Antidepressants and Antianxiety Medications for RN Practice Outline

Antidepressants and Antianxiety Medications for RN Practice

Outline Introduction to depression and anxiety ◦ Diagnostic criteria for major depression ◦ Monoamine hypothesis of depression Overview of major anti-depressant medications ◦ ◦ ◦ SSRIs SNRIs MAOIs TCAs Atypicals Overview of major anti-anxiety medications ◦ Benzodiazepines ◦ Barbiturates ◦ Buspirone Practice questions and case studies

Depression: Diagnosis Diagnostic criteria for major depressive disorder (MDD) in DSM-V: 5 or more of following in the same 2 week period (SIG-E-CAPS): ◦ ◦ ◦ ◦ Sleep: insomnia or hypersomnia Interest: loss of pleasure in activities (anhedonia) Guilt: feelings of worthlessness Energy: lack of energy, fatigue Cognition: difficulty concentrating Appetite / weight loss: decreased or increased Psychomotor: increased activity (agitation) or decreased (lethargic) Suicidal ideation / preoccupation with death One criterion must be depressed mood or anhedonia Not related to other mental health problem (esp. bipolar disorder) or substance abuse, or a complicated grief reaction

Depression: Monoamine Hypothesis Basic idea: depression is caused by an imbalance of particular monoamine neurotransmitters (5 HT, DA, NE) ◦ For example, not enough 5 HT in certain CNS region causes symptoms ◦ All anti-depressants increase amounts of one or more neurotransmitter in CNS ◦ Therefore, the cause of depression is a lack of one or more neurotransmitter What is wrong with this line of thinking?

SSRIs: Why are these special? SSRI = selective serotonin re-uptake inhibitor Mechanism of action: block re-uptake of serotonin in the synaptic cleft. The end result is more serotonin activity in the CNS ◦ Selective: not a lot of effect on dopamine and norepinephrine activity ◦ Safe in overdose Some great advantages: ◦ Relatively safe in overdose ◦ Lower side effect profile than other options

SSRIs: Do they work? STAR*D trial: Sequenced Treatment Alternatives to Relieve Depression Largest ever RCT of the effectiveness of SSRIs ◦ After exclusion criteria, 2876 adult participants with at least moderate MDD, 7 year follow-up 37% had full remission of depressive symptoms ◦ Among people with remission, mean time to any response was 6 weeks and time to remission was 7 weeks ◦ 10 – 15 percent had response but not full remission 25% of those who failed the first stage had remission when switching to another medication ◦ Each additional medication switch results in smaller and smaller numbers of remission Take home message: SSRIs are an important tool for many people with depression. They are not a magic bullet.

SSRIs: Combination with Therapy Many studies and meta-analyses show that pharmacotherapy plus psychotherapy combined better than either alone Ideally MDD, GAD, etc. treated with both Reasons for monotherapy with medication alone: ◦ Patient preference: therapy takes a lot of time, patient may not be comfortable with therapy, cultural issues ◦ Severe disease: May need medication effect before patient can engage in therapy ◦ Availability of services: insurance gaps, availability of trained therapists in a given area, cognitive issues may require a specialist

SSRIs: Other non-pharmacologic approaches Physical exercise Electroconvulsive therapy Light therapy (especially for seasonal depression) CAM (acupuncture, St. John’s wort, yoga, etc. )

SSRIs: Indications Major depressive disorder (MDD) Generalized anxiety disorder (GAD) Obsessive-compulsive disorder (OCD) Post-traumatic stress disorder (PTSD) Social anxiety disorder (SAD) Panic disorder Bulimia and binge-eating disorder Premature ejaculation And more!

SSRIs: 6 Major Agents Celexa (citalopram) Lexapro (escitalopram) Prozac (fluoxetine) Luvox (fluvoxamine) Paxil (paroxetine) Zoloft (sertraline)

SSRIs: Nitty Gritty Usually start at lowest dose (e. g. , 10 – 20 mg fluoxetine) and titrate upwards over weeks and months as necessary Usually no immediate benefit; need to wait at least 2 – 4 weeks to feel it If no effect at 6 – 8 weeks, need dosage adjustment, or switch to different agent May take several months to reach full effect Goal is symptoms remission (not just “better”) For first episode: Treat for 1 year after remission For second episode: Treat indefinitely Counseling point: Do not expect this medication to alleviate symptoms immediately. Need to be patient. Unfortunately you get side effects before you get benefits.

SSRIs: Safety in Pregnancy SSRIs cross placenta, but are not known to be highly teratogenic Most are pregnancy category C ◦ Paroxetine is category D – some potential increased risk of fetal cardiac malformations Potential risks need to be weighed against risk of untreated depression during pregnancy

SSRIs: Common(ish) Adverse Effects Mnemonic for common adverse effects: SSRI-M ◦ Stimulate the CNS: ◦ Anxiety / jitteriness / sweating / agitation (especially fluoxetine and sertraline) ◦ Drowsiness / fatigue (especially paroxetine and fluvoxamine) ◦ ◦ OR Stomach issues: Nausea / vomiting / diarrhea / constipation, and changes in weight (usually gain) Reproductive problems Insomnia Miscellaneous: dry mouth, headache, dizziness, asthenia (brain fog), SIADH, hyponatremia Over 50% may have side effects initially. Many adverse effects tend to fade with a few weeks or months of therapy. Specific effects vary by person: depends on particular medication, individual’s biology, and other drug-drug interactions Counseling points: 1) Important to educate and encourage – early side effects cause people to self-discontinue 2) Counsel to switch time of day dose is taken based on drowsiness vs. activation

SSRIs: Sexual Dysfunction All SSRIs may cause decreased libido and anorgasmia (in men and women) and delayed ejaculation (in men) Unlike other effects, may not fade away over time Does not happen to everyone, but can be frustrating; common cause of medication discontinuation Strategies for handling this: ◦ Switch to a different agent ◦ Lower the dose ◦ Switch to / augment with atypical (bupropion, mirtazapine) Counseling point: Let patients know that there are other options to work with. Don’t just give up altogether on treating the depression.

SSRIs: Serious Adverse Effects Serotonin syndrome Seizure threshold Suicidality in. Sanity (mania)

SSRIs: Serotonin Syndrome Potentially life-threatening clinical syndrome caused by excess serotonin in CNS and peripheral nervous system HARM mnemonic ◦ ◦ Hyperthermia Autonomic instability with delirium Rigidity Myoclonus Rare. Likely to occur only in massive overdose and/or in combination with other serotonergic drugs ◦ ◦ ◦ Opioids: tramadol, meperidine, others 5 HT-1 agonists: triptans (migraine drugs) Recreational drugs: MDMA, LSD, others Herbal supplement: St. John’s wort Other anti-depressants

SSRIs: Seizure Risk May reduce seizure threshold Need to use cautiously in individuals with seizure problems

SSRIs: Suicide Risk 2004: FDA mandated a black box warning on SSRIs, saying they may increase suicidal ideation and/or behaviors (not necessarily completed suicides) in children / adolescents / young adults ◦ Was later expanded to TCAs and MAOIs Difficult to know the truth: ◦ Confounding by indication ◦ Early study design ◦ Measuring suicidality ◦ Relatively rare event There is little evidence of increased risk with adults older than age 25. If there is increased risk, probably highest during first weeks and months Counseling point: Need to balance small (potential) risk in suicidality with risk of untreated depression, which itself is a risk factor for suicide. Counsel patients and parents to have a low threshold to speak with provider about new suicidality. ◦ If a patient really needs an anti-depressant, this concern should not dissuade them.

SSRIs: Treatment-emergent Mania / Hypomania Some concern than SSRIs (and other anti-depressants) can trigger episodes Particular concern when person has been misdiagnosed with MDD (instead of bipolar disorder) ◦ Very important to rule out bipolar disorder before treating for MDD ◦ There is still some role for anti-depressants in bipolar depression, but needs to be with caution Counseling point: Instruct patients and family to watch for signs of mania / hypomania after starting SSRI

SSRIs: Prozac (fluoxetine) First SSRI, approved for depression in the U. S. in 1987 Prototype drug Tends to be activating Very long half-life means no need to taper Often used in pediatric patients

SSRIs: Paxil (paroxetine) Particularly sedating ◦ May be useful in people with insomnia and depression Anticholinergic, anti-alpha, and anti-histamine activity tends to cause heavy side effect burden ◦ Dry mouth, orthostatic hypotension, weight gain, more sexual dysfunction, etc. Not recommended in elderly

SSRIs: Celexa (citalopram) Few drug-drug interactions ◦ SSRI of choice when drug-drug interactions are an issue May prolong QTc interval, theoretically lead to fatal polymorphic ventricular tachycardia (torsade to pointes) ◦ Need to be cautious in patients taking other QTc prolonging agents

Anti-depressant Discontinuation Syndrome Occurs when suddenly stopping medication after weeks, months, or years. Need to taper medication slowly to avoid this. Symptoms: dizziness, fatigue, headache, nausea ◦ Can also cause agitation / anxiety, chills / sweats, insomnia, myalgias, tremor, etc. ◦ Rarely can cause electric shock sensations, ataxia, hallucinations Not life-threatening but can be very uncomfortable; usually gone in 1 – 2 weeks Counseling point: Let patients know to coordinate with prescriber when stopping the medication.

SNRIs: Major differences from SSRIs Very similar principles as SSRIs Prototype is Effexor (venlafaxine), which came out in 1993 Cymbalta (duloxetine) is also SNRI Despite the name, inhibit reuptake of both 5 -HT and NE Many of the same issues as SSRIs ◦ Can cause tachycardia and elevated blood pressure Other uses: ◦ Neuropathic pain (diabetic neuropathy, etc. ) ◦ Migraine prophylaxis

Atypical Anti-Depressants: Bupropion Mechanism: DA and NE reuptake inhibitor Common side effects: dry mouth, tremor, nervousness Serious side effect: particularly lowers seizure threshold Two major advantages: ◦ Relatively weight neutral (or weight loss), usually no sexual dysfunction Other uses: ◦ Smoking cessation (reduce tobacco cravings) ◦ Unlike SSRIs / SNRIs, not used to treat GAD

Atypical Anti-Depressants: Mirtazapine Enhances 5 -HT and NE transmission, and 5 -HT 2 a antagonist Sedation comes from antihistamine effect, but doesn’t have anticholinergic effect like TCAs or Major side effects: sedation and increased appetite ◦ Good choice for people struggling with sleep and/or poor appetite / underweight

Atypical Anti-Depressants: Trazodone Mechanism of action: 5 -HT 2 a antagonist Very sedating (due to anti-histamine activity) Also may cause priapism, and orthostasis (alpha-blockade) Often used off-label for insomnia even in people without depression ◦ Rarely used as monotherapy for depression

TCAs: Introduction Tricyclic antidepressants Imipramine first tested in 1955, followed by amitriptyline ◦ Others include clomipramine, doxepin, desipramine, nortriptyline, etc. Mechanism of action: NE and 5 -HT reuptake inhibitors (similar to SNRIs) ◦ Also antagonist at 5 -HT, alpha, histamine, and muscarinic receptors – dirty drugs! ◦ Not clear whether these produce any therapeutic effect, but they do produce side effects Effective for depression with many of the same caveats and counseling – major reason for limited use is (1) side effect profile, and (2) danger in overdose

TCAs: Adverse Effects (many) Anti-muscarinic: blurred vision, xerostomia, urinary retention, sinus tachycardia, constipation, aggravation of glaucoma Alpha blockade: orthostasis, dizziness, reflex tachycardia Anti-histamine: drowsiness, weight gain Other: potentially has the same sexual side effects as SSRIs, caution in seizure disorders, can contribute to serotonin syndrome Overdoses: relatively narrow therapeutic index ◦ CNS toxicity: may cause altered delirium ◦ Cardiac: arrhythmias may be life threatening (look for wide QRS interval) Numerous side effects and potential toxicity limit TCA use ◦ May still be useful in treatment-resistant disease

TCAs: Clinical Uses MDD and anxiety disorders ◦ Probably just as effective as SSRIs and SNRIs, but not preferred due to side effect profile Often a lower dose is needed for indications other than depression ◦ Neuropathic pain ◦ Migraine prophylaxis ◦ Insomnia (doxepin)

MAOIs: Introduction Monamine oxidase (MAO) is a CNS enzyme that deaminates (inactivates) excess neurotransmitters (NE, DA, 5 -HT) Monoamine oxidase inhibitors (MAOIs) inhibit this enzyme, resulting in increased levels of these neurotransmitters Most common agent is phenelzine (Nardil) Some history: ◦ Iproniazid (related to a TB drug, isoniazid) tested in 1952 as a TB treatment, but found to be effective for depression in TB patients ◦ Iproniazid and related compounds later found to inhibit MAO monoamine hypothesis of depression ◦ Started modern era of antidepressant medications ◦ Fun (but useless) fact: iproniazid and later drugs are hydrazine derivatives (e. g. , rocket fuel)!

MAOIs: Adverse Effects Serious drug-food interactions. Why? ◦ ◦ MAO exists in the gut and liver as well as the CNS One role of MAO is to deaminate (deactivate) tyramine. Inhibition of MAO build-up of tyramine causes release of stored catecholamine Catecholamine toxicity results in hypertensive crisis, along with arrhythmias, seizures, and stroke Tyramine is found in aged cheeses, wine, pickled foods, chicken liver, etc. Need to “wash out” for 2 weeks before starting another antidepressant; takes that long for enzyme activity to recover Toxicity limits use: these are last-line antidepressants, after multiple SSRI/SNRI/atypical/TCA failures

Anxiety Specific Medications Benzodiazepines Barbiturates Buspirone

Benzodiazepines: Mechanism of Action Recall: gamma-aminobutyric acid (GABA) is main inhibitory neurotransmitter in CNS Binding of GABA to GABA receptors in CNS opens ligand-gated chloride channels on surface of neuron chloride (anion) enters cell hyperpolarizes cell more difficult for action potentials to occur reduces neural excitability

Benzodiazepines: Mechanism of Action GABA receptors consist of many subunits and specific binding sites Benzodiazepines bind to BZ receptors on GABA complexes (distinct from GABA binding sites) Binding causes an increase in GABA’s affinity for the GABA binding site End result is more frequent opening of chloride channels in response to GABA More inhibitory effect Crosses placenta and into breast milk – not normally recommended during pregnancy or breast feeding

Benzodiazepines: Clinical Uses Anxiolytic ◦ Used in many anxiety states: GAD, phobias, PTSD, social anxiety disorder, OCD, anxiety related to other disorders (schizophrenia, etc. ) Insomnia Agitation ◦ Often used to control behavior when non-verbal de-escalation fails Alcohol withdrawal Anterograde amnesia ◦ Used for conscious sedation (midazolam) Anticonvulsant ◦ Especially status epilepticus Muscle relaxant ◦ Particularly diazepam

Benzodiazepines: Role in Anxiety Treatment Rapid, immediate, “as needed” relief of anxiety Not recommended for chronic treatment due to dependence and side effects, yet many people take these for months and years Ideal treatment strategy for anxiety: start SSRI / SNRI and add a low-dose benzodiazepine ◦ Treat for 4 – 6 weeks until SSRI / SNRI achieves some effect, then discontinue benzodiazepine In practice, does not always work this way. May have a role in chronic treatment if SSRI / SNRI not completely effective, or in panic disorder, PTSD, etc.

Benzodiazepines: Distinction Between Agents Main important difference is duration of action ◦ Long-acting: chlordiazepoxide, diazepam, clonazepam ◦ Intermediate-acting: lorazepam, alprazolam, temazepam ◦ Short-acting: oxazepam, triazolam, midazolam

Benzodiazepines: Dependence and Withdrawal Physical and psychological dependence occurs with chronic use ◦ Long-acting agents less likely to cause dependence / severe withdrawal ◦ Schedule IV Need to taper these over weeks and months to prevent withdrawal syndrome ◦ Includes tremors, anxiety, nausea / vomiting, hallucinations / psychosis, seizures, and can be fatal in severe cases Counseling point: Educate patients about potential for withdrawal and need to coordinate with prescriber if they want to stop these after regular use

Benzodiazepines: Toxicity Excess benzodiazepine can cause drowsiness and confusion ◦ May progress to ataxia and impaired motor skills Therapeutic index is relatively wide; unlikely to cause fatal overdose on its own ◦ Can be very dangerous if combined with other CNS depressants (alcohol, opiates, etc. ) Flumazenil is a benzodiazepine antagonist, can be used as a rescue drug in overdose Counseling point: Educate patients about potential toxicity – don’t assume people know about this! Educate to not drive or operate heavy machinery while taking the drug

Barbiturates: Historical Relic? Mechanism of action: similar to benzodiazepines – prolongs GABA-induced chloride channel opening. Block sodium-channels at higher doses. Largely replaced by benzodiazepines for anxiolytic use ◦ Narrow therapeutic range: can cause respiratory depression ◦ Similar potential for dependence and withdrawal ◦ Many problems with CYP 450 induction Still may have some role in anesthesia (thiopental) and seizure disorders (phenobarbital)

Buspirone Mechanism of action: 5 -HT 1 a receptor partial agonist Useful for GAD, but does not really treat depressive symptoms Low side effect profile: may cause headache, dizziness, nausea, nervousness Takes a few weeks to work, not useful for “as needed” anxiolysis Unlike benzodiazepines, does not potentiate effects of other CNS depressants and not habit forming

Frontiers of Psychopharmacology Recent resurgence of research on use of psychedelic drugs for MDD / anxiety / PTSD and more ◦ Ketamine: anesthetic and recreational dissociative ◦ MDMA: club drug ◦ LSD and psilocybin: hallucinogens Research is very early; watch for more in the future

Practice Question 1 55 year-old teacher began to experiences changes in mood. He was losing interest in his work and lacked the desire to play daily tennis as normal. He was preoccupied with feelings of guilt, worthlessness, and hopelessness. In addition to the psychiatric symptoms, he complained of muscle aches throughout the body. Physical and laboratory tests were unremarkable. After 6 weeks of therapy with fluoxetine, his symptoms resolved completely. However, he began complaining of sexual dysfunction. Which of the following drugs might be useful? a) Fluvoxamine (SSRI) b) Sertraline (SSRI) c) Citalopram (SSRI) d) Bupropion (Atypical) e) Lithium (Mood-stabilizer)

Practice Question 2 A 25 -year old woman has a long history of depressive symptoms accompanied by low back and sharp leg pain secondary to a motor vehicle accident 4 years ago. Physical and laboratory tests are unremarkable. Which of the following drugs might be useful in this patient? a) Fluoxetine (SSRI) b) Sertraline (SSRI) c) Phenelzine (MAOI) d) Mirtazapine (Atypical) e) Duloxetine (SNRI)

Practice Question 3 Which anti-depressant drug is most sedating? a) Fluoxetine (SSRI) b) Duloxetine (SNRI) c) Nortriptyline (TCA) d) Citalopram (SSRI) e) Venlafaxine (SNRI)

Practice Question 4 Which agent would be a poor choice in a 70 -year old elderly female with depressive symptoms due to the drug having significant alpha-1 receptor antagonism and thus a higher risk for falls due to orthostatic hypotension? a) Lithium (Mood-stabilizer) b) Bupropion (Atypical) c) Escitalopram (SSRI) d) Imipramine (TCA) e) Sertraline (SSRI)

Practice Question 5 Which of the following is correct regarding benzodiazepines? a) They directly open chloride channels b) Benzodiazepines have analgesic effects c) Clinical improvement in anxiety requires 2 – 4 weeks of treatment d) All have some sedative effects e) Benzodiazepines readily produce general anesthesia

Practice Question 6 Which of the following agents has a rapid anxiolytic effect and would be best for the acute management of anxiety? a) Buspirone b) Venlafaxine (SNRI) c) Lorazepam (BZ) d) Escitalopram (SSRI) e) Duloxetine (SNRI)

Practice Question 7 Which agent is best used in the emergency room setting for patients who are believed to have received too much of a benzodiazepine drug or taken an overdose of benzodiazepines? a) Diazepam b) Ramelteon c) Flumazenil d) Doxepin e) Naloxone

Case Study 1 65 year old woman s/p right hip fx and ORIF x 4 days ago. Healing well, no signs of post-op complications, now in SNF for rehab. She is A+O x 4. You are an RN taking care of her today. Today she seems down. When pressed, complains to you of low mood. Other PMH: osteoporosis, seizure disorder (well-controlled), essential hypertension, hyperlipidemia, hypothyroid, type 2 diabetes mellitus Medications: Oxycodone 5 mg q 4 h prn, vitamin D / calcium supplement, hydrochlorothiazide 12. 5 mg, atorvastatin 80 mg, levothyroxine 50 mcg, metformin 750 mg BID What other subjective information do you want to know? Objective information?

Case Study 1 (continued) You tell the provider your findings and they evaluate the patient the next day. She agrees with your findings and decides to prescribe an anti-depressant. However, she slept through all her psychiatry lectures in school, and thinks maybe should start bupropion and/or paroxetine. What would you recommend and why? What other treatments might you recommend and why?

Case Study 1 (continued) Flash forward 3 months later: Her depressive symptoms have resolved on whatever SSRI / SNRI / etc. she was put on. You are the diabetes education RN seeing her in clinic today. Off hand she mentions that she stopped taking her anti-depressant 1 day ago because she bought some St. John’s wort and her sister-in-law told her it is a more natural remedy for depression. What are the risks in the situation, and what is the appropriate counseling for this patient?

Case Study 2 22 year old male admitted to surgical unit for appendicitis. He is 1 day post lap-appendectomy. He is complaining of feeling particularly on edge and requests prn anxiety medication. Other PMH: “Anxiety, ” insomnia, IVDU (heroin, uses regularly x 3 years but has not used in about 4 weeks because he’s trying to quit, went through mild withdrawal already) Medications: Morphine IV by PCA, lorazepam 2 mg BID prn anxiety (his home dose, which he’s used for a while) What subjective information do you need to know to take care of this patient today? What objective information do you need to know to take of this patient today?

Case Study 2 (continued) After you determine it is safe to give the lorazepam, you administer 2 mg PO. About 2 hours later he is much calmer. He tells you he doesn’t really think the dose of lorazepam he uses at home is enough and thinks he’ll ask his doctor for an increased dose. He tells you he’s used citalopram in the past for anxiety for a few days but it made him upset to his stomach so he stopped. What are the risks for this patient, and what is the appropriate counseling?

Case Study 3 83 year old woman admitted to the medicine unit for fever and cough. CXR showed RLL pneumonia, she was started on antibiotics. On day 2 of hospitalization her respiratory status is improved but she is feeling pretty anxious. The hospitalist writes for lorazepam 0. 5 mg IVP prn anxiety. She had a dose from night shift just before you came on. She is relatively healthy at baseline without significant cognitive problems. When you go in to assess her, she is alert, oriented to self only, and you catch her picking at her IV site. Overall she still seems pretty anxious. She can have more lorazepam in about 30 minutes. What would be your priority for this patient?