Breast Feeding

• Some drug is found in mother’s breast milk

✽ Generally considered safe to breast feed while taking valproate

• If drug is continued while breast feeding, infant should be monitored for possible adverse effects

• If infant shows signs of irritability or sedation, drug may need to be discontinued

✽ Bipolar disorder may recur during the postpartum period, particularly if there is a history of prior postpartum episodes of either depression or psychosis

✽ Relapse rates may be lower in women who receive prophylactic treatment for postpartum episodes of bipolar disorder

• Atypical antipsychotics and anticonvulsants such as valproate may be safer than lithium during the postpartum period when breast feeding

VALPROATE: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• Manic phase of bipolar disorder

• Works well in combination with lithium and/or atypical antipsychotics

• Patients for whom therapeutic drug monitoring is desirable

Potential Disadvantages

• Depressed phase of bipolar disorder

• Patients unable to tolerate sedation or weight gain

• Multiple drug interactions

• Multiple side effect risks

• Pregnant patients

Primary Target Symptoms

• Unstable mood

• Incidence of migraine

• Incidence of partial complex seizures

Pearls (for bipolar disorder)

✽ Valproate is a first-line treatment option that may be best for patients with mixed states of bipolar disorder or for patients with rapid-cycling bipolar disorder

✽ Seems to be more effective in treating manic episodes than depressive episodes in bipolar disorder (treats from above better than it treats from below)

✽ May also be more effective in preventing manic relapses than in preventing depressive episodes (stabilizes from above better than it stabilizes from below)

• Only a third of bipolar patients experience adequate relief with a monotherapy, so most patients need multiple medications for best control

• Useful in combination with atypical antipsychotics and/or lithium for acute mania

✽ May also be useful for bipolar disorder in combination with lamotrigine, but must reduce lamotrigine dose by half when combined with valproate

• Usefulness for bipolar disorder in combination with anticonvulsants other than lamotrigine is not well demonstrated; such combinations can be expensive and are possibly ineffective or even irrational

✽ May be useful as an adjunct to atypical antipsychotics for rapid onset of action in schizophrenia

✽ Used to treat aggression, agitation, and impulsivity not only in bipolar disorder and schizophrenia but also in many other disorders, including dementia, personality disorders, and brain injury

• Patients with acute mania tend to tolerate side effects better than patients with hypomania or depression

• Multivitamins fortified with zinc and selenium may help reduce alopecia

• Association of valproate with polycystic ovaries is controversial and may be related to weight gain, obesity, or epilepsy

• Nevertheless, may wish to be cautious in administering valproate to women of childbearing potential, especially adolescent female bipolar patients, and carefully monitor weight, endocrine status, and ovarian size and function

✽ In women of childbearing potential who are or are likely to become sexually active, should inform about risk of harm to the fetus and monitor contraceptive status

• Association of valproate with decreased bone mass is controversial and may be related to activity levels, exposure to sunlight, and epilepsy, and might be prevented by supplemental vitamin D 2,000 IU/day and calcium 600–1,000 mg/day

• New delayed-release capsule of valproic acid (Stavzor) may be easier to swallow than other formulations

• A prodrug of valproic acid, valpromide, is available in several European countries

• Although valpromide is rapidly transformed to valproic acid, it has some unique characteristics that can affect drug interactions

• In particular, valpromide is a potent inhibitor of liver microsomal epoxide hydrolase and thus causes clinically significant increases in the plasma levels of carbamazepine-10,11-epoxide (the active metabolite of carbamazepine)

Suggested Reading

Bowden CL. Valproate. Bipolar Disorders 2003;5:189–202.

Gill D, Derry S, Wiffen PJ, Moore RA. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011;(10):CD009183.

Landy SH, McGinnis J. Divalproex sodium – review of prophylactic migraine efficacy, safety and dosage, with recommendations. Tenn Med 1999;92:135–6.

Macritchie KA, Geddes JR, Scott J, Haslam DR, Goodwin GM. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev 2001;(3):CD003196.

Smith LA, Cornelius V, Warnock A, Tacchi MJ, Taylor D. Pharmacological interventions for acute bipolar mania: a systematic review of randomized placebo-controlled trials. Bipolar Disord 2007;9(6):551–60.

VARENICLINE

VARENICLINE: THERAPEUTICS

Brands

• Chantix

• Champix

see index for additional brand names

Generic?

No

Class

• Smoking cessation treatment; alpha 4 beta 2 partial agonist at nicotinic acetylcholine receptors

Commonly Prescribed for

(bold for FDA approved)

• Nicotine addiction/dependence

How the Drug Works

• Causes sustained but small amounts of dopamine release (less than with nicotine)

• Specifically, as a partial agonist at alpha 4 beta 2 nicotinic acetylcholine receptors, varenicline activates these receptors to a lesser extent than the full agonist nicotine and also prevents nicotine from binding to these receptors

• Most prominent actions are on mesolimbic dopaminergic neurons in the ventral tegmental area

How Long Until It Works

• Recommended initial treatment trial is 12 weeks; an additional 12-week trial in individuals who stop smoking after 12 weeks may increase likelihood of long-term abstinence

If It Works

• Reduces withdrawal symptoms and the urge to smoke; increases abstinence

If It Doesn’t Work

• Evaluate for and address contributing factors, then reattempt treatment

• Consider switching to another agent

Best Augmenting Combos for Partial Response or Treatment Resistance

• Best to attempt other monotherapies

Tests

• None for healthy individuals

VARENICLINE: SIDE EFFECTS

How Drug Causes Side Effects

• Theoretically due to increases in dopamine concentrations at receptors in parts of the brain and body other than those that cause therapeutic actions

Notable Side Effects

• Dose-dependent nausea, vomiting, constipation, flatulence

• Insomnia, headache, abnormal dreams

Life-Threatening or Dangerous Side Effects

• Rare activation of agitation, depressed mood, suicidal ideation, suicidal behavior

Weight Gain

• Reported but not expected

• Some patients report weight loss

Sedation

• Reported but not expected

• Some patients report activation and insomnia

What to Do About Side Effects

• Wait

• Adjust dose

• If side effects persist, discontinue use

Best Augmenting Agents for Side Effects

• Dose reduction or switching to another agent may be more effective since most side effects cannot be improved with an augmenting agent

VARENICLINE: DOSING AND USE

Usual Dosage Range

• 1 mg twice daily

Dosage Forms

• Tablet 0.5 mg, 1 mg

How to Dose

• Patient should either set a quit date and then begin taking varenicline one week before the quit date or start varenicline and then quit smoking between days 8 and 35 of treatment

• Initial 0.5 mg/day; after three days increase to 1 mg/day in two divided doses; after 4 days can increase to 2 mg/day in two divided doses

Dosing Tips

• Varenicline should be taken following a meal and with a full glass of water

• Providing educational materials and counseling in combination with varenicline treatment can increase the chances of success

• Initial recommended treatment duration is 12 weeks; for individuals who have stopped smoking after 12 weeks continued treatment for an additional 12 weeks can increase the likelihood of long-term abstinence

• For patients who are unsuccessful in their attempt to quit following 12 weeks of treatment or those who relapse following treatment, it is best to attempt to address factors contributing to the failed attempt and then reintroduce treatment

Overdose

• Limited available data

Long-Term Use

• Treatment for up to 24 weeks has been found effective

Habit Forming

• No

How to Stop

• Taper to avoid withdrawal effects, but no well-documented tolerance, dependence, or withdrawal reactions

Pharmacokinetics

• Elimination half-life 24 hours

Drug Interactions

• Does not inhibit hepatic enzymes or renal transport proteins, and thus is unlikely to affect plasma concentrations of other drugs

• Is not hepatically metabolized and thus is unlikely to be affected by other drugs

• Side effects may be increased if varenicline is taken with nicotine replacement therapy

Other Warnings/Precautions

• Monitor patients for changes in behavior, agitation, depressed mood, worsening of preexisting psychiatric illness, and suicidality

• Use cautiously in individuals with known psychiatric illness

• Discontinuing smoking may lead to pharmacokinetic or pharmacodynamic changes in other drugs the patient is taking, which could potentially require dose adjustment

Do Not Use

• If there is a proven allergy to varenicline

VARENICLINE: SPECIAL POPULATIONS

Renal Impairment

• For severe impairment, maximum recommended dose is 0.5 mg twice per day

• For patients with end-stage renal disease undergoing hemodialysis, maximum recommended dose is 0.5 mg once per day

• Removed by hemodialysis

Hepatic Impairment

• Dose adjustment not generally necessary

Cardiac Impairment

• Effective in patients with cardiovascular disease; small increased risk of certain cardiovascular adverse effects in these patients

Elderly

• Some patients may tolerate lower doses better

Children and Adolescents

• Safety and efficacy have not been established

Pregnancy

• Risk Category C [some animal studies show adverse effects; no controlled studies in humans]

• Pregnant women wishing to stop smoking may consider behavioral therapy before pharmacotherapy

• Not generally recommended for use during pregnancy, especially during first trimester

Breast Feeding

• Unknown if varenicline is secreted in human breast milk, but all psychotropics assumed to be secreted in breast milk

• Recommended either to discontinue drug or bottle feed

VARENICLINE: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• More effective than other pharmacotherapies for smoking cessation

Potential Disadvantages

• Not well studied in patients with comorbid psychiatric disorders

Primary Target Symptoms

• Cravings associated with nicotine withdrawal

Pearls

• More effective than nicotine or bupropion

• Unlike nicotine or bupropion, the patient cannot “smoke over” varenicline since varenicline, but not the others, will block the effects of additional smoked nicotine if the patient decides to smoke during treatment

• Although tested in the general population excluding psychiatric patients, where smoking rates in the U.S. are about 20–25%, there is great unmet need for smoking cessation treatments in patients with psychiatric disorders, especially attention deficit hyperactivity disorder and schizophrenia, which have smoking rates in the U.S. as high as 50–75%

• Smoking cessation treatment in patients with comorbid psychiatric disorders is not well studied

• Preliminary results suggest that varenicline is not associated with worsening of psychiatric symptoms in stable patients with schizophrenia, schizoaffective disorder, or depression

• Patients with comorbid psychiatric disorders should be closely monitored in terms of their psychiatric symptoms, especially suicidality

Suggested Reading

Cerimele JM, Durango A. Does varenicline worsen psychiatric symptoms in patients with schizophrenia or schizoaffective disorder? A review of published studies. J Clin Psychiatry 2012;73(8):e1039–47.

Jorenby DE, Hays JT, Rigotti NA. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006;296(1):56–63.

Meszaros ZS, Abdul-Malak Y, Dimmock JA, et al. Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia: a randomized, placebo-controlled pilot trial. J Clin Psychopharmacol 2013;33(2):243–7.

Rollema H, Coe JW, Chambers LK, et al. Rationale, pharmacology and clinical efficacy of partial agonists of alpha4beta2 nACh receptors for smoking cessation. Trends Pharmacol Sci 2007;28(7):316–25.

Wu P, Wilson K, Dimoulas P, Mills EJ. Effectiveness of smoking cessation therapies: a systematic review and meta-analysis. BMC Public Health 2006;6:300.

VENLAFAXINE

VENLAFAXINE: THERAPEUTICS

Brands

• Effexor

• Effexor XR

see index for additional brand names

Generic?

Yes

Class

• SNRI (dual serotonin and norepinephrine reuptake inhibitor); often classified as an antidepressant, but it is not just an antidepressant

Commonly Prescribed for

(bold for FDA approved)

• Depression

• Generalized anxiety disorder (GAD)

• Social anxiety disorder (social phobia)

• Panic disorder

• Posttraumatic stress disorder (PTSD)

• Premenstrual dysphoric disorder (PMDD)

How the Drug Works

• Boosts neurotransmitters serotonin, norepinephrine/noradrenaline, and dopamine

• Blocks serotonin reuptake pump (serotonin transporter), presumably increasing serotonergic neurotransmission

• Blocks norepinephrine reuptake pump (norepinephrine transporter), presumably increasing noradrenergic neurotransmission

• Presumably desensitizes both serotonin 1A receptors and beta adrenergic receptors

• Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, venlafaxine can increase dopamine neurotransmission in this part of the brain

• Weakly blocks dopamine reuptake pump (dopamine transporter), and may increase dopamine neurotransmission