5 Psychiatry Studies Pharmacists Should Know About


Over the years, a number of landmark clinical studies in the field of psychiatry have been published, shaping how we treat mental illness. Here are 5 that every pharmacist should know about.

More than 43 million American adults experience mental illness in a given year, according to the National Alliance on Mental Illness. Additionally, about 1 in 5 youth aged 13 to 18 will experience a severe mental disorder at some point during their lives. Alarmingly, it is estimated that only about 40% of adults with a mental health condition received mental health services in the past year, and statistics show that serious mental illness costs the United States $193.2 billion in lost earnings per year.

Over the years, a number of landmark clinical studies in the field of psychiatry have been published, shaping how we treat mental illness today. Here are 5 that every pharmacist should know about:

1. CATIE (2005)1

For more than 60 years, antipsychotics have been the cornerstone of schizophrenia treatment. In the 1990s, second-generation, also known as atypical, antipsychotics were introduced, offering the prospect of superior efficacy and a better safety profile. Despite this, there was a lack of consistent and robust clinical studies on long-term improvement with atypical, compared with conventional antipsychotics. CATIE was a randomized, double-blind study designed to compare the effectiveness of atypical and conventional antipsychotic drugs.

A total of 1493 patients with schizophrenia aged 18 to 65 were randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), risperidone (1.5 to 6.0 mg per day), or ziprasidone (40 to 160 mg per day) for up to 18 months or until treatment was discontinued. The primary outcome measure was the discontinuation of treatment for any cause. A number of secondary endpoints were included to further assess efficacy and safety of treatment.

Overall, 74% of patients in the study discontinued their antipsychotic before 18 months (64% olanzapine, 75% perphenazine, 82% quetiapine, 74% risperidone, 79% ziprasidone). The time to discontinuation of treatment was significantly longer in the olanzapine group versus quetiapine (HR=0.63; p<0.001) and risperidone (HR=0.75; p=0.002). Numerical improvements were seen with olanzapine, versus perphenazine (HR=0.78; p=0.021) and ziprasidone (HR=0.76; p=0.028). However, the results did not reach predefined statistical significance. Fewer patients in the olanzapine group than in the other 4 groups were hospitalized for an exacerbation of schizophrenia (11% versus 15-20%, p<0.001). Olanzapine was associated with more discontinuation for weight gain or metabolic effects, while perphenazine was associated with more discontinuation for extrapyramidal effects.


Patients receiving olanzapine experienced a longer time to discontinuation, compared with other antipsychotics, but they also had greater weight gain, hyperglycemia, and hyperlipidemia.

2. STAR-D (2006)2

Depression is a common mood disorder that can be treated with various pharmacologic and non-pharmacologic interventions. When medications are used, patients often require several sequential treatment steps to obtain symptomatic remission. STAR-D was funded by the National Institute of Mental Health to determine the effectiveness of different treatments for people with major depressive disorder (MDD) who have not responded to initial treatment with an antidepressant. With its publication, STAR-D became the largest and longest study of its time to evaluate depression treatment.

Over a 7-year period, researchers enrolled more than 4000 patients, aged 18 to 75, with MDD. The study used a 4-step treatment protocol for MDD. Step 1 consisted of citalopram only. If patients did not achieve remission they were randomly assigned to the step 2 treatment, which consisted of 3 augmentation strategies (citalopram plus bupropion SR, citalopram plus buspirone, and citalopram plus cognitive therapy) and 4 switch strategies (bupropion SR, sertraline, venlafaxine, or cognitive therapy alone). Steps 3 and 4 consisted of additional treatment modalities and combination therapies. The primary outcome was ratings of the Quick Inventory of Depressive Symptomatology—Self-Report (QIDS-SR16).

The QIDS-SR16 remission rates were 36.8%, 30.6%, 13.7%, and 13% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. When looking at the 3 medication switch strategies in step 2, the treatments did not differ significantly with respect to outcomes, tolerability, or adverse events. In assessing step 2 augmentation strategies, SR bupropion was associated with a greater reduction from baseline in QIDS-SR-16 scores than was buspirone (25.3% vs. 17.1%; p<0.009) and had a lower dropout rate due to intolerance (12.5% vs. 20.6%; p<0.009).


When more treatment steps are required, lower acute remission rates and higher relapse rates during the follow-up phase are to be expected. Augmentation of citalopram with bupropion may be particularly advantageous in people who require additional treatment.

3. STEP-BD (2007)3

Episodes of depression are frequent causes of disability among those with bipolar disorder. However, the effectiveness and safety of antidepressant medications for depressive episodes in these patients had not been well studied. At the time, antidepressants were commonly used as adjuncts to mood-stabilizing medication for bipolar disorder, despite limited evidence on their effectiveness and none having FDA-approved indications.

STEP-BD was a double-blind, randomized, placebo-controlled study designed to evaluate the effectiveness of treatments for bipolar disorder and to provide results that would be generalizable to routine clinical practice. A total of 179 participants with bipolar depression were randomly assigned to receive up to 26 weeks of treatment with a mood stabilizer (lithium, valproate, or carbamazepine), plus an adjunctive antidepressant (paroxetine or bupropion) or a mood stabilizer plus a matching placebo. The primary outcome was durable recovery, defined as euthymia for at least 8 consecutive weeks.

At the end of the study, there was no significant difference between the combination and monotherapy group in terms of meeting the primary endpoint (23.5% vs 27.3%; p=0.40). When looking at some of the secondary endpoints, the combination of a mood stabilizer plus antidepressant had numerically better results than mood stabilizer alone, though none reached statistical significance. The rate of any individual adverse event did not differ significantly between the 2 groups.


Adjunctive treatment with antidepressants does not appear to improve clinical outcomes in people with bipolar disorder taking a mood stabilizer.

4. BALANCE (2010)4

By 2009, lithium carbonate had been established for more than 40 years as standard maintenance treatment for bipolar disorder. Although lithium reduces the risk of relapse and suicide, it presents with some limitations including its narrow therapeutic index, adverse effect profile, and it may not be effective for all patients. Anticonvulsant and second-generation antipsychotic drugs have increasingly been used as alternatives to lithium, though their long-term safety and efficacy compared with lithium has not been as well-established. Despite limited clinical trials on the subject, combination therapy was often being used in clinical practice after failure of first-line monotherapy.

As a result, researchers conducted a randomized, open-label, trial to evaluate whether a combination of lithium plus valproate sodium is better than monotherapy with either drug alone for relapse prevention in bipolar I disorder. A total of 330 patients aged 16 and older were recruited from 41 sites and randomly assigned in a 1:1:1 ratio to receive lithium monotherapy, valproate monotherapy, or a combination of the 2 agents. The primary outcome was time to new intervention for an emerging mood episode or admission to hospital which was compared between groups. Participants were followed up for up to 24 months.

Study results showed that the primary outcome occurred in occurred in 59 of 110 (54%) of participants on combination therapy, 76 of 110 (69%) on valproate and 65 of 110 (59%) on lithium carbonate. The hazard ratio of the primary outcome significantly favored the combination group, compared with valproate monotherapy (HR=0.59; p=0.0014). However, the difference did not reach statistical significance when compared with lithium monotherapy (HR=0.82; p=0.23). Notably, the data showed a significant benefit of lithium monotherapy over valproate monotherapy (HR=0.71; p=0.0472). The subgroup analyses taking into account the baseline severity of bipolar disorder and nature of most recent mood episode did not show significantly different results. No significant differences between groups were noted in serious adverse events.


Combination therapy with lithium, plus valproate, is more likely to prevent relapse than is valproate monotherapy, regardless of the baseline severity of illness.

5. CAMS (2014)5

Anxiety disorders are among the most common childhood-onset psychiatric disorders with 12-month and life-prevalence estimates in adolescence at 25% and 32%, respectively. As a result, using safe and effective treatment is imperative to provide both short- and long-term relief of symptoms. To better understand the treatment needs of children and adolescents, NIHM funded the CAMS study to compare the acute efficacy and durability of several treatment approaches in youth with separation, generalized, and social anxiety disorders.

The study enrolled 488 children and adolescents aged 7 to 17 (mean = 10.6 years) to participate in 2 phases of the study. In phase 1, participants were randomized in a 2:2:2:1 ratio to 12 weeks of cognitive behavioral therapy (CBT), sertraline (SRT), CBT + SRT (COMB), or medication management/pill placebo (PBO). Phase 2 consisted of 6 months of maintenance treatment. Those randomized to PBO were offered active treatment if nonresponsive at week 12 or over follow-up but not included in the analysis of study results. Primary outcomes included responder status based on the dichotomized Clinical Global Impression-Improvement Scale and anxiety severity measured by the Pediatric Anxiety Rating Scale.

Study results showed that all 3 active treatments (CBT, SRT, COMB) were more effective than PBO alone. At the end of week 12, COMB was associated with a significantly higher response rate than either CBT or SRT alone (80.7% vs 59.7%, 54.9%; p<0.001). The difference between the 2 monotherapy groups was non-significant (p=0.419). The majority (>80%) of acute responders maintained positive response at both weeks 24 and 36, with COMB continuing to maintain an advantage over CBT and SRT alone. Notably, the study showed a relatively low placebo rate (28.3%) which suggests that monitoring and supportive care alone is not likely to be effective for the majority of children with anxiety disorders. All treatments in the study were well-tolerated and associated with minimal negative adverse events.


Among youth with anxiety disorders, using a combination treatment approach of cognitive behavioral therapy, plus sertraline is superior to either component alone.


  • Lieberman JA, Stroup S, McEvoy J, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-23.
  • Rush AJ, Trivedi MH, Wisniewski S, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatient requiring one or several treatment steps: A STAR*D report. Am J Psychiatry. 2006;163(11):1905-117.
  • Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-22.
  • Lewis S, Geddes JR, Goodwin G, Morriss R, Rendell J, Geddes JR, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375(9712):385-95. doi: 10.1016/S0140-6736(09)61828-6.
  • Piacentini J, Bennett S, Compton SN, Kendall PC, Birmahar B, Albano AM, et al. 24- and 36-week outcomes for the child/adolescent anxiety multimodal Study (CAMS). J Am Acad Child & Adolesc Psychiatry; 2014;53(3):297-310. doi: 10.1016/j.jaac.2013.11.010.

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