Consultant Pharmacist Approach to Major Depressive Disorder ALAN OBRINGER RPH, CPH, CGP PRESIDENT/OWNER GUARDIAN PHARMACY OF ORLANDO

Consultant Pharmacist Approach to Major Depressive Disorder ALAN OBRINGER RPH, CPH, CGP PRESIDENT/OWNER GUARDIAN PHARMACY OF ORLANDO

Objectives What is Depression? Discuss the epidemiology of depression Discuss the etiology of depression Discuss the pathophysiology of depression Discuss the signs and symptoms of depression Discuss treatments of depression How to de-prescribe depression

Spectrum of Psychiatric Disorders ANXIETY Panic disorder GAD OCD Agoraphobia AFFECTIVE Major Depression Bipolar Disorder Dysthymia PSYCHOSES Schizophrenia Schizoaffective Ripley, VC. Pharmacotherapy of Depression and Anxiety. www.unc.edu/~makie/depression_2003.ppt

What is Depression? Described as feeling Blue Unhappy Miserable Everyone feels this way at one time in their life Goes away Clinical depression Feelings interfere with everyday life Last weeks or potentially longer Januzzi et al. Archives of Internal Med 2000;160(13):1913-21

Epidemiology The true prevalence in the US is unknown Women have higher risk Lifetime risk 1.7-2.7x higher than men Incidence can happen at any age Highest in adults aged 18-29y.o. Higher incidence in patients with first degree relative 8-18% compared to 5.6% of those without 1.5-3x greater chance of developing depression Kessler, RC, Berglund, P, et al. The Epidemiology of Major Depressive Disorder. JAMA. 2003;289(23):3095-3105. doi:10.1001/jama.289.23.3095

Epidemiology Depression is the most common mental health problem in the elderly and is associated with a significant burden of illness that affects patients, their families, and communities and takes an economic toll as well. Prevalence studies suggest that 14% to 20% of the elderly living in the community experience depressive symptoms, with higher rates among the elderly in hospital (12% to 45%) and even higher rates in long-term care facilities (an estimated 40%).

Comorbidity and Depression 72.1% of those with lifetime MDD and 64% of those with 12-month MDD have at least one additional mood disorder Primarily anxiety disorder, substance abuse disorder, or impulse control disorder Kessler RC et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.

Etiology Too complex to be explained by a single social, development, or biological theory Several factors work together Reflects changes in brain transmitters Norepinephrine (NE), Serotonin (5-HT), Dopamine (DA) Belmaker, R. H., and Galila Agam. "Major depressive disorder." New England Journal of Medicine 358.1 (2008): 55-68.

Neurotransmitters and Psychiatric Pharmacotherapy Anxiolytics Norepinephrine Anti- Depressants Serotonin Anti- Psychotics Dopamine GABA (gamma-aminobutyric acid), others

Major Neurotransmitters Norepinephrine Energy Interest Motivation Anxiety Irritability Mood, Emotion, Cognitive function Sex Appetite Aggressi on Impulsivity Serotonin Drive Dopamine

Pathophysiology of Depression Exact cause unknown Believed to be chemical imbalance in the brain Genetic Triggered by stressful events Breakups Failing a class Death or illness to someone close to you Divorce Child abuse or neglect Job loss Social isolation Play a role Alcohol or drug abuse Medical conditions: Hypothyroid, cancer, chronic pain Medications Sleeping problems

Certain medications used alone or in combination can cause side effects much like the symptoms of depression. Use of Alcohol or other Drugs can lead to or worsen depression. Depression can also occur for no apparent reason at all! Ressler, Kerry J., and Charles B. Nemeroff. "Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders." Depression and anxiety 12.S1 (2000): 2-19.

DSM V Classification of Major Depressive Episode Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly due to a general medical condition or mood-incongruent delusions or hallucinations. Depressed mood most of the day nearly every day Markedly diminished interest or pleasure in all, or almost all, activities most of the day nearly every day Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day Insomnia or hypersomnia nearly every day Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) Fatigue or loss of energy nearly every day Feelings of worthlessness or excessive or inappropriate guilt nearly every day Diminished ability to think or concentrate, or indecisiveness, nearly every day Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

Signs and Symptoms of Depression The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). The symptoms are not better accounted for by bereavement (i.e., after the loss of a loved one), the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation. Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (Copyright 2013). American Psychiatric Association. All Rights Reserved..

Signs and Symptoms of Depression Complete physical, mental, and lab examination must be completed Can be caused by current medical condition or drug induced See list of proposed medical conditions, substance use, and medications

Physical Complaints These may include: Sleep disturbances such as insomnia, early morning waking, or sleeping too much Lack of energy Loss of appetite Weight loss or gain Unexplained headaches or backaches Stomachaches, indigestion or changes in bowl habits

Symptoms of Depression Vary from person to person 2 key signs are loss of interest in things you like to do, and pervasive sadness or irritability

SIGECAPS S I G E C A P S - Changes in sleep pattern - Changes in interests or activity - Feelings of guilt or increased worry - Changes in energy - Changes in concentration - Changes in appetite - Psychomotor disturbances -Suicidal ideation

Treatment 3 phases to treatment Acute phase: 6-10 weeks to obtain remission Continuation phase: 4-9 months after remission Prevent relapse Maintenance phase: 12-36 months Prevent recurrence Duration of treatment Depends on risk of recurrence Some recommend lifetime maintenance therapy for persons at greatest risk of recurrence

Treatment Non-pharmacologic Psychotherapy Not recommended as sole therapy for acute episodes of severe or psychotic depression If mild to moderate, first line therapy Can be added to pharmacologic treatment for patients with partial responses

Treatment Non-pharmacologic Electroconvulsive therapy (ECT) Used when rapid response is required Risks of other treatments outweigh benefits History of poor response to antidepressants and good response to ECT Patient preference Unilateral or bilateral administered 2-3 times weekly for 6-12 treatments Adverse effects include cognitive dysfunction, cardiovascular dysfunction, prolonged apnea, treatment-emergent mania, headache, nausea, and muscle aches Relapse rates are high in patients not taking maintenance antidepressants

Treatment Pharmacologic Can take 4-6 weeks of therapy to see response Many different categories TCAs SSRI SNRI Triazolopyridines Aminoketones Tetracyclics MAOIs

Steps for Choosing an Effective Antidepressant 1. Recognize that some antidepressants may be more effective in certain populations even though most are generally of equal effectiveness. 2. Ask about personal or family history of treatment with antidepressants, particularly about side effects. 3. Consider the burden of side effects, particularly weight gain and sexual side effects in midlife women. 4. Consider drug-drug interactions with other medications the patient is taking or may take. 5. Consider the potential lethality of the antidepressant in the case of an overdose. 6. Use antidepressant side effects for efficacy. Moore DP, Jefferson JW. Mood Disorders. In: Moore & Jefferson: Handbook of Medical Psychiatry, 2nd ed. Philadelphia: M b 2004

Algorithm for Treatment of Uncomplicated Major Depression 1st line: Favorite SSRI or TCA Failed trial: switch to alternative Partial response - increase dose, switch or augment Fully remits (maintain at least 4 to 6 months or longer) 2nd line: Switch or Augment Switch to other favorite - TCA or SSRI Augment with Li or TCA plus the SSRI (consult with psychiatrist) 3rd line: Failed or Partial response to 2nd line Consult with psychiatrist Switch (nefazodone, mirtazapine, bupropion, venlafaxine) Add newer agent (vortioxetine, aripiprazole) Augment with Li or TCA plus the SSRI Adapted from Wells B et al: in Pharmacotherapy, 10th ed, Dipiro, eds., 2016

Mechanism of Action SSRIs Inhibits reuptake of 5-HT into the pre-synaptic neuron SNRIs (Venlafaxine, Desvenlafaxine, Duloxetine) Inhibits re-uptake of 5-HT and NE into the pre-synaptic neuron Aminoketones (Bupropion) Inhibits re-uptake of NE and DA into the pre-synaptic neuron Triazolopyridines (Trazodone) Not fully understood Thought to inhibit re-uptake of 5-HT and antagonist of 5-HT 2A/2C receptors Tetracyclics (Mirtazapine) Exact mechanism unknown Thought to work through 5-HT receptor antagonism

Mechanism of Action Tricyclic Antidepressants Inhibits both 5-HT and NE reuptake Antagonist at both receptors Monoamine Oxidase Inhibitors Work on monoamine oxidase by inhibiting them from breaking down neurotransmitters

Mechanism of Action Aripiprazole, Brexpiprazole (Abilify, Rexulti) Acts as a D 2 partial agonist Partial agonist at the 5-HT 1A receptor, and like the other atypical antipsychotics displays an antagonist profile at the 5-HT 2A receptor Vortioxetine (Trintellix) Atypical antidepressant (a serotonin modulator and stimulator)

Treatments

Adverse Events Celexa Gi distress, N/V, headache, sedation, dizziness, agitation, Stevens-Johnson Syndrome (SJS) Sertraline Gi distress, N/V, headache, insomnia, dizziness, agitation, SJS Duloxetine Constipation, nausea, headache, dizziness, insomnia, decreased appetite, SJS Buproprion Tachyarrhythmia, nausea, constipation, dizziness, headache, insomnia, agitation, anxiety Trazodone Diarrhea, nausea, dizziness, headache, insomnia, nervousness Mirtazapine Increased appetite, constipation, dizziness Amitriptyline Weight gain, constipation, blurred vision

Follow-Up Considerations In The First Three Months Week 2 4 Treatment Actions Check patient compliance to medication usage. Assess for adherence, side effects, suicidal ideation, and patient response. Adjust, as appropriate, medication and dosage. Re-check patient compliance to medication usage. Assess for adherence, side effects, suicidal ideation, and patient response. 6 Adjust, as appropriate, medication and dosage. 7-12 Monthly communication with patient; Patients Appointments every 3rd or 4th week; Further Medication or Medication Dosage Adjustments; Goal: Remission

Treatment Goal The goal of treatment with antidepressant medication in the acute phase is the remission of major depressive disorder symptoms APA Practice Guidelines for the Treatment of Psychiatric Disorders.

If Initial Treatment Ineffective Medication trial should last 8-12 weeks If no side effects or tolerability issues, increase dosage every 2-3 weeks until Remission achieved Max dose achieved Side effects limit titration Combine antidepressants and psychotherapy Combine antidepressants or consider augmentation trial Considering tailoring your treatment for specific sub-populations (e.g., elderly, midlife women etc). Texas Medication Algorithm Project (TMAP) Treatment of Major Depressive Disorder Clinician s Manualhttp://www.dshs.state.tx.us/mhprograms/tmapover.shtm Kaiser Permanente Care Management Institute. Depression clinical practice guidelines. http://www.guideline.gov/summary/summary.aspx?doc_id=9632&nbr=5152&ss=6&xl=999.

De-prescribing Antidepressants Old thinking: 50% of patients with Major Depression will experience recurrence Admission into a nursing home or other long-term care facility can be a trigger for depression New thinking: 50% of patients with Major Depression will NOT experience recurrence Like the loss of a loved one or other traumatic event, admission into a long-term care facility can be overcome Patients of all ages who are started on antidepressant therapy should be monitored closely for emergence and worsening of suicidal thoughts and behaviors

De-prescribing Antidepressants Questions to ask: Is the resident benefiting from the antidepressant therapy? What are the benefits to stopping therapy and what are the risks of stopping therapy? Is this the best course of action for MY patient?

De-prescribing Antidepressants If used for longer than six weeks, all antidepressants have the potential to cause withdrawal syndromes if they are stopped or rapidly reduced. How to reduce the dose: The usual recommended period for antidepressant dose reduction is a minimum of four weeks. Monitor for withdrawal symptoms. Use half-life of the medication to determine taper plan. If switching to another antidepressant consider a wash-out period equivalent to a minimum of 5 halflives of the drug being stopped.

Conclusion Depression one of the most common mental health disorders in adults Pharmacologic intervention is the cornerstone for treatment Antidepressants focus on inhibiting the uptake of 5-HT, NE, and DA neurotransmitters

QUESTIONS

References Teter C.J., Kando J.C., Wells B.G. (2011). Chapter 77. Major Depressive Disorder. In J.T. DiPiro, R.L. Talbert, G.C. Yee, G.R. Matzke, B.G. Wells, L.M. Posey (Eds), Pharmacotherapy: A Pathophysiologic Approach, 8e. Retrieved February 23, 2012 from http://www.accesspharmacy.com.lp.hscl.ufl.edu/content.aspx? aid=7988626. All drug info from Micromedex and Lexicomp handheld information Table 77-2 DSM-IV-TR Criteria for Major Depressive Episode Wagner AK, Chan KA, Dashevsky I, et al. FDA drug prescribing warnings: is the black box half empty or half full? Pharmacoepidemiol Drug Saf. 2006 Jun;15(6):369-86. Keks, Hope, Keogh et al. Switching and stopping antidepressants. Aust Prescr. 2016 Jun; 39(3): 76 83. Ripley, VC. Pharmacotherapy of Depression and Anxiety. www.unc.edu/~makie/depression_2003.ppt