Which comes first, Selective Serotonin Reuptake Inhibitor (SSRI) or antipsychotic, in treating a patient?

Treatment Sequencing: SSRI vs Antipsychotic

The choice between starting an SSRI or antipsychotic first depends entirely on the primary diagnosis and target symptoms—antipsychotics should be initiated first for psychotic disorders (schizophrenia, bipolar mania with psychosis, delusional disorder), while SSRIs should be started first for primary mood and anxiety disorders (depression, OCD, anxiety disorders). 1

For Psychotic Disorders

Start with an antipsychotic as monotherapy:

• In schizophrenia, antipsychotics are the first-line treatment and should be initiated immediately for psychotic symptoms lasting ≥1 week with distress or functional impairment 1
• For bipolar mania with psychosis, the treatment of choice is a mood stabilizer plus an antipsychotic (98% expert consensus), not an SSRI 2
• In delusional disorder, an antipsychotic alone is the only recommended treatment 2
• SSRIs should not be used as first-line agents in schizophrenia—meta-analyses show no global support for SSRI augmentation improving negative symptoms, and they are not effective for primary psychotic symptoms 3, 4

When to Consider Adding an SSRI Later

• SSRIs may be added as augmentation therapy only after antipsychotic stabilization if comorbid depression or OCD symptoms persist 3
• For treatment-resistant depression in schizophrenia, olanzapine plus fluoxetine combination has shown efficacy, but this is added after antipsychotic treatment is established 5
• Close monitoring is required when combining antipsychotics with SSRIs due to potential drug interactions and side effects 3

For Mood and Anxiety Disorders

Start with an SSRI as first-line monotherapy:

• For major depressive disorder without psychotic features, SSRIs are first-line treatment (79% expert consensus for nonpsychotic depression) 1, 2
• For OCD, SSRIs are the first-line pharmacological treatment based on efficacy, tolerability, and safety profile 1
• For anxiety disorders (generalized anxiety, social anxiety, panic, separation anxiety), SSRIs are recommended as first-line medication 1
• Antipsychotics are not recommended for nonpsychotic depression, anxiety disorders, or panic disorder 2

When to Add an Antipsychotic Later

• For psychotic major depression, the treatment of choice is an antipsychotic plus an antidepressant (98% expert consensus), but both should be started together, not sequentially 2
• For treatment-resistant depression (failure of two adequate antidepressant trials), there is limited support (36% expert consensus) for adding an atypical antipsychotic to the antidepressant 2
• For severe agitated nonpsychotic depression, an antidepressant alone remains first-line (77% expert consensus); adding an antipsychotic is only second-line 2

For OCD Specifically

SSRIs come first, antipsychotics only for augmentation:

• SSRIs are first-line pharmacological treatment for OCD with an 8-12 week trial at therapeutic doses required to assess efficacy 1
• Antipsychotics should only be considered as augmentation therapy if OCD remains treatment-resistant after adequate SSRI trials 1
• In the context of OCD treated first with an SSRI, if a benzodiazepine or antipsychotic was later added to reduce anxiety, the antipsychotic should be tapered first when discontinuing medications 1

For Comorbid Conditions

Treat the most severe and impairing disorder first:

• When a patient has two disorders requiring different medications, remove the medication for the disorder that is less severe or more likely to remit 1
• For ADHD plus depression, if depression is more impairing, start the antidepressant first; if ADHD was never impairing until depression emerged, the stimulant might be discontinued first 1
• For ODD with comorbid ADHD, target the ADHD with stimulants or atomoxetine first, as this may improve oppositional behavior; antipsychotics are not first-line unless severe aggression is present 1

Critical Caveats

• Never use antipsychotics for nonpsychotic conditions as first-line unless severe aggression or agitation poses safety concerns 1, 2
• When combining medications, keep the one with the most prophylactic efficacy or least long-term side effect potential—for bipolar disorder, this typically means tapering the antipsychotic before the mood stabilizer 1
• SSRIs require 2-6 weeks for clinically significant improvement and up to 12 weeks for maximal effect, so early assessment of efficacy should be cautious 1
• Antipsychotics show therapeutic response within 4 weeks at adequate doses in schizophrenia; if no response, switch to a different antipsychotic rather than adding an SSRI 1