Psychopharmacology for Mental Health Professionals

- Ashwini Sabnis,M.D

“ Hell is empty and all the devils are here”

- William Shakespeare

Options for Treatment

Depression

SSRI

Atypical Anti-

depressants

TCA

DNRI

Serotonin Modulators

SNRI

SSRI

• Citalopram ( Celexa)• Escitalopram ( Lexapro)• Fluoxetine ( Prozac, Sarafem)• Fluvoxamine ( Luvox)• Paroxetine ( Paxil)• Sertraline ( Zoloft)• Vortioxetine ( Brintellix)

Mechanism of Action

• Reuptake inhibition occurs soon after SSRIs are started, and the full therapeutic effects of SSRIs may not appear for three to eight (or more) weeks after treatment has started. The full clinical response may require additional “downstream” effects

Side Effects

• Daytime sedation associated with malaise, diminished mental energy, or emotional blunting .

• Other side effects include diaphoresis, diarrhea, hyperprolactinemia, and syndrome of inappropriate antidiuretic hormone (SIADH) and hyponatremia .

PS

• [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders

Dosing of newer SSRI’s

• Brintellix: Initial: 10 mg once daily; increase to 20 mg once daily as tolerated; consider 5 mg once daily for patients who do not tolerate higher doses. Maintenance: 5-20 mg once daily.

• This drug may be potentially inappropriate for use in geriatric patients with a history of falls or fractures [moderate for SIADH]

PS

• Citalopram causes dose-dependent QT interval prolongation, which can lead to a life-threatening cardiac arrhythmia, torsade de pointes (ventricular tachycardia)

• based upon a review that found no cases of citalopram induced sudden cardiac death among patients who were taking up to 60 mg per day of citalopram and were free of identified risk factors for QT prolongation and torsade de pointes

PS - continued

• Other SSRIs have been associated with QT prolongation, but appear to be unlikely to cause serious arrhythmia when used in usual recommended doses and in patients without other risk factors

• Risk Factors are baseline QT prolongation, underlying heart disease (particularly heart failure, myocardial infarction, and left ventricular hypertrophy), bradycardia, electrolyte imbalance(especially hypokalemia and hypomagnesemia), concurrent use of more than one drug that can prolong the QT interval

Other Side-effects

-Nausea and sedation may be more likely to occur with paroxetine and fluvoxamine-diarrhea with sertraline and -activation may be more likely to occur with fluoxetine and sertraline.

Serotonin-norepinephrine reuptake inhibitors ( SNRI)

• Desvenlafaxine ( Pristiq)• Duloxetine ( Cymbalta)• Milnacipran ( Savella)• Venlafaxine ( Effexor)- poor responses or intolerable side effects during first-line treatment with selective serotonin reuptake inhibitors (SSRIs)

SNRI- Mechanism of Action

• SNRIs vary in their affinity for the serotonin transporter and norepinephrine transporter. Desvenlafaxine, duloxetine, and venlafaxine are more potent inhibitors of serotonin reuptake than norepinephrine reuptake, whereas milnacipran blocks reuptake of norepinephrine more preferentially.

Side Effects

• Nausea • Dizziness • Sweating • Constipation• Anorexia • Nausea • Dry mouth• Headache

Atypical Anti-Depressants

• Bupropion ( Wellbutrin)• Mirtazapine ( Remeron)-atypical antidepressants are often first-line treatment if the drug has a desirable characteristic (eg, sexual side effects and weight gain occur less often with bupropion than SSRIs).

Bupropion

• it inhibits presynaptic reuptake of dopamine and norepinephrine (with a greater effect upon dopamine)

• Drugs that increase the plasma concentration of bupropion raise the risk of seizure.

Mirtazapine

-increases release of norepinephrine and serotonin-high affinity for histamine H1 receptors (which probably accounts for the drug’s sedative properties)

Side effects

• Dry mouth • Nausea • Insomnia• Dizziness• Anxiety • Dyspepsia • Sinusitis • Tremor

Serotonin modulators

-Nefazodone ( Serzone) -Trazodone -Vilazodone ( Viibryd)Serotonin modulators antagonize postsynaptic serotonin receptors and inhibit reuptake of postsynaptic serotoninSerotonin modulators increase serotonergic neurotransmission and can cause the serotonin syndrome.

SM-Continued

• Nefazodone is used to treat major depression and premenstrual syndrome

• Trazodone used as a hypnotic to treat insomnia in the context of depression, as well as insomnia associated with antidepressants (eg, bupropion or fluoxetine)

• Vilazodone is used to treat major depression

Dosing of Viibryd

• starting dose for major depression is 10 mg per day at bedtime, for one week .

• The dose is then increased to 20 mg per day for week two

• and then to the target dose of 40 mg per day • The drug should be taken with food to

increase bioavailability

Side-effects

• Diarrhea • Nausea • Sexual dysfunction • Dizziness • Insomnia • Vomiting

Tricyclic and tetracyclic drugs

• Amitriptyline ( Elavil)• Amoxapine ( Asendin)• Clomipramine ( Anafranil)• Desipramine (Norpramin)• Doxepin• Imipramine ( Tofranil)• Maprotiline ( Ludiomil)• Nortriptyline ( Pamelor)• Protriptyline• Trimipramine

• Tricyclics in the United States are -Amitriptyline -Imipramine- Desipramine - Nortriptyline- Clomipramine (is commonly used in Europe) -Nortriptyline and desipramine tend to be the best tolerated

Continued

• Amitriptyline blocks reuptake of both serotonin and norepinephrine, but more potently blocks reuptake of serotonin.

• amitriptyline is highly sedating, associated with weight gain, anticholinergic side effects

Mechanism of Action

• Desipramine blocks reuptake of norepinephrine and serotonin, but more potently blocks reuptake of norepinephrine

• Doxepin has the strongest affinity for histamine H1 receptors among all cyclic antidepressants and is thus highly sedating

Overdose concern

• Most concerning is that all of the tricyclic and tetracyclic antidepressants are dangerous in overdose

• The toxicity is usually due to prolongation of the QT interval, leading to arrhythmias. Overdose of cyclic antidepressants can also cause anticholinergic toxicity and seizures

MAOI

• Tranylcypromine ( Parnate)• Phenelzine ( Nardil)• Selegiline ( Emsam)

Continued

MAOIs can be useful agents for the treatment of "atypical" depression (eg, depression with hyperphagia, hypersomnia, leaden paralysis, and rejection sensitivity), and in treatment-resistant patients.MAOIs have potent hypotensive effects, patients experience dizziness. This is important with elderly patients (hypotensive effects and more likely to fall and sustain fractures)

Dietary Restrictions of MAOI’s

Absolutely restricted:

Aged cheeses

Aged and cured meats

Improperly stored or spoiled meats, fish, or poultry

Banana peel; broad bean pods

Soy sauce and other soy condiments

Draft beer

Consume in moderation:

Red or white wine (no more than two 4-ounce glasses per day)

Bottled or canned beer, including nonalcoholic (no more than two 12-ounce servings per day)

Anti-Psychotics Options

First Generation

• Haldol, Thorazine,Perphenazine

Second Generation

• Risperdal, Olanzapine, Aripiprazole

Anti-psychotics

• First-generation antipsychotics - were introduced more than 50 years ago- high rates of extrapyramidal side effects (EPS),

including rigidity, bradykinesia, tremor, and akathisia (restlessness). They also frequently lead to tardive dyskinesia—hyperkinetic, involuntary movements most readily observed in the face and extremities.

FGA

• Haldol• Droperidol• Fluphenazine ( Prolixin)• Perphenazine• Chlorpromazine ( Thorazine)• Thioridazine

SGA

• Risperidone( Risperdal)• Quentiapine( Seroquel)• Olanzapine ( Zyprexa)• Aripiprazole ( Abilify)• Palliperidone ( Invega)• Illoperidone ( Fanapt)• Asenapine ( Saphris)• Lurasidone ( Latuda)• Clozapine ( Clozaril)

Dosing of AP

• Quetiapine is typically started at 50 mg once daily at bedtime. The dose is then increased every day by 50 to 100 mg to reach the target dose of 300 to 600 mg per day within one to two weeks of starting the medication

• Lurasidone is started at 20 mg once daily in the evening and is taken with a meal (eg, >350 calories) to limit gastrointestinal side effects. The dose can be increased every two to seven days by increments of 20 mg per day to optimize effectiveness and tolerability. The target dose range is 20 to 120 mg per day.

Dosing of AP

• Olanzapine is typically started at 5 mg once daily at bedtime,who do not respond within one week, the dose is increased by 5 mg per day. The maximum dose is 15 to 20 mg per day, depending upon tolerability.

Abilify

• Depression(adjunctive with antidepressants): Oral: Initial: 2 to 5 mg/day (range: 2 to 15 mg/day); dose adjustments of up to 5 mg/day may be made in intervals of ≥1 week, up to a maximum of 15 mg/day. Note: Dosing based on patients already receiving antidepressant therapy.

Schizophrenia Dosing of Abilify

• Oral: 10 or 15 mg once daily; may be increased to a maximum of 30 mg once daily (efficacy at dosages above 10 to 15 mg has not been shown to be increased). Dosage titration should not be more frequent than every 2 weeks.

• IM, extended release: 400 mg once monthly (doses should be separated by ≥26 days); Note: Tolerability should be established using oral aripiprazole prior to initiation of parenteral therapy; due to the half-life of oral aripiprazole it may take up to 2 weeks to fully assess tolerability. Continue oral aripiprazole (or other oral antipsychotic) for 14 days during initiation of parenteral therapy.

Invega

• Oral: Usual: 6 mg once daily in the morning; titration not required, though some may benefit from lower or higher doses (range: 3 to 12 mg daily). If exceeding 6 mg daily, increases of 3 mg daily are recommended no more frequently than every 5 days, up to a maximum of 12 mg daily.

• IM: Note: Prior to initiation of IM therapy ( Invega Sustena), tolerability should be established with oral paliperidone or oral risperidone.

Invega Sustena

• Initial: 234 mg on treatment day 1 followed by 156 mg 1 week later with both doses administered in the deltoid muscle.

• The second dose may be administered 4 days before or after the weekly time point.

• Maintenance: Following the 1-week initiation regimen, begin a maintenance dose of 117 mg every month administered in either the deltoid or gluteal muscle.

• Some patients may benefit from higher or lower monthly maintenance doses (monthly maintenance dosage range: 39 to 234 mg). The monthly maintenance dose may be administered 7 days before or after the monthly time point.

Conversion from oral to im injection

• Initiate IM therapy as described using the 1-week initiation regimen. Patients previously stabilized on oral doses can expect similar steady state exposure during maintenance treatment with IM therapy using the following conversion:

• Oral extended release dose of 12 mg daily, then IM maintenance dose of 234 mg monthly

• Oral extended release dose of 6 mg daily, then IM maintenance dose of 117 mg monthly

• Oral extended release dose of 3 mg daily, then IM maintenance dose of 39 to 78 mg monthly

Fanapt Dosing

• Schizophrenia: Oral: Initial: 1 mg twice daily; titrate to the recommended dosage range with dosage adjustments not to exceed 2 mg twice daily (4 mg daily) every 24 hours;

• to avoid orthostatic hypotensive effects,recommended dosage range: 6 to 12 mg twice daily (maximum: 24 mg daily)

Saphris Dosing

• Initial: 5 mg twice daily. Daily doses >20 mg/day in clinical trials did not appear to offer any additional benefits and increased risk of adverse effects.

• Maintainence: Initial: 5 mg twice daily; may increase to 10 mg twice daily after 1 week based on tolerability

Latuda

• The drug is supplied as 20, 40, 80 and 120 mg tablets intended for once daily dosing with a meal.

• The suggested initial dose is 40 mg daily for most patients

• The maximum daily dose of 160 mg received approval based upon results of a 6 week efficacy trial available only in abstract form

SGA

Quetiapine has a low incidence of extrapyramidal symptoms even at higher dosesZiprasidone's advantages include lower risks of weight gain, diabetes, and hyperlipidemiaAripiprazole's advantages include a lower risk of weight gain, increased lipid or prolactin levels, extrapyramidal effects and sedation

SGA

• Paliperidone, iloperidone, asenapine, and lurasidone are newer antipsychotics that have been subject to fewer studies and less clinical experience than other second-generation drugs

• Paliperidone can be used to treat psychosis in patients with hepatic impairment

• Lurasidone has lower risk of weight gain, lipid dysregulation, and QT prolongation compared to other drugs in this class.

SGA

• Clozapine is unique among second-generation antipsychotic drugs for its efficacy in treating psychotic symptoms of schizophrenia that persist in response to other antipsychotics and reduced rates of extrapyramidal symptoms and tardive dyskinesia. Potential adverse effects include agranulocytosis, seizure, and myocarditis. Patients taking clozapine require weekly to monthly monitoring of white blood cell counts

Benztropine( Cogentin)

• Drug-induced extrapyramidal symptoms • Initial: 1 to 2 mg 2 to 3 times daily for reactions

developing soon after initiation of antipsychotic medication.

• Titrate gradually at 0.5 mg increments • Usual dosage is 1 to 4 mg once or twice daily up to a

maximum daily dose of 6 mg.• Treatment may be continued for 1 to 2 weeks, after

which treatment should be withdrawn to reassess continued need for therapy.

Buspirone

• Buspirone has a high affinity for serotonin 5-HT1A and 5-HT2 receptors.

• Generalized anxiety disorder (GAD): Initial: 7.5 mg twice daily; may increase every 2-3 days in increments of 2.5 mg twice daily to a maximum of 30 mg twice daily

• a dose of 10-15 mg twice daily was most often used in clinical trials that allowed for dose titration

Bipolar Options

Lithium

Anti-psychotics

Benzodiazepines

Bipolar Disorder

• Lithium• Anticonvulsants(Carbamazepine ,Valproate) • Antipsychotics• Benzodiazepines

Lithium Dosing

• Monitor serum concentrations and clinical response (efficacy and toxicity) to determine proper dose

• Bipolar disorder (acute mania, acute depression [off-label use], and maintenance):

• Immediate release: Initial: Initiate at low dose (eg, 300 mg 3 times daily or less); increase gradually based on response and tolerability ; usual dosage: 900 to1,800 mg daily in 3 to 4 divided doses

• Extended release: Initiate at low dose (eg, 450 mg 2 times daily or less); increase gradually based on response and tolerability; usual dosage: 900 to 1,800 mg daily in 2 divided doses

Tegretol

• Carbamazepine is usually started at a dose of 100 mg to 200 mg one or two times per day. The dose should be increased by 200 mg per day every one to four days, to a final dose of about 800 to 1000 mg per day, although the effective dose may range between 200 and 1800 mg per day.

• Carbamazepine is typically administered twice daily. Therapeutic serum levels have not been established for treating acute manic episodes.

Depakote

• Valproate or divalproex is usually started at a dose of 250 mg two or three times per day. The dose is increased by 250 mg to 500 mg every one to three days as tolerated to reach a therapeutic serum level, which generally occurs with 1500 mg to 2500 mg per day Valproate is usually administered twice daily

• Long acting once daily dose is available• Oral loading and rapid titration to a full dose within

one to two days by prescribing 20 mg/kg/day may result in earlier improvement

Lamictal Dosing

( Regimens not containing carbamazepine, phenytoin, phenobarbital, primidone, rifampin, lopinavir/ritonavir, or valproic acid)• Initial: Weeks 1 and 2: 25 mg once daily; • Weeks 3 and 4: 50 mg once daily• Week 5: 100 mg once daily • Week 6 and maintenance: 200 mg once daily

Lamictal Dosing

• Regimens containing valproic acid: Initial: Weeks 1 and 2: 25 mg every other day; Weeks 3 and 4: 25 mg once daily; Week 5: 50 mg once daily; Week 6 and maintenance: 100 mg once daily

Lamictal Dosing

• Regimens containing carbamazepine, phenytoin, phenobarbital, primidone, rifampin, or lopinavir/ritonavir, and without valproic acid: Initial: Weeks 1 and 2: 50 mg once daily; Weeks 3 and 4: 100 mg daily in divided doses; Week 5: 200 mg daily in divided doses; Week 6: 300 mg daily in divided doses; Maintenance: Up to 400 mg daily in divided doses

Trileptal- off label for Bipolar

• The initial dose is 300 mg taken twice daily, which is titrated by 600 mg/day at weekly intervals to a target dose of 1200 to 2400 mg/day taken twice daily

PS

• Based upon randomized trials, quetiapine, lurasidone, and olanzapine are each efficacious as monotherapy for treating bipolar major depression

• lurasidone is efficacious as adjunctive therapy in patients who do not respond to monotherapy with lithium or valproate

Mood Stabilizers

• A meta-analysis of 8 randomized trials (1124 manic or mixed episode patients) compared haloperidol, olanzapine, quetiapine, or risperidone with placebo as adjunctive treatment for patients

• who did not respond to lithium, valproate, or carbamazepine monotherapy .

• Improvement was greater in patients who received an adjunctive antipsychotic.

Resistant Cases

• A severe manic episode that does not respond to one medication combination

• should be treated with a second medication combination.

• Generally, lithium is switched to valproate or vice versa. • As an example, for patients who do not respond to

lithium plus haloperidol within two weeks of reaching target doses,

• we suggest tapering and discontinuing lithium at the same time that valproate is started and titrated up.

Continued

• Patients who do not respond to lithium plus an antipsychotic or to valproate plus the same antipsychotic,

• we suggest starting a third medication combination involving lithium or valproate plus an antipsychotic

• patients who do not respond to lithium plus an antipsychotic or to valproate plus the same antipsychotic,

• we suggest starting a third medication combination involving lithium or valproate plus an antipsychotic

Refractory

• Electroconvulsive therapy • Treatment with lithium or valproate plus asenapine,

clozapine, or paliperidone• Allopurinol which is typically used to prevent attacks

of gouty arthritis and nephropathy, has been studied as adjunctive treatment for mania

• Tamoxifen is a centrally active protein kinase C inhibitor that has demonstrated efficacy for treating manic episodes (antiestrogen effects preclude its use )

Benzodiazepines

• Clonazepam ( Klonopin)• Diazepam ( Valium)• Lorazepam ( Ativan)• Alprazolam ( Xanax)• Temazepam ( Restoril)

Benzodiazepines

• should be used with caution, their use need not be entirely avoided

• They may be appropriate during acute, maintenance, or long-term treatment of GAD, either as monotherapy or, more commonly, as an adjunct to antidepressant treatment

• Side effects of benzodiazepines include impairment of psychomotor performance, amnesia, dependence and withdrawal symptoms after long-term treatment, and rebound anxiety after short-term treatment

• Withdrawal and cognitive or learning impairment are more likely for persons taking higher doses

Other Anxiolytics

• Buspirone (serotonergic system via blockade of 5HT1A autoreceptors)

• Tiagabine• Hydroxyzine

Sleeping Aids

• Zaleplon (for patients who have difficulty maintaining sleep (ie, sleep maintenance insomnia)

• Zolpidem (short-term treatment of insomnia characterized by difficulty with sleep initiation)

• Eszopiclone(effective for both sleep onset insomnia and sleep maintenance insomnia )

• Ramelteon ( Melatonin Agonist)• Temazepam( Restoril)

OTC

• Valerian• Melatonin• Diphenhydramine• Alcohol(self-prescribed as a sleep aid because

it decreases the time required to fall asleep, at least in the short-term)

Prescribing Cascades• new drug is prescribed to treat symptoms arising from an

unrecognized adverse drug event related to an existing therapy • initiation of anti-Parkinson therapy for symptoms arising from use of

drugs such as antipsychotics or metoclopramide. The anti-Parkinson drugs can then lead to new symptoms, including orthostatic hypotension and delirium.

• cholinesterase inhibitors (eg, donepezil, rivastigmine, and galantamine) are commonly used for the management of dementia symptoms

• cholinesterase inhibitors may cause diarrhea and urinary incontinence. A prescribing cascade occurs when the prescription of a cholinesterase inhibitor is followed by a prescription for an anticholinergic therapy (eg, oxybutynin to treat incontinence

Stepwise Approach

• Review current drug therapy • Discontinue unnecessary therapy • Consider adverse drug events for any new

symptom • Consider nonpharmacologic approaches • Substitute with safer alternatives • Reduce the dose • Prescribe beneficial therapy • Simplify the dosing schedule

THE END

Shakespeare said,