Treatment Modalities

PSYCHOPHARMACOLOGIC AGENTS

Food and Drug Administration (FDA) pharmaceutical pregnancy classification
Receptors targeted by psychopharmacologic agents
Pharmacologic treatment of depression
- Names and doses of commonly used agents
- Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs)
- Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)
- Alternative agents
Pharmacologic treatment of anxiety
- Agents used to treat anxiety
Pharmacologic treatment of bipolar disorder
- Evidence of efficacy of selected agents
- Names and doses of commonly used agents
- Specific characteristics of:
  - Lithium
  - Valproate
  - Carbamazepine
  - Lamotrigine
Pharmacologic treatment of psychosis
- “Typical” (first-generation) neuroleptics
- “Atypical” (second-generation) antipsychotics
- Clozapine
Medications used in the treatment of dementia
- Names and doses of commonly used agents
- Anticholinesterase and N-methyl-D-aspartic acid (NMDA)agents
Medications used in the treatment of attention-deficit hyperactivity disorder (ADHD)
- Names and doses of commonly used agents
- Summary of properties of stimulants
Medications used for treatment of substance dependence and withdrawal
- Alcohol
- Nicotine
- Opiates
Sedative-hypnotics and other sedating drugs
Proposed herbal remedies for psychiatric symptoms
Common adverse effects and their management
Somatic Therapies
Psychotherapies

TABLE 5-1 Food and Drug Administration Pharmaceutical Pregnancy Classification

Category A: Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters)
Category B: animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women OR animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester
Category C: animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks
Category D: there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks
Category X: studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh the potential benefits

PHARMACOLOGIC TREATMENT OF DEPRESSION

Choosing an Agent

See p. 65 for a general discussion of diagnosis and treatment
Clinical outcomes, quality-of-life outcomes, and cost analyses provide minimal guidance
Initial choice should be based on adverse effects, interactions with other medications, and tolerability

Dosages

Start at a low dose and titrate gradually in elderly patients, and provide adequate milligrams per kilograms in children
Increase the dose after 1 to 2 weeks
Doses may need to be higher with chronic illness or comorbid conditions (e.g., anxiety)

Monitoring

Follow-up visits should be done twice or month or more for several months, especially with severely depressed or suicidal patients
Monitor adherence to prescribed treatment

Changing and Augmenting Therapy

Can switch medications (to same or different class) or supplement with adjunctive medication if there has been no response by 8 to 12 weeks at a maximal dose
Typical augmentation strategies include lithium, lamotrigine, other anticonvulsants, buspirone, stimulants, low doses of atypical antipsychotics (e.g., quetiapine), and natural supplements(continued)

TABLE 5-2 Receptors Targeted by Psychopharmacologic Agents

Class and Receptors Affected	Relevant Transporters and Clearance Mechanisms	CNS Targets	Actions	Agonists	Antagonists	Functional Pathways
Dopamine (DA) D2 D4	↓DAT ↓MAO	DA neurons in nigrostriatal, mesolimbic and tuberoinfundibular circuits D2: DA cell bodies, terminals; lactotrophs (anterior pituitary) D4: frontal cortex, medulla, midbrain (VTA)	D2, D4: ↓AC, ↓cAMP, ↑K+, ↓C⁻ conductance DAT: Na⁺/K⁺ pump, clears DA from synaptic cleft MAO: catabolizes monoamines	D2: bromocriptine, pramipexole DAT: Bupropion and Wellbutrin (?), amphetamines (increase DA-release), methylphenidate (blocks reuptake) MAO: MAOIs	D2: typical and atypical antipsychotics D4: atypical antipsychotics	Cognition Motor activity Motivation and reward Prolactin production (inhibitory) Sleep Mood Attention and learning
Norepinephrine (NE) α₁ α₂	↓SERT ↓MAO	Neurons originate mostly in the locus ceruleus and innervate the forebrain and cerebellum	α₁: ↑IP₃ DAG/Ca²⁺ α₂: ↓ AC, ↓cAMP, ↑K⁺, ↑Cl⁻ (autoreceptor) NET: Na⁺/Cl⁻ driven NE transporter, clears NE MAO: catabolizes monoamines	NET: SNRIs, NRIs, TCAs, bupropion (block reuptake), amphetamines (increase release of NE) α₂: clonidine (agonist), mirtazapine (antagonizes and increases release of NE, 5HT) MAO: MAOIs	NET: trazodone α₁: TCAs, low-potency typical antipsychotics, trazodone, atypical antipsychotics	Arousal Attention Vasopressin
Serotonin (5-OH-tryptamine, 5HT) 5HT_1A,B,D,E,F 5HT_2A,B,C 5HT₃ 5HT_4,6,7	↓ SERT ↓ MAO	5HT_1A: limbic: postsynaptic, raphe 5HT_2A: cortex 5HT_2C: widespread 5HT₃: hippocampus, solitary tract, postrema 5HT₅: hypothalamus, corpus callosum, ventricles 5HT₆: striatum, limbic areas, cortex 5HT₇: cortex, thalamus, midbrain, raphe NN; SERT (reuptake): presynaptic cortical, neostriatum, thalamus, limbic	5HT_1A,B,D,E,F: ↓AC,↓cAMP, activates K⁺ channels 5HT_2A,B,C: ↑IP₃/DAG/Ca²⁺ 5HT₃: ligand-gated Na+ channel 5HT_4,5,6,7: ↑AC, ↑cAMP 5HTT: Na⁺/K⁺ ATPase-dependent, clears 5HT MAO: catabolizes monoamines (NE, 5HT, DA)	5HT_1A: buspirone/BuSpar (partial), TCAs (upregulate) 5HT₂: TCAs (downregulate) 5HT_2aA2C: trazodone (downregulate) 5HT_2/3: mirtazapine/Remeron (antagonist) 5-HTT: SRIs, SNRIs, TCAs, trazodone/ Desyrel SRIs (block reuptake)	5HT_1A: buspirone 5HT₂: atypical antipsychotics, trazodone 5HT_2A/2C/3: mirtazapine	Mood Sleep Aggression Appetite Metabolism Sexuality Anger Vomiting
5HT, serotonin; AC, adenylyl cyclase; AChE, acetylcholinesterase; cAMP, cyclic adenosine monophosphate; CNS, central nervous system DA, dopamine; DAG, diacylglycerol; DAT, dopamine transporter; IP₃, inositol-1,4,5-triphosphate; mACh, muscarinic acetylcholine; MAO, monoamine oxidase; MAOIs, monoamine oxidase inhibitors; NE, norepinephrine; NET, norepinephrine transporter; NRI, norepinephrine reuptake inhibitor; PLC, phospholipase C; SERT: serotonin transporter; SNRI, serotonin and norepinephrine reuptake inhibitor; SRI, serotonin reuptake inhibitor; TCA: tricyclic and tetracyclic antidepressant.

TABLE 5-3 Amino Acids and Other Transmitters

Class and Receptors Affected	CNS Targets	Actions	Agonists	Antagonists
GABA, GABA_A	Limbic, cortical areas	GABA_A: ↑Cl-conductance (hyperpolarizes)	GABA_A: Benzodiazepines (BZ₁ or BZ₂ receptors); other hypnotics
Glutamate, NMDA	NMDA in cortex, hippocampus, striatum, septum, amygdala	NMDA: inotropic: ↑Na⁺, ↑Ca²⁺, ↑CaMKII		NMDA: memantine/Namenda
Histamine/H1	Tuberoma-mmillary neurons to forebrain	H1: ↑IP3/DAG/Ca²⁺	H₁: (e.g., mirtazapine, doxepin)	H₁: TCAs, mirtazapine, trazodone, low-potency typical antipsychotics, antihistamines (diphenhy-dramine)
Melatonin/MT₁, MT₂	From suprachiasmatic nucleus		MT₁, MT₂ agonists (e.g., ramelteon)
DAG, diacylglycerol; GABA, γ-aminobutyric acid; IP₃: inositol-1,4,5-triphosphate; NMDA, Nmethyl-D-aspartic acid; TCA, tricyclic and tetracyclic antidepressant.

Maintenance

The goal should be complete remission of symptoms
Continue for at least 6 months, even after recovery

Cessation

Early withdrawal and discontinuation syndromes can occur within days after rapid discontinuation of short-acting agents
- SSRIs and SNRIs: may include dizziness, nausea, fatigue, muscle aches, chills, anxiety, irritability
- TCAs: irritability, agitation, sleep disturbance, flu-like symptoms, cardiac arrhythmia (rare)
- MAOIs: delirium, agitation, myoclonic jerks, insomnia
- Bupropion, fluoxetine, mirtazapine: uncommon
Continuation of MAOI effects after cessation may interact with other agents and foods to induce delirium and death (SSRIs, meperidine, tyramine in foods)
Rapid discontinuation of antidepressant can lead to increased risk of relapse, sometimes with more severe depression than in past
Reducing doses slowly over 2 to 4 weeks of medications with short halflives may reduce the risk of early and later adverse outcomes

Pregnancy

All antidepressants are category C (some animal studies show adverse effects, but no controlled studies in humans are available) or D (there is evidence of risk to human fetuses, but the potential benefits may justify the risk)
Consider cognitive behavioral therapy (CBT), interpersonal therapy, supportive therapy, electroconvulsive therapy (ECT), and hospitalization when medications are contraindicated

TABLE 5-4 Pharmacologic Agents For Depression (Food and Drug Administration Approved and Off Label)

Drug Type	Actions	Therapeutics	Limitations, Contraindications, and Side Effects
Selective serotonin reuptake inhibitors	Block reuptake of 5HT at SERT	Common initial treatment Nonlethal in overdose Generally mild adverse effects Low doses may work for panic and anxiety disorders, but, patients with OCD require high doses	May lead to weight gain, agitation, insomnia or sedation GI and sexual side effects common Discontinuation syndrome with drugs that have short half-life (e.g., paroxetine)
Serotonin norepinephrine reuptake inhibitors	Block reuptake of 5HT and NE at both SERT and NET sites	FDA indication for depression Duloxetine, high doses of venlafaxine, or tertiary-amine TCAs may be used for neuropathic pain	Liver disease: duloxetine is contraindicated High blood pressure: venlafaxine is contraindicated Duloxetine: relatively dangerous in overdose Early discontinuation syndrome is common with venlafaxine
Bupropion (Wellbutrin, Zyban)	Weakly blocks uptake of DA and NE at DAT and NET sites	Adverse sexual effects are rare May be stimulating Often useful as an SRI adjunct Help with smoking cessation	May lower the seizure threshold at higher doses and perhaps with bulimia or alcohol-dependence
Mirtazapine (Remeron)	Agonist at α₂ adrenergic and 5HT-2a, -2C, -3 auto, and other receptors to facilitate release of both NE and 5-HT Blocks H1 receptors (sedating)	Moderate sexual adverse effects Useful for patients with ansomnia or anorexia	May cause weight-gain, sedation, autonomic effects, or rare neutropenia (monitor CBC)
Tricyclic agents (TCAs: amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine)	Block reuptake of 5HT and NE if tertiary-amines (amitriptyline), but mainly NE if secondary amines (desipramine)	Now held as a secondary option for otherwise resistant depression Often reduce tics Overdoses can be lethal (cardiotoxicity and delirium)	Contraindicated with glaucoma, past MI, diabetes Risks: weight-gain, GI symptoms, urinary retention, elderly patients
Monoamine oxidase inhibitors (phenelzine, selegiline, tranylcypromine)	Prolonged anti-MAO-A and B actions Selegiline has some MAO-B selectivity at low doses (safer with sympatho-mimetics), but MAO-A inhibition is more antidepressant	Third-line treatment for resistant depression Autonomic and sexual effects mimic those of the anticholinergics	Dietary restrictions to avoid tyramine and other sympathomimetics Many drug interactions (especially SSRIs and methylphenidate) May be lethal in overdose
Lamotrigine Lamictal)	Blocks voltage-nsitive Na⁺-channels, inhibits release of excitatory amino acids glutamate and aspartate	Increase the dose slowly and monitor to avoid adverse effects (skin toxicity: dose and rate dependent, worse with valproate); restart at original dose if discontinued >4 days	May cause mild (common) or severe (rare) rash and blood dyscrasias
Quetiapine (Seroquel)	Atypical antipsychotic, serotonin/dopamine antagonist; strongly anti-H₁ (sedative) Metabolite may block NET	Helpful for patients with anxiety and insomnia (low doses) or psychosis (high doses)	Weight gain, sedation, orthostatic hypotension
Atomoxetine (NRI, Strattera)	Mainly a NET inhibitor	Weakly effective in patients with ADHD	Not clearly effective in MDD
Stimulants (methylphenidate, amphetamines)	Mainly release and prevent reuptake of DA and NE	Used in treatment-resistant depression and in elderly patients to assist with appetite and energy	Potential for abuse May induce mania in bipolar disorder (as can all antidepressants as doses increase) May worsen OCD and induce tics
5HT, serotonin; ADHD, attention-deficit hyperactivity disorder; CBC, complete blood count; DA, dopamine; DAT, dopamine transporter; GI, gastrointestinal; MAO, monoamine oxidase; MDD, major depressive disorder; MI, myocardial infarction; NE, norepinephrine; NET, norepinephrine transporter; NRI, norepinephrine reuptake inhibitor; OCD, obsessive-compulsive disorder; SERT, serotonin transporter; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

PHARMACOLOGIC TREATMENT OF ANXIETY

Choosing an Agent

See p. 52 for a general discussion of diagnosis and treatment
SSRIs and SNRIs are first-line agents for most of the disorders
TCAs and MAOIs are effective but are typically associated with more side effects (continued)
MAOI use is supported by controlled trials in panic disorder, posttraumatic stress disorder and social anxiety disorder
TCAs have no good evidence for use in patients with social anxiety disorder
Benzodiazepine are efficacious, fast acting, and generally well tolerated but have abuse potential
Studies have shown efficacy for buspirone, but results in clinical practice are less reliable (continued)

TABLE 5-5 Selective Serotonin Reuptake Inhibitors

Agents (brand): citalopram (CIT; Celexa), escitalopram (ESC; Lexapro), fluoxetine (FLU; Prozac), fluvoxamine (FLV; Luvox; OCD only), paroxetine (PAR; Paxil), sertraline (SER; Zoloft)

Indications (FDA-approved indications in bold): MDD (all), GAD (ESC, SER), panic disorder (FLU, PAR, SER), OCD (FLU, FLV, PAR, SER), premenstrual dysphoric disorder (FLU, PAR, SER), social anxiety disorder (PAR, SER), bulimia

Contraindications:

Contraindicated with MAOI agents (washout ≥2 wks, ≥5 wks with fluoxetine)
Contraindicated with pimozide and thioridazine
Avoid other SSRIs, triptans, tryptophan, lithium, tramadol, linezolid, St. John’s Wort, and fluconazole because of the risk of serotonin syndrome
Caution with NSAIDS (risk of GI bleeding)
Caution with diuretics (SIADH)

Adverse effects:

CNS: mania; exacerbation of depression, suicidality, weakness, cognitive disturbances, somnolence, insomnia, seizures (rare)

GI: nausea (improves later), xerostomia, anorexia or weight gain, diarrhea, increased LFTs (rare), GI bleed (rare), bruxism (rare)

Cardiovascular: arrhythmias (rare), decreased BP, dizziness

Metabolic: sweating, rash or urticaria, bleeding (rare), hyponatremia, SIADH, increased blood glucose, gout, osteoporosis, galactorrhea

Urologic: decreased libido, late ejaculation

Augmentation: bupropion, quetiapine, stimulants

Overdose: relatively safe

Withdrawal: symptoms include dizziness, lightheadedness, insomnia, fatigue, anxiety, agitation, nausea, headache

Metabolism: hepatic: 2D6: fluoxetine, paroxetine, sertraline, citalopram, escitalopram; 3A4/2C19: fluvoxamine

Pregnancy: category C

BP, blood pressure; CNS, central nervous system; FDA, Food and Drug Administration; GAD, generalized anxiety disorder; GI, gastrointestinal; LFT, liver function test; MAOI, monoamine oxidase inhibitor; MDD, major depressive disorder; NSAID, nonsteroidal antiinflammatory drug; OCD, obsessive-compulsive disorder; SIADH, syndrome of inappropriate antidiuretic hormone; SSRI, selective serotonin reuptake inhibitor.

TABLE 5-6 Serotonin Norepinephrine Reuptake Inhibitors

Agents (brand): desvenlafaxine (DES; Pristiq), duloxetine (DUL; Cymbalta), venlafaxine (VEN; Effexor)

Indications (FDA-approved indications in bold): MDD (all), GAD (VEN), social phobia (VEN), panic disorder (VEN), diabetic neuropathy pain, fibromyalgia

Contraindications and interactions:

Contraindicated with MAOI agents
Use caution when using phenothiazine, TCAs, ciprofloxacin, ketoconazole,
Use caution when using SSRIs, triptans, tryptophan, lithium, tramadol, linezolid, cyclobenzaprine, and St. John’s Wort because these can lead to serotonin syndrome (see p. 41 for more information)
Use caution in patients with glaucoma, seizure disorder
Bulimia and alcohol dependence are relative contraindications

Adverse effects:

CNS: mania, agitation, depression exacerbation, suicidality (thoughts), asthenia or fatigue, dizziness, headache, insomnia or somnolence, tremor, blurred vision, seizures (rare)

GI: weight loss (rare gain), decreased appetite, nausea, constipation or diarrhea, xerostomia; bulimia and alcohol dependence are relative contraindications; increased LFTs

Cardiovascular: high BP (VEN: dose dependent), orthostatic decreased BP

Metabolic: increased blood glucose (rare), hyponatremia or SIADH (rare); increased sweating

Urologic: decreased libido, late ejaculation; urinary frequency or hesitation

Augmentation: mood stabilizers, atypical antipsychotics, Modafinil, benzodiazepines, gabapentin, lithium, buspirone, thyroid hormone; use caution with mirtazapine (two dual agents)

Overdose: relatively safe

Withdrawal: milder than with SSRIs (dizziness, lightheadedness, insomnia, fatigue, anxiety, agitation, nausea, headache, sensory disturbances)

Metabolism: hepatic: increased DUL levels with quinidine; decreased DUL levels with carbamazepine, phenobarbital, and rifampin

Pregnancy: category C

BP, blood pressure; CNS, central nervous system; FDA, Food and Drug Administration; GAD, generalized anxiety disorder; GI, gastrointestinal; LFT, liver function test; MAOI, monoamine oxidase inhibitor; MDD, major depressive disorder; SIADH, syndrome of inappropriate antidiuretic hormone; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Dosages

Start slow because patients with anxiety are very sensitive to somatic side effects
Antidepressant doses used for depression are usually effective but in some cases it may be necessary to use higher doses

TABLE 5-7 Selective Serotonin Reuptake Inhibitors and Serotonin and Norepinephrine Reuptake Inhibitors

Medication and Route	Initial Dose (Dosing Range, mg/day)	Cost per Month (overage Dose)
Selective Serotonin Reuptake Inhibitors
Citalopram (Celexa): 10-, 20-, and 40-mg tablets	10-20 (20-60)	$10 (20 mg/day) Celexa: $81
Escitalopram (Lexapro): 10- and 20-mg tablets 5-mg/5 mL solution	5-10 (10-20)	$84 (20 mg/day) No generic
Fluoxetine (Prozac): 10- and 20-mg tablets 20-mg/5 mL solution. 90-mg tablets (weekly)	10-20 (20-80)	$10 (20 mg/day) Prozac: $66 Weekly: $88 (30 mg)
Fluvoxamine (Luvox,-CR): 25-, 50-, and 100-mg tablets CR 100- and 150-mg tablets	25-50 (50-300)	$35 (100 mg/day) Luvox: $109 CR: $117
Paroxetine (Paxil, -CR): 10-, 20-, 30-, and 40-mg suspension CR 12.5, 25, 37.5 mg tablets	10-20 (20-60) (CR: 2.5-62.5)	$53 (30 mg/day), Paxil $90, CR $94
Sertraline (Zoloft): 25-, 50-, and 100- mg tablets	25-50 (50-200)	$13 (50 mg/day) Zoloft: $87
Serotonin and Norepinephrine Reuptake Inhibitors
Desvenlafaxine (Pristiq): 50-mg tablets	50 (50-100)	$122 (50 mg/day)
Duloxetine (Cymbalta): 20-, 30-, and 60-mg tablets	20 (40-120)	$125 (60 mg/day)
Venlafaxine (Effexor, Effexor XR): regular: 25-, 37.5-, 50-, 75-, and 100-mg tablets XR: 150- and 300-mg tablets	75 (25-175) (TID dosing) XR: 25-50 (75-175)	$50 ($75 BID) Effexor: $135 XR: $107
BID, twice a day; TID, three times a day.
June 2008 average cost per month from online pharmacies.

Monitoring

Monitor adherence to prescribed treatment, particularly when prescribing medications with abuse potential

Changing and Augmenting Therapy

Beta-blockers are sometimes used to reduce autonomic arousal in patients with panic attacks
Beta-blockers are helpful to reduce performance anxiety, but not generalized anxiety or social phobia (continued)

TABLE 5-8 Tricyclic Antidepressants

Agents (brand): amitriptyline (Elavil), clomipramine (Anafranil), desipramine (Norpramin), doxepin (Sinequan), imipramine (Tofranil), nortriptyline (Pamelor), protriptyline (Vivactil), trimipramine (Surmontil)

Indications (FDA-approved indications in bold): MDD, enuresis (IMI), dysthymia, panic disorder, agoraphobia, bulimia, ADHD, diabetic neuropathy, urinary incontinence, disorders of ejaculation, pain, sleep disorders

Contraindications and interactions:

Contraindicated with MAOIs (2-wk washout minimum)
Contraindicated for acute post-MI
Contraindicated in porphyria
Use caution with QT-prolonging drugs such as haloperidol, quetiapine, risperidone, ziprasidone, venlafaxine and class I and III antiarrhythmics (beta-blockers, CCBs, clonidine, digitalis)
Use caution with SSRIs, triptans tryptophan, lithium, tramadol, linezolid, St. John’s Wort, (serotonin syndrome)
Use caution with amphetamines (methylphenidate): increased cardiac side effects
Use caution with anticoagulants (may increase plasma levels)
Use caution with cimetidine

Adverse effects:

CNS: Suicidality, insomnia/nervousness, cognitive disturbances, delirium, paresthesias, tremor, blurred vision, rare seizures or tinnitus, increased risk of falls

GI: Constipation, ileus (rare), xerostomia (rare), hepatoxicity, weight gain

Cardiovascular: PR-prolongation, QTc prolongation, other ECG changes, arrhythmias, torsade de pointes (with risk of sudden death); all worse with overdoses

Metabolic: sweating, photosensitivity

Sexual: decreased libido, late ejaculation

Monitor: ECG, weight and BMI, glucose, lipid panel; if at risk for electrolyte disturbances, check K and Mg

Augmentation: lithium, lamotrigine, atypical antipsychotics, buspirone

Overdose: dangerous (arrhythmia); see p. 239

Withdrawal: rapid discontinuation may lead to sleep disturbance, GI distress, and mania

Metabolism: hepatic: 2D6 inhibitors (e.g., paroxetine) increase TCA levels

Pregnancy: category D

ADHD, attention-deficit hyperactivity disorder; BMI, body mass index; CCB, calcium channel blocker; ECG, electrocardiography; FDA, Food and Drug Administration; GI, gastrointestinal; IMI, imipramine; MAOI, monoamine oxidase inhibitor; MDD, major depressive disorder; MI, myocardial infarction; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Maintenance

The goal should be complete remission of symptoms
Use of benzodiazepines should be time limited

Cessation

Benzodiazepines must be tapered off slowly because of physiologic dependence (continued)

TABLE 5-9 Monoamine Oxidase Inhibitors

Agents: phenelzine (Nardil), tranylcypromine (Parnate), selegiline patch (EMSAM)

Indications (FDA-approved indications in bold): MDD, treatment-resistant depression, panic disorder, social anxiety disorder, bulimia

Contraindications and interactions:

Hypertensive crisis with tyramine (or sympathomimetic-containing foods or drugs) with seizures, delirium, fever, collapse, coma, intracranial bleed; can block with phentolamine. Do not mix with other MAOIs; cocaine or other stimulants; OTC products with dextromethorphan, meperidine, or nasal decongestants; or appetite suppressants with sympathomimetic effects
Avoid with SSRIs, tramadol, duloxetine, venlafaxine, buspirone, bupropion
Do not use in the presence of recent cardiac event or CVA, headache, or liver disease
Use caution with anesthetics and ziprasidone

Adverse effects:

CNS: insomnia, agitation, suicidality, sedation, dizziness, headache, fatigue, blurred vision, seizures (rare)

GI: constipation, xerostomia, hepatotoxicity (rare), weight gain, hypoglycemia in diabetics, increased LFTs

Cardiovascular: acute hypertension, orthostatic hypotension, sustained hypotension, arrhythmia

Sexual: decreased libido, late ejaculation

Augmentation: lithium, lamotrigine, atypical antipsychotics, buspirone

Overdose: may lead to agitation, hyperthermia, and hemodynamic instability

Withdrawal: minimal symptoms; as class, tapers over 2-3 weeks

Metabolism: hepatic CYP450 1A2

Pregnancy: category C

CNS, central nervous system; CVA, cerebrovascular accident; FDA, Food and Drug Administration; GI, gastrointestinal; LFT, liver function test; MAOI, monoamine oxidase inhibitor; MDD, major depressive disorder; OTC, over the counter; SSRI, selective serotonin reuptake inhibitor.

Pregnancy

All antidepressants are category C (some animal studies show adverse effects, but no controlled studies in humans are available) or D (there is evidence of risk to human fetuses, but the potential benefits may justify the risk)
Benzodiazepines are category D (evidence of risk to human fetuses; potential benefits may justify the risk) or X (should not be used in pregnancy)
Consider CBT, interpersonal therapy, supportive therapy, ECT, and hospitalization when medications are contraindicated

PHARMACOLOGIC TREATMENT OF BIPOLAR DISORDER

Choosing an Agent

See p. 76 for a general discussion of diagnosis and treatment
There is a significant risk of fetal malformation when using valproate and carbamazepine in women of childbearing age (continued)
If an agent works for acute mania, it can be continued for maintenance
Antipsychotics used in the acute manic phase should be discontinued upon stabilization unless they are being used to treat psychosis

TABLE 5-10 Tricyclic Antidepressants and Monoamine Oxidase Inhibitors

Medication and Formulations	Initial Dose (mg/day)	Dosing Range (mg/day)	Cost per Month (Average Dose)
Tricyclic Antidepressants
Amitriptyline (Elavil): 10-, 25-, 50-,75-, 100-, and 150-mg tablets	25	50-300	$4 (75 mg/day)
Clomipramine (Anafranil): 25-, 50-, and 75-mg tablets	25	25-300	$35 (generic: 75 mg/day) $167 (brand: 75 mg/day)
Desipramine (Norpramin): 10-, 25-, 50-, 75-, 100-, and 150-mg tablets	25	25-300	$40 (100 mg/day)
Doxepin (Sinequan): 10-, 25-, 50-, 75-, 100-, and 150-mg tablets	25	25-300	$9 (generic: 75 mg/day) $28 (brand: 75 mg/day)
Imipramine (Tofranil): 10-, 25- and 5-mg tablets	25	50-300	$9 (50 mg/day) Tofranil: $173
Nortriptyline (Pamelor): 10-, 25-, 50-, and 75-mg tablets	25	75-150	$18 (generic: 150 mg/day) $622 (brand: 150 mg/day)
Protriptyline (Vivactil): 5-, and 10-mg tablets	10-15	15-60	$155 (30 mg/day)
Trimipramine (Surmontil): 25-, 50-, and 100-mg tablets	20-30	50-300	$97 (100 mg/day)
Monoamine Oxidase Inhibitors
Phenelzine (Nardil): 15 mg tablets	30	50 mg	$60 (75 mg/day)
Tranylcypromine (Parnate): 10-mg tablets	30	40-120	$100 (30 mg/day)
Selegiline patch (EMSAM): 6-,9-, and 12-mg patches	6-12 q24 hr	6-12 q24 hr	$460 (6 mg/day)

TABLE 5-11 Alternative and Adjunctive Agents for the Treatment of Depression

Generic (Brand) and Formulations	Initial Dose (mg/day)	Dosing Range (Total mg/day)	Cost per Month (Average Dose)	Clinical Considerations
Bupropion: Wellbutrin-SR, Wellbutrin-XL, Zyban) 75-, and 100-mg tablets SR: 100- and 150-mg tablets XL: 150-, and 300-mg tablets	25-50 (TID dosing) SR: 50-100 (BID dosing) XL: 150 (QD dosing)	150-450 (TID dosing) SR: 100-400 (BID dosing) XL: 150-450 (QD dosing)	$86 (300 mg) $116 (300 mg as brand-SR) $125 (300 mg as brand-XL)	Often used as adjunctive medication with SSRIs and SNRIs Fewer sexual side effects than with SSRIs and SNRIs Lowers seizure threshold
Buspirone (BuSpar as an adjunct): 5-, 10-, 15-, and 30-mg tablets	15	15-60	$23 (20 mg)	Often used as an adjunctive medication for anxiety and depression
Mirtazapine (Remeron): 15-, 30-, and 45-mg tablets	15	15-45	$46 (generic 30 mg) $93 (brand 30 mg)	Used as an adjunctive medication or as second-line agent, particularly for patients with insomnia
Nefazodone (Serzone): 50-, 100-, 150-, 200-, and 250-mg tablets	100	100-600	$50 (150 mg)	Limited use because of cases of hepatotoxicity (need to follow LFTs in patients)
Olanzapine + fluoxetine (ODC, Symbyax): 6 + 25-mg, 6 + 50-mg, 12 + 5-mg, 12 + 25-mg, 12 + 50-mg, 12 tablets	6 + 25	6 + 25-12 + 50	$300 (6 + 25 mg)	Recently released agent See side effects olanzapine
BID, twice a day; LFT, liver function test; QD, every day; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TID, three times a day.

TABLE 5-12 Agents Used to Treat Anxiety Disorders

Drug	Initial Dose (Dosing Range, mg/day)	Advantages	Disadvantages
Selective Serotonin Reuptake Inhibitors
Please refer to Table 5-5 for class specific information
Citalopram (Celexa) Escitalopram (Lexapro) Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Paroxetine CR (Paxil CR) Sertraline (Zoloft)	10-20 (20-60) 10 (10-30) 10 (10-80) 50 (50-300) 10 (10-50) 12.5 (12.5-50) 25 (25-100)	Low abuse risk May dose once daily Low interaction risk Low toxicity with overdose	May increase anxiety initially Common sexual and GI dysfunction Delayed onset of action
Mixed Serotonin and Norepinephrine Reuptake Inhibitors
Please refer to Table 5-6 for class specific information
Duloxetine (Cymbalta) Venlafaxine XR (Effexor XR)	40 (40-120) (may use divided dosing) 37.5 (75-375)	Fast acting Well tolerated	May increase anxiety, agitation, or initially Common sexual and GI dysfunction Delayed onset of action Venlafaxine may cause elevated BP
Benzodiazepines (Selected)
Please refer to Table 5-30 for class specific information
Alprazolam (Xanax) Clonazepam (Klonopin) Diazepam (Valium) Lorazepam (Ativan)	0.25-0.5 (2-10) (TID dosing) 0.5 (1-5) (BID dosing) 5 (5-40) (BID, TID, or QID dosing) 1-2 (3-16) (TID or QID dosing)	Fast acting Well tolerated Low cost	High abuse liability Risk of withdrawal syndrome Dissociation, sedation Ataxia Requires multiple doses per day if short half life
Tricyclic Antidepressants (Selected)
Please refer to Table 5-8 for class specific information
Amitriptyline (Elavil) Clomipramine (Anafranil) Imipramine (Tofranil)	10-25 (50-300) 12.5-25 (100-250) 10-25 (50-300)	Low cost Once-daily dosing Very well studied and long used	Clomipramine is also an SNRI Not well tolerated Anticholinergic effects Sedating
		Option when modern agents fail	Cardiac depressants Toxic; lethal on overdose
Monoamine Oxidase Inhibitors
Please refer to Table 5-9 for class specific information
Phenelzine (Nardil) Selegiline (Eldepryl) Selegiline patch (EMSAM) Tranylcypromine (Parnate)	15 (60-90) (daily or BID) 5-10 (10-20) 6 (12) 10-20 (20-60) (BID dosing)	Efficacious in treatment-refractory cases	Dietary restrictions to avoid hypertensive crises with sympathomimetics (e.g., tyramine, NeoSynephrine) Many drug interactions (e.g., SSRIs, methylphenidate) Toxic; lethal on overdose
Atypical Antipsychotics
Please refer to Table 5-20 for class specific information
Aripiprazole (Abilify) Olanzapine (Zyprexa) Risperidone (Risperdal and Consta) Quetiapine (Seroquel) Ziprasidone (Geodon)	2 (2-30 2.5 (2.5-30) 0.25-0.5 (0.5-6) 12.5 (25-400) (daily or divided dosing) 40 (40-160)	Aggressively marketed Good studies for other indications	Not well studied for treatment of anxiety Risk of metabolic syndrome Some EPS risk (especially akathisia, atypical NMS; TD with risperidone)
Anticonvulsants
Please refer to Table 5-13 for class specific information
Carbamazepine (Tegretol) Gabapentin (Neurontin) Levetiracetam (Keppra)	250 (400-1000) 500 (1000-2000) 500 (2000-3000)	Aggressively marketed	In most cases, not proven effective to treat anxiety; benefits are often exaggerated
Oxcarbazepine (Trileptal) Valproate (Depakote)	250 (600-1800) 250-500 (1000-2000)		May produce dependence and risk seizures on stopping Tremor Alopecia Sedating Weight gain Highly teratogenic (carbamazepine, valproate) Valproate can masculinize with PCOS Drug interactions (carbamazepine induces metabolism of many agents; valproate increases lamotrigine) Levetiracetam has some evidence of anxiolytic effects (off-label use) Gabapentin and oxcarbazepine are off-label use for psychiatry
Adrenergic Agents
Clonidine (anti-α₂) (Catapres) Prazosin (anti-α₁) (Minipress) Propranolol (anti-β) (Inderal)	0.1 (0.1-2.4) 1 (1-15) 20 (40-60)		Off-label use in psychiatry May lower heart rate and BP
Antihistamines
Diphenhydramine (Benadryl) Hydroxyzine (Vistaril)	12.5-25 (25-50) 25-50 (75-400)	Relatively safe Long used	Sedating Anticholinergic effects
Miscellaneous
Bupropion SR (Wellbutrin SR) Bupropion XL (Wellbutrin XL) Buspirone (BuSpar) Trazodone (Desyrel)	100 (300-400) (BID dosing) 150 (300-450) 5 (15-60) (BID or TID dosing) 25 (50-200)	Buspirone and trazodone lack the addictive properties of benzodazepines Bupropion (Zyban)is also indicated for smoking cessation	Bupropion: marketed at suboptimal doses; mild stimulant (risks agitation, insomnia); may induce seizures Buspirone is not highly effective for treating anxiety Trazodone is not very effective; side effects include priapism and sedation
BID, twice a day; BP, blood pressure; EPS, extrapyramidal side effects; GI, gastrointestinal; NMS, neuromalignant syndrome; PCOS, polycystic ovarian syndrome; QID, four times a day; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TD, tardive dyskinesia; TID, three times a day.
Adapted from Iosifescu D, Pollack M: An approach to the anxious patient: symptoms of anxiety, fear, avoidance, or increased arousal. In Stern TA (ed). The Ten-Minute Guide to Psychiatric Diagnosis and Treatment. New York, NY: Professional Publishing; 2005:205.

Dosages

Medications should be titrated to effectiveness with drug levels checked on a schedule

Monitoring

Valproate and lithium require careful monitoring of levels, particularly at the outset of treatment
Renal and hepatic function should be monitored regularly

Changing and Augmenting Therapy

Augmentation for depressive symptoms is often necessary, although there is a risk of inducing mania with the addition of antidepressants

Pregnancy

Lithium, valproate, and carbamazepine are category D (evidence of risk to human fetuses; potential benefits may justify the risk)
Valproate is teratogenic and associated with neural tube defects

TABLE 5-13 Mood-Stabilizing Agents

Agents	Initial Dose (Dosing Range), mg)	Therapeutic Consideration
Standard Agents
Lithium carbonate and citrate (Lithobid): 150-, 300-, and 600-mg tablets	300-600 (600-2400) (divided doses)	Before use, check creatinine, BUN, TSH, electrolytes, ECG (age >50 years), body weight Adjust for acute trough levels of 0.8-1.2 mEq/L with maintenance levels of 0.50-0.75 mEq/L Two or three times a year, recheck Li, electrolytes, TSH, CBC, ECG, creatinine; also check dose-changes, adding drugs, or suspected toxicity (may include creatinine clearance and urine osmolarity)
Valproate (Depakote, ER): 125-, 250-, and 500-mg tablets and oral suspension	250-500 (1200-1500)	Hepatic failure risk factors: infants, multiple anticonvulsants, higher doses, dementia Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Related Related posts: The Psychiatric Evaluation Psychiatric Emergencies Psychiatric Symptoms and Management Special Populations Clinical References Bupropion Stay updated, free articles. Join our Telegram channel Tags: Massachusetts General Hospital/McLean Hospital The: Residency Handbook of Psychiatry Jun 12, 2016 \| Posted by drzezo in PSYCHIATRY \| Comments Off on Treatment Modalities Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access