating depression.

However, approximately one-third of individuals do not achieve remission of their symptoms with initial medication or therapy. 

Those with treatment-resistant depression may experience particularly severe, persistent symptoms that impair quality of life.

While contemplating alternative treatment strategies can feel discouraging, new options have emerged that may provide help. 

Antipsychotic medications were designed to treat psychotic disorders but have shown promise for treating refractory depressive episodes as well.

These drugs have different mechanisms of action than typical antidepressants and appear to target alternative pathways in the brain.

This article explores the use of some of the best antipsychotics for treatment-resistant depression, discussing their therapeutic benefits and potential side effects.

Anxiety symptom
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What are Antipsychotic Drugs?

Antipsychotic drugs are a class of medications that are primarily used to treat psychotic symptoms, such as hallucinations, delusions, and disorganized thinking, associated with mental health conditions like schizophrenia, bipolar disorder, and brief psychotic disorder. 

They are also sometimes used to treat severe anxiety disorders, such as post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD).

Antipsychotics work by blocking the action of certain neurotransmitters in the brain, such as dopamine, which are involved in the development of psychotic symptoms.

They can help to reduce the severity of symptoms, improve cognitive function, and improve overall quality of life.

There are two main types of antipsychotic medications: typical antipsychotics and atypical antipsychotics.

Typical antipsychotics have been used for decades to treat psychotic symptoms, while atypical antipsychotics are newer and thought to have fewer side effects. 

Both types of antipsychotics are effective in treating depression, although they may have different mechanisms of action and side effect profiles.

How are Antipsychotics Different From Traditional Antidepressants?

While antipsychotics and traditional antidepressants are both used to treat depression, they work in different ways and have different mechanisms of action.

Traditional antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), work by increasing the levels of certain neurotransmitters in the brain, such as serotonin and norepinephrine. 

These neurotransmitters play a role in mood regulation and other functions.

By increasing their levels, traditional antidepressants can help to improve mood and reduce symptoms of depression.

Antipsychotics, on the other hand, work by blocking the action of certain neurotransmitters, such as dopamine and serotonin, in the brain. 

These neurotransmitters are involved in the development of psychotic symptoms, such as hallucinations and delusions, which are not typically seen in depression.

However, antipsychotics are still effective as an adjunctive therapy for MDD.

One key difference between antipsychotics and traditional antidepressants is the speed at which they take effect.

Traditional antidepressants can take several weeks to start working, while antipsychotics can start to take effect within a few days to a week. 

This faster onset of action can make antipsychotics a useful option for patients who are experiencing severe symptoms of depression and need rapid relief.

Another difference between antipsychotics and traditional antidepressants is the potential for weight gain.

Traditional antidepressants are often associated with weight gain, while antipsychotics are less likely to cause weight gain. 

This may be a consideration for patients who are concerned about weight gain or who have a history of weight-related health problems.

Finally, antipsychotics are often used in combination with traditional antidepressants, rather than as a replacement for them.

This combination therapy can be effective for patients who have not responded to traditional antidepressants or who have complex symptoms that require a multifaceted treatment approach.

Effectiveness of Antipsychotics for Depression

Antipsychotics are effective in treating depression, particularly when used as an adjunct to antidepressant therapy. 

Recognizing the efficacy of these medications, the United States Food and Drug Administration (USFDA) has approved aripiprazole and quetiapine slow-release tablets for use as adjunctive treatments in depressive disorders. 

Additionally, the combination of olanzapine and fluoxetine has received approval for addressing treatment-resistant depression.

Moreover, some other antipsychotics are also used off-label for depression treatment.

A systematic review and network meta-analysis published in 2018 by Yan and colleagues assessed the efficacy of second-generation antipsychotics in the treatment of depression. 

Their results showed that almost all antipsychotics were more efficacious than the placebo, with risperidone and aripiprazole being more efficacious and accepted than other atypical antipsychotics.

Another study published in 2019, a twelve-week controlled trial, compared remission rates between individuals treated with a combination of atypical antipsychotic medication and an antidepressant versus those treated with antipsychotic monotherapy. 

The conclusive results affirmed the efficacy of combination pharmacotherapy, emphasizing its effectiveness in the treatment of MD with psychotic features.

It is important to note that while antipsychotics can be effective in treating depression, they are not a cure-all and should be used in conjunction with other treatments, such as therapy and lifestyle changes. 

Additionally, antipsychotics can have side effects, so it is important to weigh the potential benefits and risks when considering their use.

Best Antipsychotics for Depression

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Following are some of the best antipsychotics for the treatment of depression.

1. Aripiprazole

Aripiprazole, commonly recognized by its brand name Abilify, stands as a distinctive atypical antipsychotic celebrated for its important role in mental health treatment. 

Available in oral solution and tablet forms, this medication is designed for once-daily consumption.

It can be used alone or in combination with other medications, such as mood stabilizers or antidepressants.

One of the primary uses of aripiprazole is to treat bipolar I disorder (manic depression) in adults and children at least 13 years old.

It is also used to treat major depressive disorder (MDD) in adults.

Administered alone or in conjunction with antidepressant medication, Aripiprazole has exhibited significant efficacy in two large clinical trials

These trials demonstrated that adding aripiprazole to standard antidepressant monotherapy was markedly more effective than the addition of a placebo, showcasing its potential to enhance the treatment outcomes for depression in patients with MDD.

While Aripiprazole offers promising therapeutic benefits, it is crucial to be mindful of potential side effects.

These may include headaches, nervousness, restlessness, dizziness, heartburn, constipation, diarrhea, stomach pain, changes in appetite, increased salivation, joint pain, and tiredness. 

Additionally, taking Aripiprazole, during the last three months of pregnancy may pose serious risks to the newborn, necessitating careful consideration and consultation with healthcare providers.

2. Olanzapine

Olanzapine, recognized under the brand name Zyprexa, is an atypical antipsychotic medicine.

Initially designed to address schizophrenia and bipolar disorder, olanzapine has transcended its conventional applications. 

A retrospective study of olanzapine in depressive and anxious states in primary care discussed its potential role in treating mood disorders within the bipolar spectrum or those resistant to conventional antidepressant monotherapies. 

The study suggests that olanzapine holds promise as an effective pharmacotherapeutic agent for individuals with mood disorders, including depression, expanding its utility beyond its traditional applications.

Olanzapine is available in tablet and orally disintegrating tablet forms, and is typically taken once a day with or without food.

However, it can cause side effects, and patients should be monitored closely for these.

These side effects may include dizziness, restlessness, unusual behavior, depression, difficulty sleeping, weakness, constipation, weight gain, dry mouth, and pain in the arms, legs, back, or joints. 

Additionally, some individuals may experience breast enlargement or discharge, late or missed menstrual periods, and decreased sexual ability.

3. Quetiapine

Quetiapine, also known by its brand names Seroquel and Seroquel XR, is an atypical antipsychotic medication that is used to treat a variety of mental health conditions, including schizophrenia, bipolar disorder, and major depressive disorder. 

It is available in both oral tablet and extended-release forms. Quetiapine works by altering the levels of certain neurotransmitters in the brain, such as dopamine and serotonin, which helps to regulate mood and thoughts.

In addition to its use in treating schizophrenia and bipolar disorder, quetiapine has also been shown to be effective in treating major depressive disorder. 

Research has found that quetiapine monotherapy, taken at doses ranging from 50-300 mg/day, demonstrates antidepressant effects in patients with major depressive disorder, regardless of the severity of their baseline symptoms. 

This suggests that quetiapine may be a useful treatment option for patients who have not responded to other antidepressant medications or who have experienced side effects from other medications.

Common side effects of quetiapine may include speech problems, dizziness, drowsiness, fatigue, fast heartbeats, upset stomach, vomiting, constipation, stomach pain, and nausea. 

It is important to note that quetiapine can have a significant impact on blood sugar levels, and patients with diabetes or a history of hypoglycemia should be closely monitored while taking this medication.

4. Risperidone

Risperidone, known by the brand name Risperdal, stands as a prominent atypical antipsychotic acclaimed for its efficacy in addressing schizophrenia and bipolar disorder. 

Available in both oral and injectable forms, the latter providing a long-acting option lasting 2–4 weeks, risperidone has become a cornerstone in the treatment of mental health conditions.

As a prescription-only medication, it is accessible to most adults and children aged 5 years and older.

Operating by influencing neurotransmitters like dopamine, risperidone does not offer a cure for mental health conditions but rather plays a crucial role in managing and controlling symptoms. 

Beyond its conventional applications, risperidone has also been used for depression treatment, with numerous studies highlighting its effectiveness. 

Notably, a randomized, double-blind, placebo-controlled study investigated its use as an adjunct treatment alongside first-line antidepressants.

The results showed risperidone’s efficacy as an adjunct treatment, particularly for individuals undergoing standard antidepressant therapy.

While risperidone brings promise to mental health treatment, it is essential to be mindful of potential side effects.

Common occurrences include drowsiness, movement-related issues, and headaches. Additionally, Risperidone may increase appetite, potentially leading to weight gain. 

5. Brexpiprazole

Brexpiprazole, branded as Rexulti, is an atypical antipsychotic medication used to treat various mental health conditions, including schizophrenia, depression, and agitation associated with dementia due to Alzheimer’s disease. 

It belongs to a class of drugs known as serotonin-dopamine activity modulators, which work by modulating the activity of serotonin and dopamine neurotransmitters in the brain.

Brexpiprazole was approved by the FDA in July 2015 for the treatment of schizophrenia and as an adjunctive treatment for major depressive disorder (MDD).

The recommended dosage range for brexpiprazole is 2-4 mg for schizophrenia and 2 mg for depression augmentation.

Clinical studies have underscored Brexpiprazole’s efficacy as a useful adjunctive therapy for depression, offering a favorable side effect profile and comparable efficacy to existing agents. 

It has been shown to improve symptoms of depression, including anxiety, sleep disturbances, and fatigue, in patients who have not responded to other treatments.

While Brexpiprazole contributes significantly to mental wellness, it is essential to be aware of potential side effects.

Mild reported side effects include weight gain, sleepiness, akathisia (restlessness), nasopharyngitis (common cold), headache, constipation, and unusual dreams or insomnia.

6. Cariprazine

Cariprazine, branded as Vraylar, is a relatively new antipsychotic medication that has gained popularity for its unique mechanism of action and favorable side effect profile. 

It was first approved by the FDA in 2015 for the treatment of schizophrenia and acute manic or mixed episodes associated with bipolar I disorder.

In 2022, its indications were expanded to include adjunctive therapy for major depressive disorder.

Cariprazine is available in capsule form, with dosages ranging from 1.5mg to 4.5mg.

Studies have shown that the 1.5mg dose is effective in reducing depressive symptoms in adults with major depressive disorder who have not responded to antidepressants alone.

Research shows many key benefits of cariprazine, including its lower risk of causing significant weight gain, hyperlipidemia, and hyperglycemia compared to other antipsychotics.

Common side effects of cariprazine may include involuntary muscle movements, upset stomach, vomiting, drowsiness, and feeling restless.

These side effects are generally mild and temporary, and they often resolve on their own within a few weeks of treatment.

Cariprazine has shown promise in clinical trials as a monotherapy and adjunctive therapy for various psychiatric disorders.

Its efficacy in reducing depressive symptoms and its favorable side effect profile make it a valuable treatment option for patients who have not responded to other treatments.

7. Ziprasidone

Ziprasidone, also known by its brand name Geodon, is an atypical antipsychotic medication used to treat schizophrenia and bipolar disorder. 

Available in dosage forms of intramuscular powder for injection (20 mg) and oral capsules (20 mg to 80 mg), ziprasidone exhibits improved absorption when taken with food, enhancing its efficacy.

The intramuscular form is typically used for acute agitation in patients with schizophrenia.

In the context of depression, Ziprasidone has demonstrated notable efficacy as an adjunctive treatment.

When added to escitalopram, a study revealed that Ziprasidone exhibited antidepressant effects in adults with MDD after eight weeks of open-label escitalopram treatment.

However, some side effects of ziprasidone can include a cough, difficulty with speaking, drooling, feelings of fear or nervousness, trouble sitting still, loss of balance control, muscle trembling, jerking, stiffness, and a strong urge to keep moving.

What to Expect When Starting Antipsychotic Treatment

When starting antipsychotic treatment for depression, it’s important to know what to expect.

Here are some things to keep in mind:

1. Initial evaluation: Before starting antipsychotic treatment, your healthcare provider will typically perform an initial evaluation to assess your symptoms, medical history, and other factors.

2. Dosage adjustments: Your healthcare provider may start you on a low dose of the medication and gradually increase the dosage over time, depending on your response to the medication.

3. Monitoring: Your healthcare provider will closely monitor your symptoms, side effects, and response to the medication over time.

4. Potential side effects: Antipsychotics can have significant side effects, such as weight gain, metabolic changes, and movement disorders.

Your healthcare provider will monitor you for these side effects and may adjust your dosage or switch you to a different medication if necessary.

5. Follow-up appointments: Regular follow-up appointments with your healthcare provider are important to ensure that the medication is working effectively and to monitor for any side effects.

6. Medication adherence: It’s important to take your medication as directed by your healthcare provider.

Missing doses or stopping the medication abruptly can lead to a relapse of depression symptoms.


Antipsychotic medications can be an effective treatment option for depression, particularly for those who have not responded to other treatments. 

However, while some studies suggest that antipsychotics can be effective in treating depression, other studies have raised concerns about the potential for side effects and the lack of long-term data on their safety and efficacy.

It is important for doctors to carefully weigh the potential benefits and risks of antipsychotics when considering their use for depression. Patients should be closely monitored for side effects and their response to treatment should be regularly assessed. 

By working closely with your healthcare provider and following their recommendations, you can maximize the effectiveness of antipsychotic treatment and improve your quality of life.


1. How do antipsychotics compare to other treatments for depression?

Antipsychotics are typically used as a last resort for treating depression after other treatments have failed.

They are often used in combination with other medications, such as antidepressants, and therapy. 

Studies have shown that antipsychotics can be effective in treating depression when other treatments have not worked, but they may not be as effective as other treatments for all patients.

2. Can antipsychotics be used to treat other mental health conditions?

Yes, antipsychotics can be used to treat other mental health conditions, such as bipolar disorder, schizophrenia, and anxiety disorders.

They are also sometimes used to treat sleep disorders and certain movement disorders.

3. How do I know if antipsychotics are right for me?

If you are considering using antipsychotics to treat your depression, it is important to discuss the potential benefits and risks with your healthcare provider.

They will be able to determine whether antipsychotics are appropriate for you based on your medical history, symptoms, and other factors.

4. How do I take antipsychotics?

Antipsychotics are typically taken orally, once or twice a day.

It is important to follow the dosage instructions carefully and not stop taking the medication without consulting your healthcare provider.



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