What is the difference between antipsychotics and antidepressants in clinical practice?

Antipsychotics vs Antidepressants: Clinical Distinctions

Antipsychotics and antidepressants are fundamentally different drug classes with distinct primary indications: antipsychotics target psychosis and dopamine dysregulation (primarily in schizophrenia and bipolar disorder), while antidepressants target mood symptoms and serotonergic/noradrenergic systems (primarily in major depressive disorder).

Primary Indications and Mechanisms

Antidepressants

• Antidepressants are first-line treatment for major depressive disorder, dysthymia, and subsyndromal depression 1
• Second-generation antidepressants (SSRIs, SNRIs, bupropion, mirtazapine) work primarily through serotonergic and noradrenergic mechanisms 1
• Selection should be based on adverse effect profiles, cost, and patient preferences rather than efficacy differences, as all second-generation antidepressants show equivalent effectiveness for depression 1
• Response rates are approximately 50% for first-line treatment, with 38% of patients not achieving response and 54% not achieving remission within 6-12 weeks 1

Antipsychotics

• Antipsychotics are indicated for schizophrenia, acute mania, and psychotic features across diagnoses—they reduce psychosis regardless of underlying condition 2
• All currently available antipsychotics work as dopamine D2 receptor blockers or partial agonists 2
• Antipsychotics are not specific to schizophrenia; they provide antipsychotic effects beyond nonspecific sedation 2
• Effect sizes for relapse prevention in schizophrenia are larger than for acute treatment 2

Overlapping Clinical Applications

Antipsychotics in Mood Disorders

• Three second-generation antipsychotics have FDA approval for adjunctive treatment of major depressive disorder: quetiapine, aripiprazole, and olanzapine 3
• Quetiapine and lurasidone are FDA-approved for bipolar depression 3
• Antipsychotics are effective for depression only at subantipsychotic doses; full antipsychotic doses are dysphorogenic and produce depression-like symptoms 3
• The antidepressant effect is not universal—it appears unique to quetiapine, aripiprazole, and possibly lurasidone, with ziprasidone showing insignificant antidepressant action 3

Combination Therapy for Psychotic Depression

• Practice guidelines recommend combining an antidepressant with an antipsychotic for major depressive disorder with psychotic features 4
• However, only 5% of patients with psychotic depression receive adequate combination therapy (therapeutic antidepressant dose plus high-dose antipsychotic) in usual care 4
• This represents a significant treatment gap given the high morbidity of psychotic depression 4

Critical Adverse Effect Differences

Antidepressant Side Effects

• Bupropion has the lowest rate of sexual dysfunction compared to SSRIs 5
• Paroxetine has higher rates of sexual dysfunction and anticholinergic effects that worsen cognitive function 5
• SSRIs are associated with increased risk for suicide attempts compared to placebo, requiring close monitoring within 1-2 weeks of initiation 1
• Monitoring for suicidal thoughts and behaviors should begin 1-2 weeks after starting antidepressants, with greatest risk in the first 1-2 months 1

Antipsychotic Side Effects

• Antipsychotics carry FDA black box warnings for QTc prolongation and sudden death (thioridazine, droperidol) 1
• Most antipsychotics cause some degree of QTc prolongation: thioridazine (25-30ms), ziprasidone (5-22ms), while aripiprazole causes none 1
• Intramuscular dosing is preferred over intravenous administration in emergency settings to minimize cardiac risk 1
• Second-generation antipsychotics vary markedly in metabolic side effects (weight gain, diabetes risk) 6

Treatment Algorithms

For Major Depressive Disorder Without Psychosis

• Start with a second-generation antidepressant selected based on side effect profile 1
• For cognitive symptoms ("brain fog"), bupropion is first-line due to lower cognitive side effects and activating properties 5
• SNRIs (venlafaxine, duloxetine) are second-line for cognitive symptoms 5
• Avoid paroxetine and TCAs due to anticholinergic effects that worsen cognition 5
• Assess response within 1-2 weeks and modify treatment if no adequate response by 6-8 weeks 1
• Continue treatment 4-9 months after response for first episode; longer for recurrent depression 1

For Major Depressive Disorder With Psychotic Features

• Combine a therapeutic dose of antidepressant with a high dose of antipsychotic 4
• This combination is essential but significantly underutilized in clinical practice 4

For Bipolar Depression

• Consider quetiapine, lurasidone, or lumateperone as FDA-approved options 7
• Use subantipsychotic doses to avoid dysphorogenic effects 3

Common Pitfalls to Avoid

• Do not use full antipsychotic doses when treating depression—this produces depression-like symptoms 3
• Do not assume all antipsychotics have antidepressant properties; this effect is agent-specific 3
• Do not combine fluoxetine with thioridazine or pimozide due to risk of fatal arrhythmias 8
• Do not discontinue antidepressants prematurely; maintain for at least 4-9 months after remission 1
• Intramuscular administration of antipsychotics is safer than intravenous in emergency settings 1