ConsultantPharmacistApproach to Major DepressiveDisorderALAN OBRINGER RPH, CPH, CGPPRESIDENT/OWNERGUARDIAN PHARMACY OF ORLANDO

ObjectivesWhat is Depression?Discuss the epidemiology of depressionDiscuss the etiology of depressionDiscuss the pathophysiology of depressionDiscuss the signs and symptoms of depressionDiscuss treatments of depressionHow to de-prescribe depression

Spectrum of Psychiatric Disorders

ANXIETY

AFFECTIVE

PSYCHOSES

Panic disorderGADOCDAgoraphobia

Major DepressionBipolar DisorderDysthymia Schizophrenia

Schizoaffective

Ripley, VC. “Pharmacotherapy of Depression and Anxiety”. www.unc.edu/~makie/depression_2003.ppt

What is Depression?Described as feeling

Blue UnhappyMiserable

Everyone feels this way at one time in their life

Goes awayClinical depression

Feelings interfere with everyday lifeLast weeks or potentially longer

Januzzi et al. Archives of Internal Med 2000;160(13):1913-21

EpidemiologyThe true prevalence in the US is unknownWomen have higher risk

Lifetime risk 1.7-2.7x higher than menIncidence 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 without1.5-3x 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

EpidemiologyDepression 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.

EtiologyToo complex to be explained by a single social, development, or biological theorySeveral factors work togetherReflects 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.

Anxiolytics

Norepinephrine

Anti-Psychotics

Dopamine

Anti-Depressants

Serotonin

Neurotransmitters and Psychiatric Pharmacotherapy

GABA (gamma-Aminobutyric acid), others

Mood, Emotion,Cognitive functionMotivation

SexAppetiteAggressi

on

AnxietyIrritabilityEnergy

Interest Impulsivity

Drive

Norepinephrine Serotonin

Dopamine

Major Neurotransmitters

Pathophysiology of DepressionExact 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 completedCan be caused by current medical condition or drug inducedSee list of proposed medical conditions, substance use, and medications

Physical ComplaintsThese may include:

Sleep disturbances such as insomnia, early morning waking, or sleeping too muchLack of energyLoss of appetiteWeight loss or gainUnexplained headaches or backachesStomachaches, 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

- 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

SIGECAPS

Treatment3 phases to treatment

Acute phase: 6-10 weeks to obtain remissionContinuation phase: 4-9 months after remission

Prevent relapseMaintenance phase: 12-36 months

Prevent recurrence Duration of treatment

Depends on risk of recurrenceSome recommend lifetime maintenance therapy for persons at greatest risk of recurrence

TreatmentNon-pharmacologic

PsychotherapyNot recommended as sole therapy for acute episodes of severe or psychotic depressionIf mild to moderate, first line therapyCan be added to pharmacologic treatment for patients with partial responses

TreatmentNon-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

TreatmentPharmacologic

Can take 4-6 weeks of therapy to see responseMany different categories

TCAsSSRISNRITriazolopyridinesAminoketonesTetracyclicsMAOIs

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 alternativePartial response - increase dose, switch or augmentFully remits (maintain at least 4 to 6 months or longer)

2nd line: Switch or AugmentSwitch to other favorite - TCA or SSRIAugment with Li or TCA plus the SSRI (consult with psychiatrist)

3rd line: Failed or Partial response to 2nd lineConsult with psychiatristSwitch (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 ActionSSRIs

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 understoodThought to inhibit re-uptake of 5-HT and antagonist of 5-HT 2A/2C receptors

Tetracyclics (Mirtazapine)Exact mechanism unknownThought to work through 5-HT receptor antagonism

Mechanism of ActionTricyclic Antidepressants

Inhibits both 5-HT and NE reuptakeAntagonist at both receptors

Monoamine Oxidase InhibitorsWork on monoamine oxidase by inhibiting them from breaking down neurotransmitters

Mechanism of ActionAripiprazole, Brexpiprazole (Abilify, Rexulti)

Acts as a D2 partial agonistPartial agonist at the 5-HT1A receptor, and like the other atypical antipsychotics displays an antagonist profile at the 5-HT2Areceptor

Vortioxetine (Trintellix)Atypical antidepressant (a serotonin modulator and stimulator)

Treatments

Adverse EventsCelexa

Gi distress, N/V, headache, sedation, dizziness, agitation, Stevens-Johnson Syndrome (SJS)

SertralineGi distress, N/V, headache, insomnia, dizziness, agitation, SJS

DuloxetineConstipation, nausea, headache, dizziness, insomnia, decreased appetite, SJS

BuproprionTachyarrhythmia, nausea, constipation, dizziness, headache, insomnia, agitation, anxiety

TrazodoneDiarrhea, nausea, dizziness, headache, insomnia, nervousness

MirtazapineIncreased appetite, constipation, dizziness

AmitriptylineWeight gain, constipation, blurred vision

Follow-Up Considerations In The First Three Months

Week Treatment Actions

2

Check patient compliance to medication usage. Assess for adherence, side effects, suicidal ideation, and patient response. Adjust, as appropriate, medication and dosage.

4Re-check patient compliance to medication usage. Assess for adherence, side effects, suicidal ideation, and patient response.

6 Adjust, as appropriate, medication and dosage.

7 - 12Monthly communication with patient; Patients Appointments every 3rd or 4th week; Further Medication or Medication Dosage Adjustments; Goal: Remission

APA Practice Guidelines for the Treatment of Psychiatric Disorders.

Treatment Goal

The goal of treatment with antidepressant medication in the

acute phase is the remission of major depressive disorder symptoms

If Initial Treatment Ineffective

Medication trial should last 8-12 weeksIf no side effects or tolerability issues, increase dosage every 2-3 weeks until

Remission achievedMax dose achievedSide effects limit titration

Combine antidepressants and psychotherapyCombine antidepressants or consider augmentation trialConsidering 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 Manual-http://www.dshs.state.tx.us/mhprograms/tmapover.shtmKaiser 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 recurrenceAdmission 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 recurrenceLike the loss of a loved one or other traumatic event, admission into a long-term care facility can be overcomePatients 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 half-lives of the drug being stopped.

ConclusionDepression one of the most common mental health disorders in adultsPharmacologic intervention is the cornerstone for treatmentAntidepressants focus on inhibiting the uptake of 5-HT, NE, and DA neurotransmitters

QUESTIONS

ReferencesTeter 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 informationTable 77-2 DSM-IV-TR Criteria for Major Depressive EpisodeWagner 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