Atypical Antipsychotics in the Treatment of Unipolar and Bipolar Depression: Friend or Foe?

An APA style article discussing the use of atypical antipsychotic psychotropic medication in the treatment of unipolar and bipolar depression.

Depression is a psychological disorder that affects approximately 15 million American adults in its unipolar form, and six million in the bipolar form (Archives of Gen. Psychiatry, 2005). These are only the actual recorded, diagnosed cases. The causes, symptoms, subtypes and effective treatments vary in each individual. There is, however, one group of people affected by mood disorders who do not respond well to treatment. Some of these people may be experiencing depression due to situational factors, while others simply do not respond well to medications. Some people have difficulty maintaining their bipolar illnesses as mood stabilizers are difficult to tolerate and do not always work well with the depression symptoms (Gentile, 2007).

Antipsychotics have been approved for the treatment of the manic states of bipolar disorder, but not with the depression symptoms (Preston, O’Neal & Talaga, 2008). Science is working towards finding new and effective ways to treat these and the aforementioned cases. A new treatment is being studied and prescribed in cases of melancholic subtypes, atypical depression states of bipolar disorder, and hard to treat depressions. This new approach is the use of atypical antipsychotic medications such as olanzapine (Zyprexa), quetiapine (Seroquel) and risperidone (Risperdal) (Parker & Malhi, 2001). This paper will explore further the studies of such drugs in the treatment of depression to determine its overall safety and effectiveness. Is there a new first line of treatment for certain types of depression, or is this simply an attempt to sell pharmaceuticals to patients who would otherwise resort to other treatments out of the psychiatric scope?

Currently Approved Treatments

Currently, depression disorders are being treated with SSRI’s (selective serotonin reuptake inhibitors), MAOI’s (monoamine oxidize inhibitors), atypical antidepressants (such as Wellbutrin), tricyclics, SNRI’s (serotonin and norepinephrine reuptake inhibitors) and NRI’s (norepinephrine reuptake inhibitors) (Preston, et al, 2008). Bipolar depression is managed with the use of mood stabilizers and sometimes the addition of a typical or atypical antipsychotic to treat the manic states. SSRI’s can sometimes be added to control the depression, but this is very risky as these medications have been known to cause a person to enter into a manic state. So what is the need for a new approach for treatment?

There are several types of depressive disorders which do not respond well to treatment. Some are purely physiological (Preston, et al, 2008). They are not founded in the basis of biological factors, but are reactive to environmental situations such as a significant loss or disappointment. These types of depression do not respond well to treatment. There are also cases that vary from one individual to the next that also do not respond well to treatment. If there can be a way to improve the quality of life for these individuals, it could mean a very large breakthrough for the world of psychology (and psychiatry).

There are also types of depression that respond better to medications such as MAOI’s, or tricyclics than they do to atypical or SSRI medications (Preston, et al, 2008). This creates a lower quality of life as the side effects that come with these medications are vast, and the health risks can be large. When a person is faced with such risky options it is important to weigh the health risks with the level of suffering and possible benefit one can gain from subscribing to such a method of treatment. Some of these people may choose to stay off medication while others suffer with drastic side effects. Atypical antipsychotics have been found to be more tolerable and possibly produce greater efficacy in the treatment of such disorders.

Bipolar disorders consist of manic states of elation or less intense hypomanic states. These states typically cycle between states of clinical major depression. Mood stabilizers are generally used to maintain the disorder as antidepressants can actually onset the mania (as previously mentioned), but that doesn’t mean mood stabilizers are always the most desirable method (Preston, et al, 2008). They contain a number of side effects, health risks and are often not neurologically tolerated well in long-term treatment (Gentile, 2007). Long-term treatment is something that is necessary for the treatment of bipolar disorder (Preston, et al, 2008).

 Typical antipsychotics are often prescribed to bipolar patients in controlling the manic states, but are not ideal for long-term usage as they have a great risk for the development of Tardive Dyskinesia, NMS (neuroleptic malignant disorder) and various other side effects (NAMI, 2009). Atypical antipsychotics are more desirable lines of defense as they do not impose as great of health risks, side effects and are more tolerated than common mood stabilizers (Gentile, 2007). Australasian psychiatrists have noticed this and have been prescribing atypical antipsychotics in the treatment of depression (Parker et al, 2001). Does this mean there is a better way to treat these disorders than the current FDA approved methods? Are antipsychotics the emerging new first line of defense in maintaining bipolar or hard to treat depression? Or, did these doctors simply receive large amounts of free samples from pharmaceutical companies; thus testing their effectiveness on patients?

Clinical Studies

Several studies have been conducted on the effectiveness of antipsychotic medications in the treatment of depression and bipolar disorder. Gordon Parker and Gin Malhi compared case studies in Australia in which atypical antidepressants were used in cases of hard to treat melancholic depression (Parker et al, 2001). They found that seven out of 24 patients responded to atypical antipsychotics, with four experiencing immediate improvements.

Paul Keck, at the University of Cincinnati, researched the effectiveness of atypical antipsychotics in monitoring bipolar disorder (Keck, 2005). His findings concluded that olanzapine alone, and olanzapine combined with fluoxetine (Prozac) improved the Montgomery-Asberg Depression Rating Scale (MADRS) overall when compared with placebo trials in those with acute bipolar I. He also conducted an 8 week controlled study with bipolar I and II sufferers who were experiencing depression. The findings showed that quetiapine significantly improved their symptoms, including suicidal ideation. Quetiapine also improved MADRS scores in this population. Keck concluded that antipsychotic medications could be important in the future treatment of bipolar disorders and depression.

Salvatore Gentile (from Salerno, Italy) conducted a meta-analysis of various studies concerning atypical antipsychotics and their effectiveness in manic, depressed and mixed states of bipolar I along with their use in maintenance versus mood stabilizers and typical antipsychotics (Gentile, 2007). The medications studied were aripiprazole (Abilify), olanzapine, quetiapine, risperidone and ziprasidone (Geodon). He researched short and long-term studies with each medication and compared the outcomes with that of typical antipsychotics. The results were very interesting.

Salvatore found that aripiprazole was not effective in treating those with bipolar, but actually caused some to enter into a manic state (Gentile, 2007). He compared this with the typical medication haloperidol (Haldol) and found that it was more neurologically tolerable, with less side effects, but did cause weight gain and several side effects nonetheless. In the long-term, aripiprazole was found to delay the onset of a manic episode, but the onset of a depressed episode was not significantly different than those taking the placebo. It should be noted that extreme cases of bi-polar I were not used in these studies.

Olanzapine was found to be most effective in the maintenance role for treating bipolar disorder with rates as effective as lithium, but drastically less side effects (Gentile, 2007). The most prevalent side effect, that is greater than those in mood stabilizers and typical antipsychotics, was weight gain. This drug (as well as quetiapine) has been reported to induce mania in other studies, but was also found to be effective in the treatment of mania. Interestingly, the studies paid for by their parent pharmaceutical companies did not show such evidence in the onset of mania. Combined with fluoxetine, the symptoms remained relatively the same only with higher gastrointestinal upset.

Quetiapine was found to work well in the maintenance of bipolar disorder with more effectiveness in bipolar I than II; significantly effective in treating the depressive phases of both bipolar I and II (Gentile, 2007). There was, again, a common side effect of weight gain noted with this medication. Those who were successful with quetiapine also responded with even greater improvement when quetiapine was paired with the mood stabilizer divalproex (Depakote).

Risperidone studies showed similar side effects as those previously listed, however, there were more serious side effects found to occur in those taking risperidone (Gentile, 2007). There was a greater incident of induced mania; however, risperidone effectively treated such states. Risperidone was not successful in the maintenance of bipolar I due to the more frequent onset of mania and ziprasidone was even less successful. It showed over twice the frequency of induced manic states compared with all other atypical antipsychotics which rules this medication out for the maintenance and treatment of depression in bipolar patients.

Michael Berk and Seetal Dodd also conducted such a meta-analysis from the University of Melbourne in Australia (Berk & Dodd, 2005). They also found that quetiapine and olanzapine were most effective in the maintenance of bipolar disorder. While atypical antipsychotics were not as effective in treating depression in bipolar patients, they did work well in the maintenance between states and in treating mania.

With so much research supporting atypical antipsychotics in the treatment of bipolar disorders, it leaves one interested as to how these have performed in treating cases of unipolar depression. If they do not work as effectively in the treatment of depressed states as in the manic states of bipolar, what is the draw to use them in unipolar depression?

 Sidney Kennedy and Raymond Lam at the University of Toronto attempt to answer these questions with their research on the use of atypical antipsychotics in the treatment of hard to treat depressions. They have found that depression symptoms significantly improved in patients with hard to treat depression when their treatment was paired with lithium and atypical antipsychotics (Kennedy & Lam, 2003). They also found that atypical antipsychotics significantly improved the remission rate for such depressions.

The use of atypical antipsychotics in treating hard to treat depression was reinforced in an interview with Dr. Richard C. Shelton, chief of adult psychiatry at the Vanderbilt University School of Medicine (Disease Management Digest, 1999). He said that these are particularly useful in treating depressions that have failed to respond to at least two prior treatments. He also supports their use in severe bipolar cases for maintenance in which the patient may face several hospitalizations per year.


In reviewing these different case studies, test trials and meta-analysis one may conclude that atypical antipsychotics are not the cure-all answer for hard to treat cases of depression or bipolar disorder. There seems to be a lot of risk involved with the use of these medications and some very undesirable side effects. When a person is faced with the decision to suffer with hard to treat depression/bipolar disorder, or try a new medication there are many factors that need to be evaluated and weighed. First of all, most of these medications studied cause extreme weight gain (Gentile, 2007). This may be a struggle the patient is already dealing with if the depression symptoms are atypical. A person may feel as though their quality of life is lowered by the gain of 30 - 100 pounds or more throughout the course of treatment.

Another risk factor to evaluate is the fact that many of these medications can in fact onset mania in a person (Gentile, 2007). This is why SSRI medications are not always used in the treatment of bipolar disorder (Parker et al, 2008). Perhaps the incident rates are lower, but it is something to seriously examine and evaluate. While a person may enjoy the elation they feel when manic, it could cause complications in their life and result in the depression which is not desirable by anyone. It is difficult to maintain a bipolar disorder if the medication is causing mania, whether or not it is effective at treating such states.

It is most interesting to find that the studies on olanzapine and quetiapine, which did not show the onset of manic symptoms, were the studies which were sponsored by the pharmaceutical companies who produce them (Gentile, 2007). These studies were mostly conducted in Australia where there seems to be a popular use for such treatment. This raises the question formerly asked about the pharmaceutical companies donating free samples to such doctors. Doctors seem to be more prevalently subscribing the medications they have free samples of, or have just been taken to dinner/presentation for (Ervin, 2009). This does not mean that these medications are in fact the most effective. Consumer education is thus needed to ensure individuals are truly protecting their rights and ultimate recovery when undergoing such treatment (Parker et al, 2008).

 This is mostly important as most of these studies reviewed noted that only acute cases of bipolar disorder participated (Gentile, 2007). This leaves a very large population open for speculation as to how they could truly benefit from such medications. They certainly are targets for being prescribed such medications should the FDA approve such usage. Why then, are these populations excluded from study? It seems as though these populations are the most difficult to treat and cause more of a need for new alternatives to common medications, yet no documented data on the actual affects of such new medications on these cases can be found.

On another note, the reported cases of hard to treat depression which respond well to lithium and antipsychotics may in fact be undiagnosed bipolar II disorder (Kennedy et al, 2003). These disorders are more difficult to diagnose as they do not always present so clearly. The use of antidepressants in the treatment of depression that doesn’t respond, unless paired with lithium or an antipsychotic sounds very bipolar. More research is needed to really identify why, in fact, these disorders (if not purely physiologically founded) are so resistant to treatment. In each of the studies reviewed, there was one common conclusion which was that further research must be done to truly evaluate these medications and their use in treating depression and bipolar disorders.


In conducting research and studying the actual facts behind the issue of using atypical antipsychotics in treating depression in unipolar and bipolar cases, one has been left with the idea that it is of the utmost importance to read the fine print and take such medical claims with a grain of salt. Pharmaceutical companies are paying for the research studies which give them authority over what gets published and what is left out of the eyes of the consumer and doctors. The life threatening side effects usually seem to be the issues that are never omitted as that creates for a greater liability and more money out of the pockets of such companies.

In terms of a drug causing someone to enter into mania; there is an unusual coincidence that studies sponsored by the money behind such drugs failed to report this. It leaves one to believe that these companies are simply trying to sell more medications to treat the most prevalent psychiatric illnesses rather than just the small niche they are currently used for. If a patient enters into induced mania there is a high chance it will not be reported as many patients say that mania is “better than sex” (Hempstead, 2009). Furthermore, since these medications are so obviously FDA approved to treat such manic states, the risk that these clients will enter into hospitalization and the scrutiny/examination of doctors is statistically lower. This begs one to ponder if it is a healthy, truly higher quality of life, for a person to be entering into and treated for mania more often throughout their lifespan? That appears to be the outcome that science is attempting to avoid, rather than the pharmaceutical companies, who have nothing but more money to gain from a new, more expansive group of clients who reach mania, now statistically, more often; requiring the seemingly better, FDA approved, use of their (what a coincidence) medication.

In terms of atypical antipsychotics being used for unipolar depression, there is much more research to be done to truly show that these should be a first line of defense. These are only for use in hard to treat cases which do not respond to the first lines of defense already being used. Some of these cases show improvement, but is it significantly relevant enough to generalize to the whole population of hard to treat cases which number at almost 50% (Kennedy et al, 2003)? The research doesn’t appear likely to support such claims. There is also the possibility of the cases that are responsive, to (in fact) be undiagnosed bipolar disorders. It is always important to weight the cost and benefits before implementing any pharmaceuticals; there are always going to be side effects and possible complications.


Archives of General Psychiatry, 2005 Jun; 62(6): 617-27

Atypical Antipsychotics for Treating Depression. Disease Management Digest, 1999. July/August.

Berk, M., Dodd, S. (2005). Efficacy of Atypical Antipsychotics in Bipolar Disorder. Drugs. 65:257-269.

Gentile, S. (2007). Atypical Antipsychotics for the Treatment of Bipolar Disorder. CNS Drugs. 21(5): 367-387.

Hempstead, K. (2009, January). Lecture: Bipolar Disorder. National University.

Keck, P. (2005). Bipolar Depression: A New Role for Atypical Antipsychotics? Bipolar Disorders. 7:34-40.

Kennedy, S., Lam, R. (2003). Enhancing Outcomes in the Management of Treatment Resistant Depression: A Focus on Atypical Antipsychotics. Bipolar Disorders. 5: 36-47.

National Alliance on Mental Illness (NAMI), 2009.

Ervin, H.N.. (2009, March). Lecture: Psychopharmacology. National University.

Parker, G., Malhi, G. (2001). Are Atypical Antipsychotic Drugs Also Atypical Antidepressants? Australian and New Zealand Journal of Psychiatry. 35: 631- 638.

Preston, J., O’Neal, J., & Talaga, M. (2008). Handbook of Clinical Psychopharpacology for Therapists. 5th ed. Oakland, CA: New Harbinger.


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