Treatment Modalities

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)D2D4

↓DAT↓MAO

DA neurons in nigrostriatal, mesolimbic and tuberoinfundibular circuitsD2: DA cell bodies, terminals; lactotrophs (anterior pituitary)D4: frontal cortex, medulla, midbrain (VTA)

D2, D4: ↓AC, ↓cAMP, ↑K+, ↓C conductanceDAT: Na+/K+ pump, clears DA from synaptic cleftMAO: catabolizes monoamines

D2: bromocriptine, pramipexoleDAT: Bupropion and Wellbutrin (?), amphetamines (increase DA-release), methylphenidate (blocks reuptake)MAO: MAOIs

D2: typical and atypical antipsychoticsD4: atypical antipsychotics

CognitionMotor activityMotivation and rewardProlactin production (inhibitory)Sleep Mood Attention and learning

Norepinephrine (NE)α1α2

↓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 drivenNE transporter, clears NEMAO: 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: trazodoneα1: TCAs, low-potency typical antipsychotics, trazodone, atypical antipsychotics

ArousalAttentionVasopressin

Serotonin (5-OH-tryptamine,5HT)5HT1A,B,D,E,F5HT2A,B,C5HT35HT4,6,7

↓ SERT↓ MAO

5HT1A: limbic: postsynaptic, raphe5HT2A: cortex5HT2C: widespread5HT3: hippocampus, solitary tract, postrema5HT5: hypothalamus, corpus callosum, ventricles5HT6: striatum, limbic areas, cortex5HT7: cortex, thalamus, midbrain, raphe NN; SERT (reuptake): presynaptic cortical, neostriatum, thalamus, limbic

5HT1A,B,D,E,F: ↓AC,↓cAMP, activates K+ channels5HT2A,B,C: ↑IP3/DAG/Ca2+5HT3: ligand-gated Na+ channel5HT4,5,6,7: ↑AC, ↑cAMP5HTT: Na+/K+ ATPase-dependent, clears 5HTMAO: catabolizes monoamines (NE, 5HT, DA)

5HT1A: buspirone/BuSpar (partial),TCAs (upregulate)5HT2: TCAs (downregulate)5HT2aA2C: trazodone (downregulate)5HT2/3: mirtazapine/Remeron (antagonist)5-HTT: SRIs, SNRIs, TCAs, trazodone/DesyrelSRIs (block reuptake)

5HT1A: buspirone5HT2: atypical antipsychotics, trazodone5HT2A/2C/3: mirtazapine

MoodSleepAggressionAppetiteMetabolismSexualityAngerVomiting

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,GABAA

Limbic, cortical areas

GABAA: ↑Cl-conductance (hyperpolarizes)

GABAA: 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 treatmentNonlethal in overdoseGenerally mild adverse effectsLow doses may work for panic and anxiety disorders, but, patients with OCD require high doses

May lead to weight gain, agitation, insomnia or sedationGI and sexual side effects commonDiscontinuation 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 contraindicatedHigh blood pressure: venlafaxine is contraindicatedDuloxetine: relatively dangerous in overdoseEarly 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 rareMay be stimulatingOften useful as an SRI adjunctHelp 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-HTBlocks H1 receptors (sedating)

Moderate sexual adverse effectsUseful 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 depressionOften reduce ticsOverdoses can be lethal (cardiotoxicity and delirium)

Contraindicated with glaucoma, past MI, diabetesRisks: weight-gain, GI symptoms, urinary retention, elderly patients

Monoamine oxidase inhibitors (phenelzine, selegiline, tranylcypromine)

Prolonged anti-MAO-A and B actionsSelegiline has some MAO-B selectivity at low doses (safer with sympatho-mimetics), butMAO-A inhibition is more antidepressant

Third-line treatment for resistant depressionAutonomic and sexual effects mimic those of the anticholinergics

Dietary restrictions to avoid tyramine and other sympathomimeticsMany 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 abuseMay 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

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    Jun 12, 2016 | Posted by in PSYCHIATRY | Comments Off on Treatment Modalities

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