Randomized controlled trials (RCTs) are the gold standard for evaluating treatment efficacy, especially in psychiatry, where controlled studies are essential for evidence-based practice. Over the years, a number of RCTs have significantly influenced psychiatry, reshaping how clinicians approach treatment, integrating therapies, and setting the foundation for modern psychiatric guidelines. This introduction summarizes ten of the most influential RCTs in psychiatry, which have contributed to pivotal shifts in treating schizophrenia, bipolar disorder, depression, and anxiety, among other mental health conditions. From comparing the effectiveness of antipsychotic medications to exploring novel approaches like ketamine for treatment-resistant depression, each trial has provided unique insights that have improved therapeutic approaches, guided policy-making, and enhanced the quality of care in mental health.

1. CATIE Trial (Clinical Antipsychotic Trials of Intervention Effectiveness)

• Year: 2005
• Focus: Compared the effectiveness of newer (second-generation) antipsychotics versus an older (first-generation) antipsychotic, perphenazine, in treating schizophrenia.
• Findings: The study found that newer antipsychotics did not outperform older medications in efficacy and often had comparable or higher side effect profiles, which impacted treatment choice in schizophrenia.
• Impact: Led to a reevaluation of prescribing practices, especially regarding cost and side effects.

2. STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder)

• Year: 2007
• Focus: Examined treatment strategies for bipolar disorder, including medication and psychotherapy combinations, to determine optimal long-term management.
• Findings: Psychosocial interventions (e.g., family-focused therapy, cognitive-behavioral therapy) combined with medication were more effective in stabilizing symptoms than medication alone.
• Impact: Highlighted the importance of integrating psychotherapy into the treatment of bipolar disorder.

3. STAR*D (Sequenced Treatment Alternatives to Relieve Depression)

• Year: 2006
• Focus: Studied treatment options for patients with major depressive disorder who did not respond to initial antidepressant treatment, involving multiple levels of medication switching or augmentation.
• Findings: Only about one-third of patients achieved remission with the first treatment; subsequent steps showed diminishing returns. This underscored the need for personalized treatment approaches.
• Impact: Influenced guidelines for treating treatment-resistant depression and underscored the importance of exploring multiple treatment options.

4. TADS (Treatment for Adolescents with Depression Study)

• Year: 2004
• Focus: Compared fluoxetine (an SSRI), cognitive-behavioral therapy (CBT), their combination, and a placebo for treating adolescent depression.
• Findings: The combination of fluoxetine and CBT was the most effective in reducing depressive symptoms. Fluoxetine alone was also effective but had a higher risk of suicidal thoughts than CBT alone.
• Impact: Informed guidelines on treating adolescent depression, leading to greater emphasis on combining psychotherapy and pharmacotherapy for safety and effectiveness.

5. PRIDE Study (Prevention of Recurrent Episodes of Depression with Cognitive Behavioral Therapy)

• Year: 2016
• Focus: Compared antidepressant medication alone versus the combination of medication and cognitive-behavioral therapy (CBT) for preventing recurrence in patients with recurrent major depression.
• Findings: Combining CBT with medication significantly reduced the risk of relapse compared to medication alone.
• Impact: Reinforced the role of CBT in long-term management of depression, particularly for relapse prevention.

6. ANCHOR Study (Adjunctive Ketamine for Chronic Treatment-Resistant Depression)

• Year: 2017
• Focus: Tested the effectiveness of ketamine as an adjunct therapy for treatment-resistant depression.
• Findings: Found that ketamine produced rapid antidepressant effects, even in patients who had not responded to other treatments.
• Impact: Opened new avenues for the treatment of treatment-resistant depression and paved the way for further exploration of ketamine and other rapid-acting antidepressants.

7. UK700 Study (Intensive Case Management for Severe Mental Illness)

• Year: 1999
• Focus: Assessed the effectiveness of intensive case management for patients with severe mental illness compared to standard case management.
• Findings: Showed that intensive case management did not significantly reduce hospital admissions but did improve engagement with services.
• Impact: Led to more realistic expectations about intensive case management, influencing policies and resource allocation in community mental health services.

8. LITHIUM Trial (Lithium for Bipolar and Related Mood Disorders)

• Year: 2004
• Focus: Investigated lithium’s efficacy for bipolar disorder compared to other mood stabilizers like valproate.
• Findings: Lithium was found to be effective in reducing suicide risk and mood stabilization.
• Impact: Reinforced lithium’s role as a cornerstone in bipolar disorder treatment, especially for its anti-suicidal effects.

9. RCT on ECT vs. Ketamine for Severe Depression (Lancet Psychiatry)

• Year: 2017
• Focus: Compared electroconvulsive therapy (ECT) and ketamine infusions in patients with treatment-resistant depression.
• Findings: Both treatments showed effectiveness, though ECT had more sustained effects. Ketamine offered a potential alternative with fewer cognitive side effects.
• Impact: Broadened treatment options for severe depression, especially for patients concerned about the side effects of ECT.

10. MULTI-PSYCH Study (Collaborative Care for Depression and Anxiety in Primary Care)

• Year: 2013
• Focus: Explored the collaborative care model, where primary care providers, psychiatrists, and care managers work together to manage depression and anxiety.
• Findings: Collaborative care improved depression and anxiety outcomes compared to standard primary care.
• Impact: Contributed to a shift toward collaborative care models in managing mental health within primary care, making mental health support more accessible.

These landmark studies have shaped psychiatric practice, offering valuable insights into effective treatments and guiding treatment standards worldwide.