This is a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy, safety, and tolerability of ITI-1284 as monotherapy treatment in patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) criteria for GAD in patients who have had inadequate response to generalized anxiety disorder treatment.

The study will be conducted in 3 periods:

• Screening Period (up to 2 weeks) during which patient eligibility will be assessed and the washout of prohibited medications will occur;
• Double-blind Treatment Period (6 weeks) during which a total of approximately 570 patients are planned to be randomized in a 1:1:1 ratio to receive one of the 3 treatments (ITI-1284 10 mg, ITI-1284 20 mg, or placebo);
• Safety Follow-up Period (1 week) during which all patients will return for a safety follow-up visit approximately 1 week after the last dose of study drug.

Inclusion Criteria:

• Provide written informed consent before the initiation of any study specific procedures;

• At Screening, meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) diagnostic criteria for moderate or severe GAD as confirmed by the Investigator or Sponsor-approved rater using the Structured Clinical Interview for DSM-5 Clinical Trials Version (SCID-5-CT), and meets all of the following at Screening and Baseline:

  • HAM-A Total score of ≥ 22;
  • HAM-A Items 1 (anxious mood) and 2 (tension) scores ≥ 2;
  • CGI-S score of ≥ 4;

• History of inadequate response (< 50% improvement in anxiety symptoms as measured by the modified Antidepressant Treatment Response Questionnaire [ATRQ] for GAD) to at least 2 of the following GAD-approved treatments: paroxetine, venlafaxine XR, duloxetine, escitalopram, or buspirone taken at an adequate dose (at least the minimum GAD-approved dose per package insert) and duration (ie, for at least 6 weeks prior to Screening) for the treatment of ongoing GAD symptoms.

Exclusion Criteria:

• Within the patient's lifetime, has one of the following confirmed DSM-5-TR psychiatric diagnoses:

  • Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder or other psychotic disorder;
  • Bipolar Disorder;

• MADRS total score > 18 at Screening or Baseline;

• In the opinion of the Investigator, the patient has a significant risk for suicidal behavior during his/her participation in the study or

  • At Screening, the patient scores "yes" on Suicidal Ideation Items 4 or 5 of the C-SSRS within 6 months prior to Screening or, at Baseline, the patient scores "yes" on Suicidal Ideation Items 4 or 5 since the Screening Visit;
  • At Screening, the patient has had 1 or more suicidal attempts within the 2 years prior to Screening;
  • At Screening or Baseline MADRS Item 10 score ≥ 5; or
  • The patient is considered to be an imminent danger to him/herself or others based on the assessment of the Investigator;

• Lifetime history of failure to respond to > 3 of the approved treatments for GAD (ie, paroxetine, venlafaxine XR, duloxetine, escitalopram, or buspirone) at an adequate dose (ie, at least the minimum dose approved for GAD per package insert) and for an adequate duration (ie, at least 6 weeks).