Pregnancy

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

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

• Possible increased incidence of fetal malformations if phenelzine is taken during the first trimester

• Should evaluate patient for treatment with an antidepressant with a better risk/benefit ratio

Breast Feeding

• Some drug is found in mother’s breast milk

• If child becomes irritable or sedated, breast feeding or drug may need to be discontinued

• Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period

• Should evaluate patient for treatment with an antidepressant with a better risk/benefit ratio

PHENELZINE: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• Atypical depression

• Severe depression

• Treatment-resistant depression or anxiety disorders

Potential Disadvantages

• Requires compliance to dietary restrictions, concomitant drug restrictions

• Patients with cardiac problems or hypertension

• Multiple daily doses

Primary Target Symptoms

• Depressed mood

• Somatic symptoms

• Sleep and eating disturbances

• Psychomotor retardation

• Morbid preoccupation

Pearls

• MAOIs are generally reserved for second-line use after SSRIs, SNRIs, and combinations of newer antidepressants have failed

• Patient should be advised not to take any prescription or over-the-counter drugs without consulting their doctor because of possible drug interactions with the MAOI

• Headache is often the first symptom of hypertensive crisis

• The rigid dietary restrictions may reduce compliance (see Table 2 after Pearls)

• Mood disorders can be associated with eating disorders (especially in adolescent females), and phenelzine can be used to treat both depression and bulimia

• MAOIs are a viable second-line treatment option in depression, but are not frequently used

✽ Myths about the danger of dietary tyramine can be exaggerated, but prohibitions against concomitant drugs often not followed closely enough

• Orthostatic hypotension, insomnia, and sexual dysfunction are often the most troublesome common side effects

✽ MAOIs should be for the expert, especially if combining with agents of potential risk (e.g., stimulants, trazodone, TCAs)

✽ MAOIs should not be neglected as therapeutic agents for the treatment-resistant

• Although generally prohibited, a heroic but potentially dangerous treatment for severely treatment-resistant patients is for an expert to give a tricyclic/tetracyclic antidepressant other than clomipramine simultaneously with an MAO inhibitor for patients who fail to respond to numerous other antidepressants

• Use of MAOIs with clomipramine is always prohibited because of the risk of serotonin syndrome and death

• Amoxapine may be the preferred trycyclic/tetracyclic antidepressant to combine with an MAOI in heroic cases due to its theoretically protective 5HT2A antagonist properties

• If this option is elected, start the MAOI with the tricyclic/tetracyclic antidepressant simultaneously at low doses after appropriate drug washout, then alternately increase doses of these agents every few days to a week as tolerated

• Although very strict dietary and concomitant drug restrictions must be observed to prevent hypertensive crises and serotonin syndrome, the most common side effects of MAOI and tricyclic/tetracyclic combinations may be weight gain and orthostatic hypotension

Table 1. Drugs contraindicated due to risk of serotonin syndrome/toxicity

Do Not Use:
Antidepressants	Drugs of Abuse	Opioids	Other
SSRIs	MDMA (ecstasy)	Meperidine	Non-subcutaneous sumatriptan
SNRIs	Cocaine	Tramadol	Chlorpheniramine
Clomipramine	Methamphetamine	Methadone	Brompheniramine
St. John’s wort	High-dose or injected amphetamine	Fentanyl	Dextromethorphan
			Procarbazine?

Table 2. Dietary guidelines for patients taking MAOIs

Foods to avoid*	Foods allowed
Dried, aged, smoked, fermented, spoiled, or improperly stored meat, poultry, and fish	Fresh or processed meat, poultry, and fish; properly stored pickled or smoked fish
Broad bean pods	All other vegetables
Aged cheeses	Processed cheese slices, cottage cheese, ricotta cheese, yogurt, cream cheese
Tap and unpasteurized beer	Canned or bottled beer and alcohol
Marmite	Brewer’s and baker’s yeast
Sauerkraut, kimchee
Soy products/tofu	Peanuts
Banana peel	Bananas, avocados, raspberries
Tyramine-containing nutritional supplement

* Not necessary for 6-mg transdermal or low-dose oral selegiline

Table 3. Drugs that boost norepinephrine: should only be used with caution with MAOIs

Use With Caution:
Decongestants	Stimulants	Antidepressants with norepinephrine reuptake inhibition	Other
Phenylephrine	Amphetamines	Most tricyclics	Phentermine
Pseudoephedrine	Methylphenidate	NRIs	Local anesthetics containing vasoconstrictors
	Cocaine	NDRIs
	Methamphetamine
	Modafinil		Tapentadol
	Armodafinil

Suggested Reading

Kennedy SH. Continuation and maintenance treatments in major depression: the neglected role of monoamine oxidase inhibitors. J Psychiatry Neurosci 1997;22:127–31.

Lippman SB, Nash K. Monoamine oxidase inhibitor update. Potential adverse food and drug interactions. Drug Saf 1990;5:195–204.

Parsons B, Quitkin FM, McGrath PJ, Stewart JW, Tricamo E, Ocepek-Welikson K, Harrison W, Rabkin JG, Wager SG, Nunes E. Phenelzine, imipramine, and placebo in borderline patients meeting criteria for atypical depression. Psychopharmacol Bull 1989;25:524–34.

PHENTERMINE-TOPIRAMATE

PHENTERMINE-TOPIRAMATE: THERAPEUTICS

Brands

• Qsymia

see index for additional brand names

Generic?

No

Class

• Norepinephrine and dopamine reuptake inhibitor (phentermine) combined with a voltage-sensitive sodium channel modulator (topiramate); weight management medication

Commonly Prescribed for

(bold for FDA approved)

• Chronic weight management (adjunct to reduced-calorie diet and increased physical activity) in adults with an initial BMI of at least 30 kg/m² (obese) or at least 27 kg/m² (overweight) in the presence of at least 1 weight-related comorbid condition

How the Drug Works

• Phentermine increases dopamine and norepinephrine by blocking both the dopamine and the norepinephrine transporters. In the hypothalamus, these 2 neurotransmitters activate POMC neurons, causing the release of POMC. POMC is then broken down into α-melanocyte-stimulating hormone, which binds to melanocortin 4 receptors to suppress appetite. However, stimulation of POMC neurons also activates an endogenous opioid-mediated negative feedback loop, which mitigates the appetite-suppressing effects.

• Theoretically, through modulation of voltage-sensitive sodium channels topiramate may reduce glutamatergic stimulation and increase GABAergic inhibition in the appetite-stimulating pathway, resulting in net inhibition of this pathway. Such an action would synergize with simultaneous activation of the appetite-suppressing pathway by phentermine. This results in more robust and long-lasting appetite suppression than with either drug alone.

How Long Until It Works

• At least 3% weight loss is generally achieved after 14 weeks; at least 5% weight loss is generally achieved after an additional 12 weeks on maximum daily dose

If It Works

• Patients may achieve 5–10% reduction from baseline in body weight

If It Doesn’t Work

• Discontinue if 5% weight loss is not achieved after 12 weeks on maximum daily dose

Best Augmenting Combos for Partial Response or Treatment Resistance

• Phentermine-topiramate itself should be administered in conjunction with reduced-calorie diet and increased physical activity

• Often best to try another strategy prior to resorting to augmentation

Tests

• Women of childbearing potential should have a negative pregnancy test before starting phentermine-topiramate and monthly during treatment

• Regular measurement of resting heart rate, especially for patients with cardiac or cerebrovascular disease or when initiating or increasing the dose of phentermine-topiramate

• Obtain a blood chemistry profile that includes bicarbonate, creatinine, potassium, and glucose at baseline and periodically during treatment

• Measurement of blood pressure prior to starting phentermine-topiramate and during phentermine-topiramate treatment is recommended in patients being treated for hypertension

PHENTERMINE-TOPIRAMATE: SIDE EFFECTS

How Drug Causes Side Effects

• CNS side effects theoretically due to excessive actions at voltage-sensitive sodium channels or excessive actions on norepinephrine and dopamine

• Weak inhibition of carbonic anhydrase may lead to kidney stones and paresthesias

• Inhibition of carbonic anhydrase may also lead to metabolic acidosis

Notable Side Effects

• Constipation, dry mouth

• Paresthesia, dizziness, dysgeusia, insomnia

• Cognitive impairment (may be more likely with rapid titration or high initial doses)

Life-Threatening or Dangerous Side Effects

• Hypoglycemia

• Increased heart rate

• Metabolic acidosis

• Kidney stones

• Secondary angle-closure glaucoma

• Oligohidrosis and hyperthermia (more common in children)

• Sudden unexplained deaths have occurred in epilepsy (unknown if related to topiramate use)

• Rare activation of suicidal ideation and behavior (suicidality)

Weight Gain

• Reported but not expected

Sedation

• Reported but not expected

What to Do About Side Effects

• Wait

• Avoid dosing in evening due to the possibility of insomnia

• In a few weeks, switch to another agent

Best Augmenting Agents for Side Effects

• Often best to try another treatment prior to resorting to augmentation strategies to treat side effects

PHENTERMINE-TOPIRAMATE: DOSING AND USE

Usual Dosage Range

• 7.5 mg/46 mg per day up to 15 mg/92 mg per day

Dosage Forms

• Capsule (phentermine mg/topiramate mg extended-release) 3.75 mg/23 mg, 7.5 mg/46 mg, 11.25 mg/69 mg, 15 mg/92 mg

How to Dose

• Initial 3.75 mg/23 mg per day; after 14 days increase to 7.5 mg/46 mg per day

• If at least 3% weight loss is not achieved after 12 weeks on 7.5 mg/46 mg per day, can increase to 11.25 mg/69 mg per day; after 14 days increase to 15 mg/92 mg per day

• Discontinue if at least 5% weight loss is not achieved after 12 weeks on 15 mg/92 mg per day

Dosing Tips

• Can be taken with or without food

• Side effects tend to abate with time but may recur again briefly with dose increases

Overdose

• Phentermine: restlessness, tremor, hyperreflexia, rapid respiration, confusion, aggression, hallucinations, panic

• Topiramate: severe metabolic acidosis, convulsions, sedation, speech disturbance, blurred or double vision, impaired coordination, hypotension, abdominal pain, agitation, dizziness

Long-Term Use

• Has been evaluated in controlled studies up to 1 year

Habit Forming

• Phentermine is a Schedule IV drug

• Topiramate is not controlled in the Controlled Substances Act

How to Stop

• For patients taking 15 mg/92 mg per day, take a dose every other day for at least 1 week prior to discontinuing treatment, due to the possibility of precipitating a seizure

Pharmacokinetics

• Phentermine mean terminal half-life approximately 20 hours

• Topiramate mean terminal half-life approximately 65 hours

• Neither phentermine nor topiramate is extensively metabolized

Drug Interactions

• May cause irregular bleeding in patients taking oral contraceptives, but does not increase risk of pregnancy; patients should be advised not to discontinue oral contraceptives if spotting occurs

• May increase effects of CNS depressants

• May potentiate hypokalemia in patients taking non-potassium-sparing diuretic agents

• Weight loss associated with phentermine-topiramate may increase the risk of hypotension in patients taking antihypertensive medications

• Carbamazepine, phenytoin, and valproate may increase the clearance of topiramate, and thus decrease topiramate levels, possibly requiring a higher dose of topiramate

• Topiramate may increase the clearance of phenytoin and thus decrease phenytoin levels, possibly requiring a higher dose of phenytoin

• Topiramate may increase the clearance of valproate and thus decrease valproate levels, possibly requiring a higher dose of valproate

• Topiramate may increase plasma levels of metformin; also, metformin may reduce clearance of topiramate and increase topiramate levels

• Topiramate may interact with carbonic anhydrase inhibitors to increase the risk of kidney stones

• Reports of hyperammonemia with or without encephalopthay in patients taking topiramate combined with valproate, though this is not due to a pharmacokinetic interaction; in patients who develop unexplained lethargy, vomiting, or change in mental status, an ammonia level should be measured

• Phentermine is contraindicated with MAOIs due to risk of hypertensive crisis