Chapter 9: Pharmacology: Mental Health Medications 7 Contact Hours By: Katie Ingersoll, RPh, PharmD, and Staff Pharmacist for a national chain Author Disclosure: Katie Ingersoll and Elite do not have any actual or potential conflicts of interest in relation to this lesson. Universal Activity Number (UAN): 0761-9999-16-135-H01-P Activity Type: Knowledge-based Initial Release Date: June 1, 2016 Expiration Date: June 1, 2018 Target Audience: Pharmacists in a community-based setting To Obtain Credit: A minimum test score of 70 percent is needed to obtain a credit. Please submit your answers either by mail, fax, or online at Pharmacy.EliteCME.com. Questions regarding statements of credit and other customer service issues should be directed to 1-888-666-9053. This lesson is $28.00. Educational Review Systems is accredited by the Accreditation Council of Pharmacy Education (ACPE) as a provider of continuing pharmaceutical education. This program is approved for 7 hours (0.7 CEUs) of continuing pharmacy education credit. Proof of participation will be posted to your NABP CPE profile within 4 to 6 weeks to participants who have successfully completed the post-test. Participants must participate in the entire presentation and complete the course evaluation to receive continuing pharmacy education credit. Learning objectives Differentiate the drug classifications, side effects, mechanisms of action, and drug interactions of antidepressant medications. Recommend a treatment plan for antidepressant therapy based on patient-specific characteristics. Discuss counseling points for medications used in the treatment of major depression. Distinguish differences in drug classifications, side effects, mechanism of action, and drug interactions between antianxiety medications. Design a treatment plan for antianxiety therapy based on patientspecific characteristics. Discuss counseling points for medications used in the treatment of anxiety disorders. Differentiate the side effects, mechanism of action, and drug interactions between medications used to treat bipolar disorder. Develop a treatment plan for bipolar therapy to prevent deterioration and stabilize the patient s condition based on patientspecific characteristics. Summary This course will review the pharmacology of medications used to treat depression, anxiety, alcoholism, bipolar disorder and schizophrenia. After reviewing the diagnosis of each disease state, the mechanism of action, side effects, drug interactions, black box Discuss counseling points for medications used in the treatment of bipolar disorders. Distinguish differences in drug classifications, side effects, mechanism of action, and drug interactions between medications used to treat schizophrenia. Recommend a treatment plan for treatment of schizophrenia based on patient-specific characteristics. Discuss counseling points for medications used in the treatment of schizophrenia. Determine differences in drug classifications, side effects, mechanism of action, and drug interactions between medications used to treat alcoholism. Design a treatment plan for treatment of alcoholism based on patient-specific characteristics. Discuss counseling points for medications used in the treatment of alcoholism. Determine appropriateness of treatment of mental health disorders in special populations, such as pregnant patients. warnings and applications will be reviewed for each medication class. Considerations for special populations will be reviewed as applicable, as well as any effects on lab results. A discussion of counseling points for each class or type of medication will also be provided. Conclusion This course will allow pharmacists to review the pharmacology of mental health medications to apply this information to clinical practice. Pre-assessment questions Prior to beginning work on this activity, test your baseline knowledge by answering the following questions. These questions may be repeated in the final examination. 1. Jackie Robinson has been diagnosed with depression, and he has been suicidal for the past few weeks after losing several baseball games in a row. Which of the following antidepressants would be the most dangerous to dispense to Jackie in a one-month supply? a. Sertraline. b. Nortriptyline. c. Duloxetine. d. St. John s Wort. Pharmacy.EliteCME.com Page 96
2. Which of the following medications is considered a short-acting benzodiazepine? a. Alprazolam. b. Diazepam. c. Chlordiazepoxide. d. Clonazepam. Introduction Mental illness, defined as diagnosable mental disorders, causes more disability in developed countries than any other group of illnesses, including cancer and cardiac disease. In fact, it is estimated that 25 percent of all adults in the United States will develop at least one mental illness during their lives. 1 The prevalence of mental illness makes it almost a certainty that pharmacists, no matter their practice setting or specialty, will care for Antidepressant pharmacology The reported incidence of depression has risen every year since early in the 20th century. In the United States, it is estimated that one in six people will experience a depressive episode at some point in their life. However, only half of the people who meet the criteria for diagnosis seek treatment for their depression. 2 According to the DSM-IV, a primary diagnosis of depression is made when a patient has either anhedonia (loss of interest in previously pleasurable activities) or consistently depressed mood and at least five of the following symptoms that last at least two weeks: 36 Changes in sleep: either hypersomnia or insomnia. Feelings of guilt or worthlessness. Fatigue or loss of energy. Decreased ability to concentrate or focus. Significant weight loss or gain. Psychomotor symptoms of retardation or agitation. Suicidal attempt or thoughts. Prescription antidepressant medication is a common treatment modality for major depression. Treatment length varies among patients. Treatment for an initial depressive episode may last from Antidepressant use in children and adolescents Antidepressant use in children and adolescents requires meticulous monitoring. The Food and Drug Administration (FDA) mandates that all antidepressants carry a warning that some children, adolescents and young adults may be at increased risk for suicidal ideation. All Selective serotonin reuptake inhibitors (SSRIs) The most commonly prescribed antidepressants, SSRIs, work by blocking the reuptake of serotonin into the presynaptic cell, increasing the serotonin in the synapse available to bind to receptors on the postsynaptic cell. These drugs are referred to as selective because they primarily have an impact on serotonin, not on other types of neurotransmitters. 3,4,5,36 The following SSRIs and doses are used for the treatment of depression: 4,5,36 Citalopram (Celexa) 10-40 mg. per day. Drug interactions There are a number of drugs that can cause harmful effects if taken in conjunction with antidepressants. That is why it is so important to explain to patients that they must inform their health care providers of all of the medications they take, including not only prescription Page 97 3. Genevive has bipolar disorder and has recently been diagnosed with hypothyroidism. Which of the following medications has the most negative effects on thyroid hormone levels? a. Lamotrigine. b. Carbamazepine. c. Lithium. d. Valproic acid. patients who are currently experiencing a mental illness. It also makes it likely that these patients are taking medications for such illnesses or will need to be prescribed appropriate pharmacotherapy. Therefore, it is imperative that all pharmacists be knowledgeable about the treatments available for various mental illnesses, their actions, dosage, side effects and potential drug interactions. This education program will provide information about the pharmacological interventions for several of the most commonly encountered mental illnesses. six months to a year, and recurrent episodes may require two years of treatment or more. Chronic depression may necessitate lifelong treatment. 3 Drugs are generally prescribed initially at a low dose, which is gradually increased according to the patient s tolerance and response to the drug. It may take from one to eight weeks for antidepressant medication to become effective, depending on the medication, dosage, and patient. Therapeutic effects are not immediately apparent, and patients should be counseled on this point. 3,4 Classes of antidepressant medications include: 3,4 SSRIs: selective serotonin reuptake inhibitors. TCAs: tricyclic and tetracyclic antidepressants. MAOIs: monoamine oxidase inhibitors. SNRIs: serotonin and norepinephrine reuptake inhibitors. Atypical antidepressants. Drug alert! Antidepressants are sometimes prescribed to treat conditions other than depression, such as panic disorder, posttraumatic stress disorder (PTSD), anxiety disorders, obsessivecompulsive disorder, and premenstrual syndromes. patients, however, should be monitored meticulously for any increase in depression or unusual behavior, particularly during the first few weeks after antidepressant therapy is initiated. 4,5 Escitalopram (Lexapro) 5-20 mg. per day. Fluoxetine (Prozac, Prozac Weekly, Sarafem) 20-60 mg. per day. Longer half-life, generally has fewer withdrawal symptoms. Considered to be the most activating of the SSRIs. Paroxetine (Paxil, Paxil CR) 10-60 mg. per day. Relatively short acting, generally has the most withdrawal symptoms. Sertraline (Zoloft) 25-200 mg. per day. Fluvoxamine (Luvox) 50-300 mg. per day. drugs, but over-the-counter medications, herbal preparations, vitamins, minerals and even nutrition supplements and weight-loss products. Many patients assume that non-prescription medications and substances such as aspirin, herbal preparations and vitamins are not Pharmacy.EliteCME.com
medications, so they do not bother to inform their health care providers that they are taking them. Patients must be counseled that any or all of these substances may interact negatively with antidepressants. Aspirin products, other non-steroidal anti-inflammatory drugs (NSAIDs), Coumadin and other drugs that increase coagulation time may increase the risk of bleeding if taken in conjunction with SSRIs. Patients who take such drugs should be cautioned about this risk and monitored closely. 4,5 When possible, alternatives to these types of drugs should be investigated while the patient is taking SSRIs. Monoamine oxidase inhibitors (MAOIs), such as phenelzine (Nardil) and isocarboxazid (Marplan), are also used in the treatment of depression. However, they must not be used in conjunction with SSRIs, nor should SSRIs be used within 14 days of MAOI therapy. Use of MAOIs in too-close conjunction with SSRIs can cause neuroleptic malignant syndrome. This syndrome can be fatal and is characterized by hyperthermia, rigidity and autonomic dysregulation. 4,5,6 Serotonin syndrome is also a serious adverse reaction to antidepressant therapy. It is more likely to occur when two or more medications that raise serotonin levels are used in combination. Serotonin syndrome is characterized by confusion, hallucinations, restlessness, loss of coordination, vomiting, tachycardia, irregular heart rates, dilated pupils, fever, changes in blood pressure and unconsciousness. 4,5 When starting a patient on SSRIs, it is important to check whether the patient is taking other medications that can increase serotonin levels. Side effects Side effects commonly associated with SSRIs include: 3,4,5 Fatigue. Headache. Tremor. Dizziness. Insomnia. Dry mouth. Nausea. Diarrhea. Pregnancy Some antidepressants may place the fetus at risk during pregnancy or the drugs may pass to the baby during breast-feeding. Paroxetine (Paxil) in particular seems to be linked to an increased risk of birth Discontinuing the drug Patients must be instructed to avoid missing several doses and must not discontinue using the drug abruptly. When discontinuing SSRIs, the dosage must be tapered gradually under the supervision of the prescriber. Abrupt discontinuation can cause withdrawal-like symptoms that include: 4,5 Counseling points for SSRIs 36 Patients should be told to take SSRIs as directed by their doctor, and to not miss doses or discontinue the medication abruptly. Counsel patients on symptoms and severity of serotonin syndrome, and tell them to notify their pharmacist or doctor if they start new medications, herbs, or supplements. Tricyclic antidepressants (TCAs) and tetracyclics TCAs and tetracyclics are among the earliest identified antidepressants and are sometimes referred to as cyclics. Although effective, they have been largely replaced by antidepressants that cause fewer side effects. If a patient is taking several medications that increase serotonin levels, the person is at risk of developing serotonin syndrome, a potentially fatal condition. Examples of serotonergic medications are linezolid (contraindicated within 14 days of taking SSRIs), MAO inhibitors (contraindicated within 14 days of taking SSRIs), triptans (such as sumatriptan, frovatriptan, and zolmitriptan), tramadol, and St. John s Wort. 36 Fluoxetine and paroxetine are inhibitors of the cytochrome P450 enzyme 2D6, and can increase the levels and incidence of side effects of CYP2D6 substrates, such as aripiprazole, clozapine, codeine, donepezil, flecanide, hydrocodone, meperidine, propafenone and tamoxifen. 36 Fluvoxamine is an inhibitor of the cytochrome P450 enzymes 1A2 and 3A4, and can increase the levels and incidence of side effects of CYP1A2 and 3A4 substrates, such as haloperidol, theophylline, tizanidine, methadone, warfarin, and carbamazepine; statin drugs, such as simvastatin, lovastatin, atorvastatin, and triazolam; and prostate medications, such as tamsulosin, alfuzosin, dutasteride, eplerenone, amiodarone,clarithromycin, erythromycin, sirolimus and tacrolimus. Other drug interactions with SSRIs include pimozide (combination contraindicated due to increased pimozide levels, increased risk of QT prolongation), thioridazine (combination contraindicated due to increased thioridazine levels), and diuretics (when used in combination, patients should be monitored for excessive electrolyte loss). Agitation or restlessness. Reduced libido. Difficulty reaching orgasm. Erectile dysfunction. Rash. Diaphoresis. Weight gain. Drowsiness. defects, including cardiac and respiratory problems. 5 Women who are considering becoming pregnant should discuss depression treatment options with their doctor before becoming pregnant. Nausea. Headache. Dizziness. Lethargy. Flu-like symptoms. Notify patients of potential side effects and when to contact a doctor or seek emergency care. Inform patients of black box warnings on antidepressants and instruct them to contact their doctor if they experience severe mood changes. However, TCAs and tetracyclics may still be prescribed for patients who do not respond to other classifications of antidepressants. 7 These drugs work by increasing the amount of norepinephrine and serotonin in the CNS by blocking their reuptake by the presynaptic Pharmacy.EliteCME.com Page 98
neurons. 4 These actions make more norepinephrine, serotonin, or both available in the brain, which, in turn, enhances the ability of neurons to send and receive messages. They also affect other types of neurotransmitters, which can cause a number of side effects. 4,7 Cyclics and doses used in the treatment of depression include: 3,4,7,36 Tertiary TCAs Amitriptyline (Elavil), 10-300 mg. per day, divided into 1-3 doses per day. Doxepin (Sinequan) 25-300 mg. per day, divided into 1-3 doses per day. Clomipramine (Anafranil) 75-250 mg. per day, divided into 3 doses per day. Imipramine (Tofranil) 100-300 mg. per day, divided into 1-3 doses per day. Trimipramine (Surmontil) 75-300 mg. per day, divided into 1-3 doses per day. Side effects Side effects of cyclic antidepressants can vary depending on the subclass. Tertiary TCAs are more likely to cause anticholinergic symptoms, such as dry mouth, urinary retention, orthostatic hypotension, and drowsiness because of the strong antagonism of acetylcholine and histamine receptors. Secondary TCAs are less likely to cause these effects because they cause less strong antagonism of acetylcholine and histamine receptors. 4,7,36 Other common side effects of cyclic antidepressants include: 4,7,36 Photophobia. Blurred vision. Constipation. Dizziness. Pregnancy There are a number of safety concerns associated with TCAs and tetracyclics. As with SSRIs, some cyclics may harm a fetus and may pass to the baby during breast-feeding. Women of childbearing age Drug interactions Adverse drug interactions are also problematic. Serotonin syndrome is a possibility as it is with SSRIs. There are specific types of drugs that, if taken in conjunction with cyclics, can cause specific, severe problems. These include: 4,7,36 CYP2D6 inhibitors: Can alter hepatic metabolism of antidepressant. Barbiturates, alcohol and other CNS depressants: Can significantly increase CNS depression and drowsiness. Lab studies and concurrent health problems Cyclics may alter blood glucose levels. Blood glucose levels should be monitored, especially if the patient is diabetic. Liver function should also be monitored as well as white and red blood counts. 4 Cyclics can also exacerbate certain chronic health problems. They are contraindicated in patients who have received an MAO inhibitor within the last 14 days or who are in the acute recovery phase following a myocardial infarction. They are to be used with caution in patients who have narrow-angle glaucoma, enlarged prostate, or a history of seizures, cardiac problems, thyroid problems, diabetes or impaired liver function. 4,7 Secondary TCAs Desipramine (Norpramin) 100-300 mg. per day, divided into 1-3 doses per day). Nortriptyline (Pamelor) 50-150 mg. per day, divided into 1-3 doses per day; *max. 150 mg./day. Protriptyline (Vivactil) 15-60 mg. per day, divided into 3-4 doses per day. Tetracyclic antidepressants Amoxapine (Asendin) 50-600 mg. per day, divided into 2-3 doses per day. Drug alert! Tricyclic antidepressants should be used with caution in patients who are suicidal. Overdose on tricyclic antidepressants can be potentially fatal from cardiovascular complications. Consider dispensing smaller quantities to suicidal patients. 36 Delayed orgasm. Decreased sex drive. Tachycardia. Confusion. Increased appetite and weight gain. Fatigue. Headache. Nausea. Seizures, especially with maprotiline (Ludiomil). Drug alert! Tricyclic antidepressants are often used to treat insomnia because of the adverse effects of drowsiness. 36 should be counseled about the potential benefits versus risks to the unborn child and to the baby during breast-feeding before becoming pregnant. 7 Serotonergic medications, such as linezolid, MAO inhibitors, SSRIs, triptans, and St. John s wort: Can cause serotonin syndrome. Evening primrose: Can cause additive effects and lower seizure threshold. Cimetidine: May increase TCA levels. Clonidine (Catapres): May decrease the anti-hypertensive effect of Catapres and cause severe, life-threatening hypertension. Quinolones (broad-spectrum antibiotics): May increase the risk of life-threatening arrhythmias. There are some environmental factors that can have an impact on patients taking cyclics. Smoking may lower drug levels. Patients who smoke must be particularly monitored for lack of drug effectiveness. Additionally, exposure to the sun may increase photophobia. Patients should be advised to avoid excessive exposure to sunlight. 4 As with SSRIs, cyclics should never be abruptly discontinued. Such abrupt discontinuation can cause withdrawal symptoms, including nausea, headache, dizziness, lethargy and flu-like symptoms. 4,7 Page 99 Pharmacy.EliteCME.com
Counseling points for TCAs 36 Patients should be told to take TCAs as directed by their doctor, and to not miss doses or discontinue the medication abruptly. Counsel patients on symptoms and severity of serotonin syndrome, and tell them to notify their pharmacist or doctor if they start new medications, herbs, or supplements. Notify patients of potential side effects and when to contact their doctor or seek emergency care. Monoamine oxidase inhibitors (MAOIs) MAOIs were the first type of antidepressant drug developed, and although effective, they, like TCAs, have been replaced by other types of antidepressants that are safer and cause fewer side effects. 8 One of the major concerns with MAOIs is that they generally necessitate dietary restrictions. If these drugs are taken in conjunction with a diet high in tyramine-containing foods, life-threatening hypertension may occur. 4,8 However, MAOIs may still be prescribed if the patient does not respond to other types of antidepressants. Monoamine oxidase is an enzyme that helps to remove the neurotransmitters serotonin, dopamine and norepinephrine from the brain. MAOIs work by nonselectively inhibiting this removal, increasing the availability of these neurotransmitters in the brain and enhancing neuron communication. However, MAOIs also affect other neurotransmitters in the brain and in the digestive system, such as 5HT, 3 causing significant side effects. 8 Side effects Side effects of MAOIs include: 4,8 Headache. Insomnia. Dizziness. Nausea. Arrhythmias. Low blood pressure. Diarrhea. Dry mouth. Pregnancy There are significant safety concerns associated with the use of MAOIs. As with other classifications of antidepressants, MAOIs may place a fetus at risk and may pass to the infant during breast-feeding. Drug and food interactions MAOIs should never be taken in conjunction with other types of antidepressants or with St. John s wort because of the risk of serotonin syndrome. Ginseng in combination with MAOIs may cause headache, tremors or mania. Concurrent use should be avoided. 4 Patients taking MAOIs must restrict foods that contain high levels of tyramine. Tyramine is an amino acid found naturally in the body and in certain foods and is involved in the regulation of blood pressure. Interaction of tyramine and MAOIs can cause dangerous, even lifethreatening hypertension. 8 Tyramine is found in especially large amounts in aged foods or foods that contain significant amounts of yeast. Foods that have moderate to large amounts of tyramine include: 9 All tap beers. Bottled or canned beer, including nonalcoholic beer. Aged cheeses, such as cheddar, Brie and Camembert. Aged, smoked, fermented and pickled meats, such as pepperoni, salami and meat jerky. Inform patients of black box warnings on antidepressants and tell them to contact their doctor if they experience severe mood changes. Patients who are suicidal should be dispensed smaller quantities of tricyclic antidepressants because of the dangerous cardiovascular complications related to overdose. Discuss timing of dosing; generally these are taken at bedtime because they can cause drowsiness. MAOIs and doses used in the treatment of depression include: 4,8 Isocarboxazid (Marplan) 20-60 mg. per day, divided into 2-4 doses per day. Phenelzine (Nardil) 45-90 mg. per day, divided into 3-4 doses per day. Tranylcypromine (Parnate) 30-60 mg. per day, divided into 2-4 doses per day. Drug alert! Selegiline (Emsam) is a transdermal MAOI mainly used to treat Parkinson s disease, minimizing side effects by bypassing the stomach. 36 MAOIs should be avoided in patients with cardiovascular or cerebrovascular disorders, hypertension, those undergoing general anesthesia, and patients with severe renal impairment. Changes in sense of taste. Nervousness. Muscle aches. Weight gain. Difficulty urinating. Paresthesia. Erectile dysfunction. Reduced sexual desire. Difficulty reaching orgasm. Women of childbearing age should be counseled about the potential benefits versus risks to the child before becoming pregnant. 4,8 Banana peel. Breads or crackers that contain cheese. Soy products. Pickled herring. Smoked fish. Red and white wine. Yeast extracts. Patients should be provided with a list of foods that are high in tyramine and that should be avoided. A dietary consult is recommended to help patients modify their diets to reduce their intake of tyramine. Drug alert! As with any antidepressant, MAOIs should never be discontinued abruptly. Pharmacy.EliteCME.com Page 100
Counseling points for MAOIs 36 Patients should be told to take MAOIs as directed by their doctor, and to not miss doses or discontinue the medication abruptly. Counsel patients on the symptoms and severity of serotonin syndrome, and tell them to notify their pharmacist or doctor if they start new medications, herbs, or supplements. Notify patients of potential side effects and when they should contact their doctor or seek emergency care. Inform patients of black box warnings on antidepressants and tell them to contact their doctor if they experience severe mood changes. Discuss dietary restrictions with patients and provide them with a list of foods to avoid, and discuss when they should call for emergency assistance if they eat the problem foods. Serotonin and norepinephrine reuptake inhibitors (SNRIs) SNRIs work by increasing neural concentrations of the neurotransmitters serotonin and norepinephrine by preventing their reuptake by the presynaptic neuron. They are also used to treat other mental health issues, such as anxiety. 4,13,36 SNRIs and doses used to treat depression include: 4,13,36 Duloxetine (Cymbalta) 30-120 mg. per day, given once daily. Venlafaxine (Effexor, Effexor XR) 25-375 mg. per day, divided into 1-3 doses per day. Desvenlafaxine (Pristiq) 50-100 mg. per day, given once daily. Drug alert! Duloxetine can also be used to treat neuropathic pain. 36 Side effects SNRI side effects include: 4,13 Nausea (especially with duloxetine). Dizziness. Fatigue. Headache. Insomnia. Constipation. Diaphoresis. Drug interactions Duloxetine is an inhibitor of the cytochrome P450 enzyme 2D6, and can increase the levels and incidence of side effects of CYP2D6 substrates, such as aripiprazole, clozapine, codeine, donepezil, flecanide, hydrocodone, meperidine, propafenone and tamoxifen. Venlafaxine is a weak inhibitor and substrate of CYP2D6, and should be used with caution with other 2D6 medications. 36 Pregnancy There are significant safety concerns associated with the use of SNRIs. As with other classifications of antidepressants, SNRIs may place a fetus at risk and may pass to the infant during breast-feeding. SNRIs Counseling points for SNRIs 36 Patients should be told to take SNRIs as directed by their doctor and to not miss doses or discontinue the medication abruptly. Counsel patients on the symptoms and severity of serotonin syndrome, and tell them to notify their pharmacist or doctor if they start new medications, herbs, or supplements. Practice question Harry Houdini has been treated for depression for several years with sertraline. It is no longer working for him, and his doctor would like to switch him to a different antidepressant. His medical conditions include residual nerve pain from a past incident with a complicated magic trick that did not go as planned, high blood pressure, and he is taking ketoconazole for a fungal infection. He would prefer to have a medication that does not make him drowsy, as he needs to be alert when performing. What antidepressant would be best for Harry to try? a. Venlafaxine. b. Amitriptyline. Hypertension (with venlafaxine). Tachycardia. Decreased sexual desire. Blurred or double vision. Arrhythmias. Erectile dysfunction. Difficulty urinating. Other drug interactions for the SNRI class include: 4 MAOIs: Avoid use within 14 days of each other. Alcohol: May cause liver damage if used in conjunction with some SNRIs. SSRIs and other seroronergic agents, such as tramadol and triptans: May lead to serotonin syndrome. should not be used in the third trimester of pregnancy. Women of childbearing age should be counseled about the potential benefits versus risks to the child before becoming pregnant. 4,8 Notify patients of potential side effects and when they should contact their doctor or seek emergency care. Inform patients of black box warnings on antidepressants and tell them to contact their doctor if they experience severe mood changes. c. Duloxetine. d. Nefazodone. Answer: C Duloxetine would be the most appropriate option for Harry to try because it helps treat both depression and nerve pain. Venlafaxine is not advised because Harry has high blood pressure. Amitriptyline causes sedation, which Harry would like to avoid at this time. Nefazodone should not be used with ketoconazole because they are both metabolized through CYP3A4. Page 101 Pharmacy.EliteCME.com
Atypical antidepressants Atypical antidepressants are referred to as atypical because they do not fit into other classifications of antidepressants. Each is unique and works in different ways, with different side effects and safety concerns. 10 Bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL) Bupropion s exact action is unknown, but it is thought to weakly inhibit norepinephrine and dopamine reuptake, increasing available concentrations of these neurotransmitters in the brain. Its noradrenergic mechanisms are thought to cause the drug s antidepressive effect. 4,36 Bupropion is used in doses of 100-450 mg. per day, divided into 1-3 doses per day, depending on the product chosen. It is believed to be a good choice for patients who have low energy caused by depression, but it can exacerbate or cause anxiety for some people. This is due to the amphetamine-like structure of the drug molecule. Bupropion is not associated with sexual side effects or weight gain as often as other 10, 36 antidepressants. Drug alert! Bupropion is also prescribed as an aid to smoking cessation treatment. 4 Side effects of bupropion include: 4,10 Confusion. Abnormal dreams. Insomnia. Headache. Tremor. Sedation. Agitation. Dizziness. Seizures. Tachycardia. Arrhythmias. Blurred vision. Sore throat. Counseling points for bupropion 36 Patients should be told to take bupropion as directed by their doctor, and to not miss doses or discontinue the medication abruptly. Counsel patients on the symptoms and severity of serotonin syndrome, and tell them to notify their pharmacist or doctor if they start new medications, herbs, or supplements. Notify patients of potential side effects and when to contact their doctor or seek emergency care. Mirtazapine (Remeron, Remeron SolTab) Mirtazapine is believed to act by enhancing central noradrenergic and serotonergic activity. Like bupropion, mirtazapine does not cause sexual side effects that are caused by other antidepressants. It is used in doses of 15-45 mg., and because it often causes drowsiness, it is usually taken at bedtime. 10 Side effects include: 4,10 Somnolence. Dizziness. Increased appetite. Weight gain. Increased cholesterol levels. Increase or decrease in blood pressure. Decreased white blood cell count. Weakness. Atypical antidepressants used in the treatment of depression include: 10 Bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL). Mirtazapine (Remeron, Remeron SolTab). Nefazodone (Serzone). Trazodone (Desyrel, Oleptro). Rhinitis. Dry mouth. Constipation. Nausea. Vomiting. Fluctuations in weight. Excessive sweating. Contraindications include: 4 Patients who have taken MAOIs or linezolid within the previous 14 days. Patients with seizure disorders. Patients with history of eating disorders (increases the risk of seizures). Patients in alcohol withdrawal (increases risk of seizures). There are a number of potential drug interactions with bupropion use. Bupropion is an inhibitor of the cytochrome P450 enzyme 2D6, and can increase the levels and incidence of side effects of CYP2D6 substrates such as aripiprazole, clozapine, codeine, donepezil, flecanide, hydrocodone, meperidine, propafenone and tamoxifen. 36 Other drug interactions include: 4 Other antidepressants: May lower seizure threshold. Beta-blockers: Levels of beta blockers may be increased and cause adverse reactions. Nicotine replacement agents: May cause hypertension. Alcohol: May alter seizure threshold. Drug alert! Excessive sun exposure may increase the risk of photosensitivity. 4 Inform patients of black box warnings on antidepressants and tell them to contact their doctor if they experience severe mood changes. Discuss the importance of using sunscreen during periods of sun exposure because of photosensitivity. Drug alert! Bupropion is not approved for use in children. 4 Drug interactions include: 4 MAOIs: Avoid use within 14 days of MAOI therapy. CNS depressants, including alcohol: May cause additive CNS effects. CYP1A2, 2D6 and 3A4 inhibitors or inducers: May alter hepatic metabolism of mirtazapine. Mirtazapine should be used with caution in patients with cardiovascular disease, cerebrovascular disease, seizure disorders, hepatic or renal impairment or history of mania or hypomania. 4 Pharmacy.EliteCME.com Page 102
Counseling points for mirtazapine 36 Patients should be told to take mirtazapine as directed by their doctor, and to not miss doses or discontinue the medication abruptly. Counsel patients on the symptoms and severity of serotonin syndrome, and tell them to notify their pharmacist or doctor if they start new medications, herbs, or supplements. Nefazodone (Serzone) Nefazodone is thought to work by blocking serotonin type 2A receptors as well as mildly inhibiting the reuptake of serotonin, dopamine and norephinephrine. It may help to decrease anxiety in addition to alleviating depression. Nefazodone is given in doses of 100-600 mg. per day, divided into 1-2 doses per day. It is likely to cause drowsiness but is less likely to cause sexual side effects than other types of antidepressants. 10 Side effects include: 10,11 Orthostatic hypotension. (Patients should be taught to change positions slowly, especially when they first start taking the drug.) Dizziness. Headache. Dry mouth. Blurred vision. Confusion. Nausea. Sleepiness. Weakness. Flushing. Heartburn. Constipation. Pain, burning, numbness, or tingling in the hands or feet. Counseling points for nefazodone 36 Patients should be told to take nefazodone as directed by their doctor, and to not miss doses or discontinue the medication abruptly. Counsel patients on the symptoms and severity of serotonin syndrome, and emphasize that because of the number of drug interactions with this medication, it is very important to notify their pharmacist or doctor if they start new medications, herbs, or supplements. Trazodone (Desyrel, Oleptro) Trazodone is a rather weak antidepressant thought to work by inhibiting the CNS neuronal uptake of serotonin. It is likely to cause sleepiness, so is usually taken at bedtime. In addition to helping to alleviate depression, it can also help to reduce anxiety and can be helpful for patients with mild insomnia. 10,11,36 Side effects include: 4,10,11 Drowsiness. Confusion. Dizziness. Orthostatic hypotension. Dry mouth. Headache. Nausea. Weakness. Blurred vision. Arrhythmias. Fatigue. Constipation. Diarrhea. Drug alert! Trazodone has been linked to a rare condition called priapism. Priapism is a persistent, painful erection not associated Page 103 Notify patients of potential side effects and tell them when to contact their doctor or seek emergency care. Inform patients of black box warnings on antidepressants and tell them to contact their doctor if they experience severe mood changes. Discuss timing of dosing; mirtazapine is generally taken at bedtime due to drowsiness. Drug alert! Nefazodone has been associated with liver failure in some patients. Patients who have compromised hepatic function should not take this drug. 10 There are many drug interactions with nefazodone because it is a potent inhibitor of CYP3A4. Among these interactions are: 4 Carbamazepine May increase carbamazepine levels and decrease nefazodone levels. Statin drugs, such as simvastatin, lovastatin, and atorvastatin Can increase simvastatin levels and increase risk of rhabdomyolysis. Benzodiazepines, such as triazolam Can increase triazolam levels and increase CNS depression. MAOIs and linezolid Avoid use within 14 days of MAOI therapy. Prostate medications, such as tamsulosin, alfuzosin, dutasteride Can increase drug levels and adverse effect risk. Eplerenone Increases eplerenone levels and risk of hyperkalemia and arrhythmias. Amiodarone Can increase amiodarone levels and risk of arrhythmias. Clarithromycin, erythromycin Can increase clarithromycin and erythromycin levels and risk for QT prolongation and arrhythmias. Sirolimus, tacrolimus Can increase levels and increase risk of toxicity. Notify patients of potential side effects and when they should contact doctor or seek emergency care. Inform patients of black box warnings on antidepressants and tell them to contact their doctor if they experience severe mood changes. with sexual arousal. Patients who have an erection that lasts longer than four hours should seek emergency medical treatment. 10 There are a number of potentially dangerous drug interactions with trazodone. These include: 4 CYP3A4 inducers or inhibitors: May alter hepatic metabolism of trazodone. Other antidepressants: May increase the risk of serotonin syndrome. Anti-hypertensives: May increase the anti-hypertensive effect of trazodone. Digoxin and phenytoin: Trazodone may increase the levels of these drugs. MAOIs: Avoid concurrent use. Warfarin: May increase INR. Warfarin dosage may need to be adjusted. Herbs: Ginkgo biloba may increase sedation effects. St. John s wort may lead to serotonin syndrome. Alcohol: May increase CNS depression. Drug alert! Trazodone may decrease hemoglobin levels. 4 Pharmacy.EliteCME.com
Counseling points for trazodone 36 Patients should be told to take trazodone as directed by their doctor, and to not miss doses or discontinue abruptly. Counsel patients on the symptoms and severity of serotonin syndrome, and tell them to notify their pharmacist or doctor if they start new medications, herbs, or supplements. Notify patients of potential side effects, including the risk of priapism in men, and when they should contact their doctor or seek emergency care. Practice question Hermione has noticed that in the past few months, she has lost interest in magic, has been gaining weight and has been sleeping too much. Her doctor diagnosed her with depression and has determined that she should be started on an antidepressant. She is taking tamoxifen for breast cancer treatment and has high blood pressure. She does not have anxiety or any allergies to medications. Which of the following medications would be best for her to take? Herbal medicines A number of herbal medicines have been used in the treatment of depression. Patients should be cautioned that if they are consulting with herbal medicine practitioners, they MUST inform their other health care providers of any herbal supplements they are taking. Some patients believe that herbs are natural and therefore do not have adverse side effects or interactions with medicines. It is imperative that patients understand that herbs have the potential to cause dangerous, even fatal, side effects and interactions with other drugs as well as affect lab tests. St. John s wort St. John s wort is available in capsule, tablet, tincture, sublingual capsule and cream formulations. It should not be used during pregnancy and lactation, nor should it be given to children. Side effects include dizziness, insomnia, restlessness, fatigue, constipation, abdominal cramps, photosensitivity, rash and hypersensitivity. 18,19 The following drug interactions are associated with St. John s wort: 18,19 MAOIs: May increase MAOI inhibition. Avoid concurrent use. Antidepressants: May increase risk for serotonin syndrome. Avoid concurrent use. ACE inhibitors, loop diuretics and thiazide diuretics: Concurrent use may lead to severe photosensitivity. Avoid concurrent use. Ginkgo Ginkgo is a tree native to China and Japan but is now also found in Europe and the United States. It is available in capsule, fluid extract, tablets and tincture form. It should not be used during pregnancy or lactation, nor should it be given to children. It is also contraindicated in patients with coagulation or platelet disorders, hemophilia or seizures. Side effects include headache, anxiety, restlessness, nausea, vomiting, anorexia, diarrhea, flatulence and rash. 9,19 The following drug interactions are associated with ginkgo: 18,19 St. John s wort: May cause hypomania if used in conjunction with ginkgo. MAOIs: MAOI action may be increased if taken with ginkgo. Avoid concurrent use. Inform patients of black box warnings on antidepressants and tell them to contact their doctor if they experience severe mood changes. Discuss timing of dosing; trazodone is generally taken at bedtime because it can cause drowsiness. a. Paroxetine. b. Venlafaxine. c. Fluoxetine. d. Sertraline. Answer: D Sertraline would be best for Hermione for the treatment of depression. Paroxetine and fluoxetine are CYP2D6 inhibitors and can increase the side effects of her tamoxifen. Venlafaxine should be avoided in patients with high blood pressure because it has the potential to increase blood pressure. Drug alert! Herbs should only be prescribed by a practitioner who is well-versed and qualified in herbal medicine. All health care practitioners should ask their patients whether they are taking any type of herbal supplement to avoid dangerous side effects or drug interactions. A few of the herbal medicines used to treat depression are described here. Alcohol: May increase drug action. Avoid concurrent use. Amphetamines: May cause serotonin syndrome. NSAIDs: May lead to severe photosensitivity. Avoid concurrent use. Birth control: May decrease the effectiveness of birth control. Patients taking St. John s wort should limit foods high in tyramine. These include aged cheeses, beer, smoked and pickled meats, and soy products. 9,19 St. John s wort may cause increased growth hormone and decreased serum prolactin, serum iron and digoxin. 19 Anticoagulants and platelet inhibitors: May increase the risk of bleeding. Avoid concurrent use. Anticonvulsants: Ginkgo may decrease the effectiveness of anticonvulsants. Avoid concurrent use. Buspirone and fluoxetine: May cause hypomania if used concurrently. Trazadone (Oleptro, Desyrel): Concurrent use may cause increased sedation and potentially coma. Ginkgo may increase bleeding time and decrease platelet activity, thereby leading to increased risk of bleeding. 19 Pharmacy.EliteCME.com Page 104
Khat Khat is a tree found in Africa and on the Arabian Peninsula, and the raw leaves of the tree are used to make herbal medicine. It is ingested by eating the raw leaves followed by fluids. 18,19 Khat should not be used during pregnancy and lactation, nor should it be given to children. Its use is contraindicated in patients who have compromised renal, cardiac or hepatic systems. 19 Side effects include tachycardia, arrhythmias, elevated blood pressure, pulmonary edema, circulatory collapse, restlessness, insomnia, headache, hallucinations, hyperthermia, diaphoresis, nausea, vomiting, anorexia, constipation, abdominal pain and spasms, cerebral hemorrhage, decreased sperm count and decreased libido. 18,19 Antianxiety pharmacology Jeffrey is a nurse practitioner in a family practice setting. He has a reputation of being a perfectionist. He describes himself as a worrier. In fact, Jeffrey does more than worry. He feels anxious almost all of the time, even when there is no obvious reason for anxiety. He is starting to have difficulty concentrating at work and focusing on his wife and children at home. After a serious discussion with his wife, Jeffrey decides to seek help from his health care provider for treatment of anxiety. Everyone feels anxious at times. Anxiety is a normal reaction to threatening, dangerous or otherwise challenging situations. However, patients dealing with an anxiety disorder experience excessive, chronic anxiety that interferes with normal functioning. These people feel anxious even when no overt external stress exists. 14 There are two types of anxiety disorders. Generalized anxiety disorder (GAD) is characterized by anxiety or excessive worry on most days over at least six months that the patient feels he or she cannot control. To make a diagnosis of GAD, the patient must have at least three of the following symptoms: restlessness, irritability, easily fatigued, muscle tension, difficulty concentrating, or sleep difficulties. 36 Panic disorder is another type of anxiety disorder. It is characterized by panic attacks along with at least four of the following psychic or somatic symptoms: 36 Depersonalization. Fear of dying. Fear of losing control or going crazy. Antidepressants A number of antidepressants have been used to treat anxiety disorders. These include: 4,16 Fluoxetine (Prozac): SSRI antidepressant. Fluvoxamine (Luvox): SSRI antidepressant. Imipramine (Tofranil): Tricyclic antidepressant. Paroxetine (Paxil): SSRI antidepressant. Benzodiazepines Benzodiazepines are believed to work by increasing the effectiveness of the neurotransmitter GABA. They are thought to do this by binding to and opening the GABA-A receptor, which allows an influx of chloride ions into the cell and decreases the polarity of the neuron, decreasing the rate of neural firing. Patients respond by experiencing a reduction in feelings of anxiety and stress and an improvement in ability to function and concentrate. 17,36 Short-acting benzodiazepines are generally preferred when using as a sedative and for use in the elderly, because they cause less accumulation. They are also preferred in patients with liver disorders Page 105 Khat may increase the action of the following drugs: 18,19 Amphetamines. Anti-arrhythmia agents. Antihistamines. Anti-hypertensives. Beta-blockers. Calcium channel blockers. Cardiac glycosides. Decongestants. MAOIs. Drug alert! The preceding paragraphs describe only a few of the many herbal preparations used in the treatment of depression. The importance of finding out whether the patient is taking herbal preparations cannot be overemphasized. Sweating. Trembling. Shaking. Choking. Chest pain. Nausea. Abdominal pain. Palpitations. Tachycardia. Shortness of breath. Dizziness. Chills. Hot flashes. It is believed that anxiety disorders occur as a result of hyperactivity in certain areas of the brain. This is thought to be related to low levels of the neurotransmitter gamma-aminobutyric acid (GABA), which helps to regulate nerve cell activity. Family history of anxiety disorders also increases the risk of development. 14 More than 6 million people suffer from GAD in the United States. The disorder affects women (60 percent) more often than men (40 percent). Because descriptions and perceptions of anxiety vary among cultures, it is difficult to calculate an exact incidence worldwide. 15 Several drug classifications are used in the treatment of anxiety disorders. These include antidepressants, benzodiazepines, betablockers, and the drug buspirone (BuSpar), an anxiolytic. Sertraline (Zoloft): SSRI antidepressant. Venlafxine (Effexor): SSNRI antidepressant. Drug alert! For detailed information on SSRI and SSNRI antidepressants, see the potion of this program that deals with antidepressant pharmacology. because they are metabolized more easily. These drugs are generally associated with more rebound anxiety and withdrawal symptoms when discontinued than longer-acting benzodiazepines. Longer-acting benzodiazepines are associated with less rebound anxiety and are preferred when tapering patients off of this category of drugs. Drug alert! Because of the high potential for abuse and overdose, benzodiazepines are controlled substances under DEA schedule IV. Caution is advised when using these medications in patients with substance-use disorders because overdose can result in respiratory depression and death. 36 Pharmacy.EliteCME.com
Benzodiazepines can cause additive CNS depression when taken with other medications that cause CNS depression, including alcohol. Combination should be avoided when possible. 36 Benzodiazepines are in pregnancy category D. Use in pregnant women should be avoided. Side effects associated with benzodiazepines include: Anxiety. Ataxia. Behavioral disturbances. Bradycardia. Confusion. Constipation. Depression. Diarrhea. Dizziness. Drowsiness. Dry mouth. Fatigue. Headache. Impaired coordination. Insomnia. Irritability. Lethargy. Memory problems. Nausea. Respiratory depression. Risk of suicide. Sedation. Somnolence. Urinary retention. Benzodiazepines prescribed for anxiety include: 4,16,17,36 Alprazolam (Xanax): Short-acting; average half-life is 12 hours. Given in doses of 0.25-3 mg. up to three times daily. Contraindicated in patients with acute angle-closure glaucoma. Should be used with caution in patients with compromised renal, pulmonary and hepatic systems or patients with a history of substance abuse. Avoid concurrent use with kava, St. John s wort, and grapefruit juice. Concurrent use with tricyclic antidepressants may increase levels of these drugs. Smoking may decrease the effects of alprazolam. Alprazolam is a CYP3A4 substrate, and should not be used with 3A4 inhibitors, such as clarithromycin, ketoconazole, ritonavir, and nefazodone. Chlordiazepoxide (Librium): Long-acting; average halflife is 100 hours. Given in doses of 5-25 mg. up to four times daily. Should not be used in conjunction with the herb kava. Concurrent use of cimetidine may increase the risk of adverse reactions. Chlordiazepoxide may increase digoxin levels and the risk of digoxin toxicity, so patients should be closely monitored. Chlordiazepoxide may increase liver function test results and Counseling points for benzodiazepines 36 Patients should be told to take benzodiazepines as directed by their doctor, and to not miss doses or discontinue the medication abruptly. Notify patients of potential side effects and when they should contact their doctor or seek emergency care. Because benzodiazepines are controlled substances and have a high potential for addiction, it is important to emphasize that these medications should not be shared with other patients and may not be refilled early. decrease granulocyte count. This medication is a partial CYP3A4 substrate, and if used with 3A4 inhibitors such as clarithromycin, ketoconazole, ritonavir, and nefazodone, it should be given in lower doses. The drug may also cause a false-positive pregnancy test. Clonazepam (Klonopin): Long-acting; average half-life is 34 hours. Given in doses of 0.25-2 mg up to twice daily. This drug is contraindicated in patients with acute angle-closure glaucoma or significant hepatic disease. Clonazepam should be used with caution in children, patients with chronic respiratory disease, open-angle glaucoma or a history of substance abuse. It should also be used with caution in elderly patients. Clonazepam should not be used with phenytoin. This medication is a partial CYP3A4 substrate, and if used with 3A4 inhibitors, such as clarithromycin, ketoconazole, ritonavir, and nefazodone, it should be given in lower doses. Concurrent use with St. John s wort may cause a decrease in the drug s effects. Clonazepam may increase liver function test results and eosinophil count. It may decrease platelet and white blood cell count. Diazepam (Valium): Long-acting; average half-life is 100 hours. Given in doses of 2-10 mg. 2-4 times daily. Fast onset is greater than one hour. Diazepam is contraindicated in patients with acuteangle glaucoma and should be used with caution in patients with compromised liver or renal systems, depression, history of substance abuse, or chronic open-angle glaucoma. It must be used with caution in elderly or debilitated patients. Diazepam may increase digoxin level and the risk of digoxin toxicity. If used in conjunction with phenobarbital, the effects of both drugs may be increased. The herb kava may increase sedative effects and should not be used in conjunction with diazepam. Diazepam is a CYP3A4 and CYP2C19 substrate, and should not be used with 3A4 inhibitors, such as clarithromycin, ketoconazole, ritonavir, and nefazodone, and used with caution with 2C19 inhibitors, such as fluconazole, fluvoxamine, and voriconazole. Diazepam may increase liver function test results and decrease neutrophil count. Lorazepam (Ativan): Short-acting; average half-life is 15 hours. Given in doses of 0.5-2 mg. 2-3 times daily. May increase digoxin level and digoxin toxicity; smoking may decrease lorazepam s effectiveness. The herb kava may increase sedation if taken in conjunction with lorazepam. Use with caution in patients with pulmonary, hepatic or renal problems or history of substance abuse. Use with caution in elderly or acutely ill patients. Oxazepam (Serax, Oxpam): Short-acting; average half-life is eight hours. Given in doses of 10-30 mg. 3-4 times daily. Slow onset is greater than three hours. Oxazepam should be used with caution in elderly patients, those with a history of substance abuse, and those who may experience cardiac problems if they experience a decrease in blood pressure. If taken with digoxin, digoxin levels may be increased. The herb kava may increase sedative effects. Oxazepam may increase liver function test results. Drug alert! Benzodiazepines should not be discontinued abruptly. Discuss timing of dosing and emphasize that these should not be combined with alcohol or other CNS depressants, and patients should not drive while taking these medications. Remind women of childbearing age that these medications should not be taken while pregnant. Pharmacy.EliteCME.com Page 106