What are the recommended medications, including extended-release (ER) formulations, for treating mental illnesses such as depression, anxiety, bipolar disorder, and schizophrenia?

Medications with Extended-Release Formulations for Mental Illness

Schizophrenia and Psychotic Disorders

For schizophrenia, haloperidol or chlorpromazine should be routinely offered as first-line agents, with second-generation antipsychotics as alternatives when cost and availability permit. 1

First-Line Antipsychotic Options

• Typical antipsychotics (haloperidol, chlorpromazine) remain recommended first-line agents, particularly in resource-limited settings 1
• Atypical antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone) are at least as effective for positive symptoms and may be preferred when availability can be assured 1
• Clozapine should be reserved for treatment-resistant schizophrenia after failure of at least two other antipsychotic trials (one or both should be atypical agents), and only when routine laboratory monitoring is available 1

Extended-Release/Depot Formulations

• Long-acting injectable (LAI) preparations should be offered to individuals on long-term antipsychotic treatment, with patients given adequate information to choose between oral and depot preparations to improve adherence 1
• LAI formulations improve treatment adherence and reduce relapse rates compared to oral formulations, though misconceptions about their use persist 2

Treatment Duration and Monitoring

• Antipsychotic treatment must continue for at least 12 months after beginning of remission 1
• Adequate therapeutic trials require sufficient dosages over 4-6 weeks before concluding ineffectiveness 1
• First-episode patients should receive maintenance treatment for 1-2 years after the initial episode given high relapse risk 1

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Bipolar Disorder

For acute mania, lithium, valproate, or atypical antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine, ziprasidone) are recommended first-line treatments, with lithium showing superior evidence for long-term maintenance therapy. 3

Acute Mania/Mixed Episodes

• Lithium is FDA-approved for patients age 12 and older, with response rates of 38-62% in acute mania 3
• Valproate shows higher response rates (53%) compared to lithium (38%) in children and adolescents with mania and mixed episodes 3
• Atypical antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine, ziprasidone) are approved for acute mania and may provide more rapid symptom control 3
• Combination therapy with lithium or valproate plus an atypical antipsychotic is recommended for severe presentations 3

Maintenance Therapy

• Lithium or valproate should be used for maintenance treatment, continuing for at least 2 years after the last episode 1, 3, 4
• Lithium demonstrates superior evidence for prevention of both manic and depressive episodes in long-term trials 3
• Lamotrigine is approved for maintenance therapy and is particularly effective for preventing depressive episodes 3, 4
• Withdrawal of maintenance therapy dramatically increases relapse risk, with over 90% of noncompliant patients relapsing versus 37.5% of compliant patients 3, 4

Bipolar Depression

• Olanzapine-fluoxetine combination is recommended as first-line treatment for bipolar depression 3
• Antidepressants must always be combined with a mood stabilizer (lithium or valproate), never used as monotherapy due to risk of mood destabilization and mania induction 1, 3
• SSRIs (fluoxetine) are preferred over tricyclic antidepressants when antidepressants are indicated 1

Extended-Release Considerations

• Valproate extended-release formulations allow for once-daily dosing with target therapeutic range of 50-100 μg/mL 3
• Regular monitoring of serum drug levels, hepatic function, and hematological indices is required every 3-6 months 3

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Depression

While the question asks about depression, the provided evidence focuses primarily on bipolar depression rather than unipolar major depressive disorder. For bipolar depression specifically:

• Combination therapy with olanzapine-fluoxetine is the recommended first-line approach 3
• SSRIs (particularly fluoxetine) are preferred when antidepressants are used, but must always be combined with mood stabilizers 1, 3
• Antidepressant monotherapy is contraindicated in bipolar disorder due to high risk of mood destabilization 3

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Anxiety Disorders

For anxiety disorders, SSRIs are first-line treatment, with atypical antipsychotics reserved for adjunctive therapy or treatment-resistant cases. 5, 6

First-Line Treatment

• SSRIs (sertraline, paroxetine, fluoxetine) are the most studied and effective medications with favorable adverse effect profiles 5
• Continuation and maintenance treatment for 6-12 months decreases relapse rates 5

Second-Line Options

• Serotonin-potentiating non-SSRIs (venlafaxine, nefazodone, trazodone, mirtazapine) should be considered if SSRIs are not tolerated or ineffective 5
• Pregabalin has European Commission approval for generalized anxiety disorder 6

Adjunctive/Alternative Therapy

• Atypical antipsychotics (quetiapine, aripiprazole, olanzapine, risperidone) have shown efficacy as adjunctive therapy or monotherapy for generalized anxiety disorder, though this is an off-label indication 6
• Approximately 50% of participants tolerate side effects (most commonly sedation and fatigue), with significant anxiety reduction among those who continue treatment 6

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Critical Monitoring Requirements

For Lithium

• Baseline: Complete blood count, thyroid function tests, urinalysis, BUN, creatinine, serum calcium, pregnancy test in females 3
• Ongoing: Lithium levels, renal and thyroid function, urinalysis every 3-6 months 3
• Target levels: 0.8-1.2 mEq/L for acute treatment 3

For Valproate

• Baseline: Liver function tests, complete blood count, pregnancy test 3
• Ongoing: Serum drug levels, hepatic function, hematological indices every 3-6 months 3
• Target levels: 50-100 μg/mL 3

For Atypical Antipsychotics

• Baseline: BMI, waist circumference, blood pressure, fasting glucose, fasting lipid panel 3
• Follow-up: BMI monthly for 3 months then quarterly; blood pressure, glucose, lipids at 3 months then yearly 3

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Common Pitfalls to Avoid

• Never use antidepressant monotherapy in bipolar disorder - this triggers manic episodes or rapid cycling 3
• Avoid premature discontinuation of maintenance therapy - leads to relapse rates exceeding 90% 3, 4
• Do not rapid-load lamotrigine - dramatically increases risk of Stevens-Johnson syndrome 3, 4
• Never discontinue lithium abruptly - must taper over 2-4 weeks minimum to minimize rebound mania risk 3, 4
• Failure to monitor metabolic side effects of atypical antipsychotics, particularly weight gain and metabolic syndrome 3
• Inadequate trial duration - systematic trials require 6-8 weeks at adequate doses before concluding ineffectiveness 1, 3