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Antipsychotics & Worsening Depression?

Last Updated on February 3, 2024 by Diane Ridaeus

Alternative to Meds Editorial Team Medically Reviewed by Dr Samuel Lee MD

The usual treatment for depression is antidepressants — but if that doesn’t work, doctors will sometimes add antipsychotics to the mix. When antidepressants fail, a patient can be deemed “treatment resistive” and without further investigative digging, a person can be subjected to switching and swapping medications in a desperate attempt to alleviate the person’s symptoms.1,17

The video here has a wealth of information on how antipsychotic medications can be used correctly, or incorrectly, and can affect mental health in negative ways, including worsening of depression, and inducing other negative outcomes which will be discussed in more detail below.

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Antipsychotics & Worsening Depression — What is the Link?

Antipsychotics are prescribed to treat a variety of conditions, and two of the most common are bipolar disorder and schizophrenia. However, studies show that in depression treatment strategies, about 10% of depression patients as a whole are prescribed antipsychotic medication INSTEAD OF antidepressant medication, even when no psychotic features are present.2

Prescribers may or may not be aware that both antidepressants and antipsychotics can cause clinical worsening, including metabolic and neurologic effects, and suicidality. These clinical effects are not well-understood, and concerns have been published about inappropriate prescribing, especially the inclination towards polypharmacy in mental health treatment.3-6

As the name implies, antipsychotic medications are intended to dampen symptoms of psychosis and mania. And, they are very effective used in this way. However, if used long-term, antipsychotics come with a host of troubling side effects, including loss of brain volume.7

Depressive symptoms include sleep dysregulation, lethargy, fatigue, low mood, suicidality, and loss of interest or joy in life — and these are the same symptoms associated with the use of antipsychotic medications, especially over long-term use.8

How Do Antipsychotic Drugs Work?

There is much that is not known about how antipsychotics work. However, what is known is that, in general, there are two kinds of antipsychotics – termed atypical and typical antipsychotics. Both types of medication work differently and can cause varying side effects.9,10

First-generation antipsychotics are also known as typical antipsychotics. These medications are dopamine receptor antagonists (DRAs) and work to block dopamine receptors in the brain. This works to reduce dopamine activity in the brain and potentially alleviate conditions associated with overactive dopamine activity. Typical antipsychotics may also feature cholinergic, histaminergic, and noradrenergic blocking action.

Second-generation antipsychotics (often referred to as atypical antipsychotics) are serotonin-dopamine antagonists. Atypical antipsychotics also engage in serotonin receptor antagonist action, which means that these medications block dopamine receptors and serotonin receptors.

The mechanics of how these substances act on neurogenesis and other effects is not fully understood.

What Is the Most Troublesome Side Effect of Antipsychotic Medications?

Depending on the individual, what someone considers the “most troublesome side effect” of antipsychotics can vary. These medications introduce a wide range of unwanted effects, and any one may be especially distressing to the individual experiencing it. However, extrapyramidal symptoms are some of the most dangerous and concerning when it comes to physical side effects.11

Any psychiatric or emotional side effect of antipsychotic medications is worthy of concern, as well. Patients prescribed first-generation and second-generation antipsychotics are already experiencing serious mental health disorders, such as schizophrenia, bipolar disorder, or certain personality disorders. New or worsening depression can be an especially dangerous situation for these individuals. Specific side effects for antipsychotics vary from one medication to another, and these can be found on the drug’s label.12-14

Antipsychotics and Long-Term Treatment — Risks and Benefits?

When a patient is placed on antipsychotics by their caregiver, this is often for an extended period of time. Some observers feel these medications should only be used for short-term stabilization, typically during a time of crisis. And some research has questioned the use of these drugs for the purpose of maintenance, as sometimes this may do more harm than good for the patient.

Other research has shown that the longer a patient takes antipsychotic drugs, the more likely they are to experience not only reduced efficacy, meaning more frequent relapses, but also unwanted changes in brain structure and physical health.15

Antipsychotics induce a “dampening” effect on patients. In the short term, this zombie-like effect can be a reasonable trade-off for stabilization during a period of crisis. Nevertheless, research shows us that this can be an extremely disabling side effect when the patient is required to take the medication for many months — or even several years. In many cases, benefits of antipsychotics are obscured by the risks of long-term use.16

Do Antipsychotics Affect Your Mood?

Yes, antipsychotic drugs can impact mood. Prescribers may hope to alleviate low mood symptoms like depression and hopelessness. However, antipsychotic medications may instead impact mood in ways you weren’t anticipating.

Antipsychotic medications are one of many neuroleptics associated with what are referred to as “zombie-like” effects, including emotional blunting, sedation, and other mood-alterations. 17

Antipsychotics May Increase or Worsen Symptoms

There is much to be understood about antipsychotic medications, and how they work exactly. Medical consensus is that antipsychotics suppress the expression of dopamine. Hence, their use in quelling psychosis or mania. But other changes can also occur, and these are less understood. Antipsychotic medication may act upon other symptoms like anxiety, agitation, and impulsivity, but much is left to discover about how and why such neurological impacts occur, especially over long-term use.

Alongside suicidality and worsening depression, antipsychotic drugs can also result in symptoms like weight gain, frequent sedation, and anticholinergic effects, according to the many drug labels. Any of these side effects can negatively impact a person’s mental or emotional well-being.

Depression of any kind can be a debilitating condition, and as one might expect, many individuals with depression will search far and wide for an effective treatment. Some have found that alternative treatments may be a better choice to manage depression.

What Are the Alternatives to Antipsychotics?

alternatives to antipsychotics sedona drug rehab

More and more medical professionals are approaching mental health treatment by looking for the root cause of a patient’s mental health symptoms. In today’s society, the majority of cases of newly emerging psychosis happen to be in relation to marijuana use. Isolating the root cause can allow caregivers to determine the most effective treatment including integrating non-drug-based treatments, that are best for the individual.18

Antipsychotic drugs are sometimes necessary for the patient’s own safety and that of others. But after the initial crisis has passed, they aren’t the only way to successfully manage psychosis. With alternative treatments, it’s possible to be able to rely on medications less over time, giving the body and CNS a chance to re-stabilize from the onset of any antipsychotic side effects, including new or worsening depression.

The practice of treating schizophrenia and psychosis without the use of antipsychotics has seen some very promising success. In Norway, for example, drug-free treatment is offered to those experiencing psychosis, and has been met with great success for many.19

Alternative Therapies

Research in the field of mental health is constantly evolving, meaning that new therapies and forms of treatment are becoming more frequently utilized. For instance, certain kinds of physical exercise, including yoga have been linked to improved mental health and are beginning to show up in treatment more commonly.25

Orthomolecular Medicine

Eating a cleaner diet and cutting out caffeine and sugars can positively impact your mental or emotional well-being. A diet high in omega-3 fats, fresh fruits and vegetables, and low in over-processed foods and refined carbs has also shown effective in the treatment of schizophrenia, without the worsening of depression and other unwanted side effects associated with antipsychotics.

Research has demonstrated much evidence of the role of nutrition, vitamins and supplements including amino acids & omega-3 fatty acids that may assist in mental health treatment.20-24,26,27

Is it Possible to Avoid Worsening Depression & Other Side Effects of Antipsychotics?

For some, coming off the medication, or reducing the dose would be a logical way to resolve unwanted medication side effects. However, a person must be in a stabilized condition, AND, it takes a deft and knowledgeable hand to assist with lowering antipsychotic medication safely. Please don’t try it on your own.

At ATMC our approach relies on many tools such as lab testing, to investigate any hormonal, nutritional, and medical contributors to your condition. Then a wealth of therapies are blended together under the umbrella of orthomolecular medicine to achieve individual success.

Alternative to Meds Center may be able to help you reduce or in many cases to come off antipsychotics entirely in a safe and comfortable environment, under the supervision of trained medical and mental health professionals. By doing so, it becomes possible to avoid the many negative side effects of antipsychotics such as worsened depression, with a safety net in place as you explore a wide range of drug-free treatment alternatives. Call on us for more information about our services and protocols, and find out more about how we can help you or a loved one achieve long-term success in less toxic ways.


1. Voineskos D, Daskalakis ZJ, Blumberger DM. Management of Treatment-Resistant Depression: Challenges and Strategies. Neuropsychiatr Dis Treat. 2020 Jan 21;16:221-234. doi: 10.2147/NDT.S198774. PMID: 32021216; PMCID: PMC6982454. [cited 2024 Feb 2]

2. Gerhard T, Stroup TS, Correll CU, Huang C, Tan Z, Crystal S, Olfson M. Antipsychotic Medication Treatment Patterns in Adult Depression. J Clin Psychiatry. 2018 Mar/Apr;79(2):16m10971. doi: 10.4088/JCP.16m10971. PMID: 28686818; PMCID: PMC8215589. [cited 2024 Feb 2]

3. Baldessarini RJ, Vázquez GH, Tondo L. Bipolar depression: a major unsolved challenge. Int J Bipolar Disord. 2020 Jan 6;8(1):1. doi: 10.1186/s40345-019-0160-1. PMID: 31903509; PMCID: PMC6943098. [cited 2024 Feb 2]

4. Bennett F, Ferner R, Sofat R. Overprescribing and rational therapeutics: Barriers to change and opportunities to improve. Br J Clin Pharmacol. 2021 Jan;87(1):34-38. doi: 10.1111/bcp.14291. Epub 2020 Apr 14. PMID: 32216108. [cited 2024 Feb 2]

5. Mihanović, M., Restek-Petrović, B., Bodor, D., Molnar, S., Oresković, A., & Presecki, P. (2010). Suicidality and side effects of antidepressants and antipsychotics. Psychiatria Danubina, 22(1), 79–84. [cited 2024 Feb 2]

6. Wang P, Si T. Use of antipsychotics in the treatment of depressive disorders. Shanghai Arch Psychiatry. 2013 Jun;25(3):134-40. doi: 10.3969/j.issn.1002-0829.2013.03.002. PMID: 24991148; PMCID: PMC4054548. [cited 2024 Feb 2]

7. Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 2011 Feb;68(2):128-37. doi: 10.1001/archgenpsychiatry.2010.199. PMID: 21300943; PMCID: PMC3476840. [cited 2024 Feb 2]

8. Chand SP, Arif H. Depression. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: [cited 2024 Feb 2]

9. Seeman P. (2002). Atypical antipsychotics: mechanism of action. Canadian journal of psychiatry. Revue canadienne de psychiatrie, 47(1), 27–38. [cited 2024 Feb 2]

10. Nandra KS, Agius M. The differences between typical and atypical antipsychotics: the effects on neurogenesis. Psychiatr Danub. 2012 Sep;24 Suppl 1:S95-9. PMID: 22945197. [cited 2024 Feb 2]

11. Ali T, Sisay M, Tariku M, Mekuria AN, Desalew A. Antipsychotic-induced extrapyramidal side effects: A systematic review and meta-analysis of observational studies. PLoS One. 2021 Sep 10;16(9):e0257129. doi: 10.1371/journal.pone.0257129. PMID: 34506552; PMCID: PMC8432767. [cited 2024 Feb 2]

12. FDA Label Seroquel (quetiapine fumerate) approval 1997 [cited 2024 Feb 2]

13. FDA Label Zyprexa (olanzapine injectable & orally disintegrating tablets) [approval 1997, 2006] [cited 2024 Feb 2]

14. FDA label Haldol (haloperidol injectable) [approval revised 2005] [cited 2024 Feb 2]

15. Samaha AN, Seeman P, Stewart J, Rajabi H, Kapur S. “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2007 Mar;27(11):2979-2986. DOI: 10.1523/jneurosci.5416-06.2007. PMID: 17360921; PMCID: PMC6672560. [cited 2024 Feb 2]

16. Morrison P, Meehan T, Stomski NJ. Living with antipsychotic medication side-effects: the experience of Australian mental health consumers. Int J Ment Health Nurs. 2015 Jun;24(3):253-61. doi: 10.1111/inm.12110. Epub 2014 Dec 22. PMID: 25529392. [cited 2024 Feb 2]

17. Moncrieff J, Gupta S, Horowitz MA. Barriers to stopping neuroleptic (antipsychotic) treatment in people with schizophrenia, psychosis or bipolar disorder. Therapeutic Advances in Psychopharmacology. 2020;10. doi:10.1177/2045125320937910 [cited 2024 Feb 2]

18. Myles H, Myles N, Large M. Cannabis use in first episode psychosis: Meta-analysis of prevalence, and the time course of initiation and continued use. Aust N Z J Psychiatry. 2016 Mar;50(3):208-19. doi: 10.1177/0004867415599846. Epub 2015 Aug 18. PMID: 26286531. [cited 2024 Feb 2]

19. Oedegaard CH, Davidson L, Stige B, Veseth M, Blindheim A, Garvik L, Sørensen JM, Søraa Ø, Engebretsen IMS. “It means so much for me to have a choice”: a qualitative study providing first-person perspectives on medication-free treatment in mental health care. BMC Psychiatry. 2020 Aug 8;20(1):399. doi: 10.1186/s12888-020-02770-2. PMID: 32770965; PMCID: PMC7414551. [cited 2024 Feb 2]

20. van der Heijden FM, Fekkes D, Tuinier S, Sijben AE, Kahn RS, Verhoeven WM. Amino acids in schizophrenia: evidence for lower tryptophan availability during treatment with atypical antipsychotics? J Neural Transm (Vienna). 2005 Apr;112(4):577-85. doi: 10.1007/s00702-004-0200-5. Epub 2004 Sep 14. PMID: 15372327. [cited 2024 Feb 2]

21. Saleem S, Shaukat F, Gul A, Arooj M, Malik A. Potential role of amino acids in pathogenesis of schizophrenia. Int J Health Sci (Qassim). 2017 Jul-Sep;11(3):63-68. PMID: 28936154; PMCID: PMC5604273. [cited 2024 Feb 2]

22. Hoffer, A., & Osmond, H. (1964). TREATMENT OF SCHIZOPHRENIA WITH NICOTINIC ACID A Ten Year Follow‐up 1. Acta Psychiatrica Scandinavica, 40(2), 171-189. [cited 2024 Feb 2]

23. Lakhan, S. E., & Vieira, K. F. (2008). Nutritional therapies for mental disorders. Nutrition journal, 7(1), 1-8. [cited 2024 Feb 2]

24. Qureshi, N. A., & Al-Bedah, A. M. (2013). Mood disorders and complementary and alternative medicine: a literature review. Neuropsychiatric disease and treatment, 9, 639–658  [cited 2024 Feb 2]

25. Butterfield, N., Schultz, T., Rasmussen, P., & Proeve, M.J. (2017). Yoga and mindfulness for anxiety and depression and the role of mental health professionals: a literature review. The Journal of Mental Health Training, Education and Practice, 12, 44-54.

26. Onaolapo OJ, Onaolapo AY. Nutrition, nutritional deficiencies, and schizophrenia: An association worthy of constant reassessment. World J Clin Cases. 2021 Oct 6;9(28):8295-8311. doi: 10.12998/wjcc.v9.i28.8295. PMID: 34754840; PMCID: PMC8554424. [cited 2024 Feb 2]

27. Hsu MC, Ouyang WC. A Systematic Review of Effectiveness of Omega-3 Fatty Acid Supplementation on Symptoms, Social Functions, and Neurobiological Variables in Schizophrenia. Biol Res Nurs. 2021 Oct;23(4):723-737. doi: 10.1177/10998004211020121. Epub 2021 Jul 20. PMID: 34281415. [cited 2024 Feb 2]

This content has been reviewed and approved by a licensed physician.

Dr. Samuel Lee

Dr. Samuel Lee is a board-certified psychiatrist, specializing in a spiritually-based mental health discipline and integrative approaches. He graduated with an MD at Loma Linda University School of Medicine and did a residency in psychiatry at Cedars-Sinai Medical Center and University of Washington School of Medicine in Seattle. He has also been an inpatient adult psychiatrist at Kaweah Delta Mental Health Hospital and the primary attending geriatric psychiatrist at the Auerbach Inpatient Psychiatric Jewish Home Hospital. In addition, he served as the general adult outpatient psychiatrist at Kaiser Permanente.  He is board-certified in psychiatry and neurology and has a B.A. Magna Cum Laude in Religion from Pacific Union College. His specialty is in natural healing techniques that promote the body’s innate ability to heal itself.

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Medical Disclaimer:
Nothing on this Website is intended to be taken as medical advice. The information provided on the website is intended to encourage, not replace, direct patient-health professional relationships. Always consult with your doctor before altering your medications. Adding nutritional supplements may alter the effect of medication. Any medication changes should be done only after proper evaluation and under medical supervision.

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