Sad and StartledPHARMACOLOGICAL REVIEW AND MANAGEMENT OF DEPRESSION AND ANXIETY

MAJ RODNEY HO, PA-C, PH.D. , PSYCHIATRY-CAQ

Monoanime Theory•Depression is theorized to be caused from an imbalance of serotonin (5HT), Norepinephrine (NE), and Dopamine (DA)

- Resprine induced depression in a small hand of patients

- Acute Tryptophan depletion (5HT) caused depression in patients in depression remission

- CSF levels of 5-HIAA (primary metabolite of 5HT) was lower in subset of patients with depression/suicidal behavior

How TCAs/SSRIs/SNRIs work on Depression?

How SSRIs/SNRIs Work on Anxiety?

Common Antidepressants/Antianxiety Meds

•Common SSRIs: Fluoxetine (Prozac), Citalopram (Celexa), Escitalopram (Lexapro), Sertraline (Zoloft), Paxil (Paroxetine), Fluvoxamine (Luvox)

•Common SNRIs: Venlafaxine IR (Effexor), Venlafaxine XR (Effexor XR); Duloxetine (Cymbalta)•Common TCAs: Amitriptyline (Elavil), Nortryptaline (Pamelor), Impramine (Tofranil)•Atypical antidepressants/anxiety: Buproprion (Wellbutrin), Trazadone (Olpetro), Mirtazapine (Remeron), Buspirone (Buspar)

• Monoamine Oxidase Inhibitors (MAOI): Prevents breakdown of 5-HT, NE, DA- Typically prescribed by Psychiatrist or Psych NP/PA because of potential of major side effects- Last resort or treatment resistant depression- Wait 2 weeks after last dose for washout to start new antidepressant, 5 weeks if switching to fluoxetine (Prozac).

SSRIs• Takes at least 2 weeks to observe clinical benefit

• A trail is considered 6-8 weeks at least, may take up to 12 weeks for maximum benefit

• 63% of patient receiving second gen antidepressants (SSRIs/SNRIs) experience at least one side effect (Head, Red, Feed)

- Most common side effects are dizziness, dry mouth, fatigue, HA, sexual dysfunction, sweating, tremors, and weight gain

• Medication interactions

- Medications that increase bleeding time such as Warfrin, NSAIDs, and blood thinners

- Theophylline

- Clozapine and pimozide

- Lithium

- Triptans

Med/Substance induced Serotonin SyndromeGROUP A:Non-selective and irreversible MAOi A and BSelegiline (non-selective at higher doses)Rasagiline

Selective and irreversible MAOi BMoclobemideMethylene blue (non-selective at higher doses)

Selective and reversible MAOi ASelegiline (non-selective at higherdoses)RasagilineNon-selective and reversible MAOi A and BIsocarboxazidIsoniazidPhenelzineTranylcypromine

GROUP B:AntidepressantsSelective Serotonin Reuptake Inhibitors (SSRI): Paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, fluoxetineSerotonin Norepinephrine Inhibitors (SNRI): Venlafaxine, desvenlafaxine, duloxetine, Tricyclic Antidepressants: Clomipramine, imipramine

Opioids and other pain medicationsTramadol, meperidine, methadone, fentanyl (unlikely with morphine, codeine, oxycodone, buprenorphine)

Cough and cold medicationsDextromethorphan (”DM”), chlorpheniramine

Natural health productsSt. John’s wort, L-tryptophan, diet pills

Illicit drugsEcstasy (MDMA), amphetamine, cocaine

Avoid: Group A with Group A and Group A and Group BCaution: TWO or more Group B drugs especially when ONE is used at a high doseMonitor: If a patient uses a Group B drug and a second Group B drug is added, start low, increase the dose cautiously, and watch for symptoms for 24-48h after every changeBoyer & Shannon, 2005

Sertonin Syndrome

Akathisia TremorAltered mental status

Clonus

(inducible)Clonus

(sustained)Muscular

hypertonicityhyperthermia

mild symptoms

life threateningsymptoms

Boyer & Shannon, 2005; Foong, Patel, Kellar, & Grindrod, 2018

Rule Out:Meningitis/EncephalitisDrug OverdoseAlcohol/Benzo WithdrawalNeuroleptic Malignant SyndromeMalignant HyperthermiaAnticholinergic Toxicity

Treatment:1. STOP DRUG(S)2. Transfer to hospital

SSRI PearlsFLOUXETINE (PROZAC)

•FDA approved for MDD/Panic disorder

•Longest half life/good for poor compliance

•Most stimulating SSRI/good for low energy/take in the morning

•Lowest weight gain/good for eating disorders

•Highest risk of serotonin syndrome/many drug interactions

•Maybe to overstimulating for some patients/watch for akathisia/insomnia

•Wait at least 7 days after last dose for flush to start new antidepressant

PAROXETINE (PAXIL)

•FDA approved for depression/GAD

•Shortest half life/highest risk for discontinuation syndrome

•Most sedating SSRI/good for insomnia/take at night

• Few drug/drug interactions

• Increased risk for GI problems/take with food

• Greatest weight gain and sexual AEs

• Anticholinergic activity

SSRI Pearls Cont.CITALOPRAM (CELEXA)

•FDA approved for depression, good for GAD (off-label)

•Great for first choice for treatment• Decrease risk for sexual side effects •Avoid use in Congenital QT prolongation defect/caution in heart disease/problems

•Obtain ECG prior to initiation•FDA warning, SHOULD be avoided in patients with QT prolongation, congenital long QT syndrome, and persistent QTc measurmentsgreater than 500 ms

ESCITALOPRAM (LEXAPRO)

•FDA approved for for MDD/GAD

•Isomer of citalopram

• Great first choice for treatment

• Few drug to drug interactions

• Created to remove inactive ingredients and potent form

SSRI Pearls Cont.SERTRALINE (ZOLOFT)

•FDA approved for MDD/OCD/SAD/PTSD

•Low drug/drug interactions

• Highest risk of GI problems/take at night and w/food

FLOVOXAMINE (LUVOX)

FDA approved for MDD/OCD/Panic Disorder/PTSD/SAD

Effective against compulsive, depression and anxiety disorders

Less sexual side effects compared to most SSRI antidepressant

SNRI Pearls VENLFAXINE (EFFEXOR)

•FDA approved for MDD/GAD/SAD

•Indicated for ADHD

•Maybe effective in setting of chronic pain

• Depression with amotivation/fatigue as major symptom

• Fewer drug interactions

•Closely monitor BP in patients with h/o of HTN/prone to HTN

•Slow taper to prevent discontinuation syndrome (anxiety, restlessness, HA and electric shocks)

•Doses 150 mg and below works as a SSRI

CYMBALTA (DULOXETINE)

•FDA approved for MDD/GAD

•Maybe effective in treating chronic pain/fibromyalgia/diabetic neuropathy

•Less side effects compared to Effexor

•Good for sleep and pain

•Caution with use in liver disease/alcoholism

Atypical AntidepressantsBUPROPRION (WELLBUTRIN)

•Norepinephrine/dopamine reuptake inhibitor•FDA approved for MDD•Augmentation w/SSRI for sexual side effects•Stimulating effect•Maybe useful with cormorbid ADHD/quit smoking

•Possible overstimulation/agitation/increase anxiety symptoms

•Lower seizure threshold/Don’t use in eating disorders (Absolute contraindication)

MIRTAZAPINE (REMERON)

•Works through presynaptic alpha2-adrenergic antagonist, agonist to 5-HT2/3 of serotonin and histamine receptors

•FDA approved for MDD•Most sedating antidepressant•Low dosing (< 15 mg) best for insominia •Less nausea and sexual side effects•Fastest onset of working•Weight gain associated/good for associated cancer/elderly

Atypical Antidepressants Cont. BUSPIRONE (BUSPAR)

•Affinity for 5HT1A and 5HT2 receptors and moderate affinity for dopamine D2 receptors

•FDA approved for anxiety disorder

•Take up to 2-4 weeks to observe clinical benefits (anxiolytic effects)

•Mostly used for augmentation with SSRI/SNRI/TCA to enhance serotonergic effect

•Not recommended in severe renal/hepatic impairment

•Do not use PRN for anxiety

TRAZADONE (DESYREL, OLEPTRO)

•Known as a Seratonin Antagonist and Reuptake Inhibitors (SARI), histamine and alpha 1-adrenergic receptor antagonist

•FDA approved for depression, good for insomnia (off-label)

•Common side effects are sedation and similar to SSRIs (HA, GI sxs, sexual dysfunction)

•Can be used as monotherapy or combination

•Equal efficacy as SSRI for treatment of MDD

TCA pearls•Prevent the reuptake of serotonin and norepinephrine

•Drugs that have central and peripheral anticholinergic and sedative effects.

•Effective for the treatment of depression

•Caution is used because of higher toxicity and potential lethality in overdose

- Avoid use in previous and current SI or previous suicidal attempt

- Cause cardiac arrhythmias and conduct changes

•Avoid us as a first line agent in primary care and reserved when SSRI/SNRIs are ineffective

•Cause weight gain and orthostatic hypotension

Bhatt, 17 Mar 2019

Management of Depression•Patient centered approach - build rapport, set expectations for medication response and side effects

•Partial Response-25% to 50% depression symptoms reduction

•Response-50% or more depression symptoms reduction

•Ultimate goal is total remission of depression symptoms

- Measured using screening/diagnostic questionnaires (Ex. PHQ-9 severity: 0-4 none, 5-9 mild, 10-14 moderate, 15-19 moderately severe, 20-27 severe)

- Ask for baseline function before depression (What did you enjoy doing before you were depressed?/What were you like before you were depressed?)

- SIGECAPs evaluation/resolution of symptoms

- Adequate trial of medication is minimum of 6 weeks

- Continue with SSRI treatment 4-9 months after remission/discontinue sooner causes increase risk for relapse

Rule out Bipolar Disorder (Have you every felt like you were a machine with lots of energy and did not sleep for 2-3 days in a row?)

Depression Treatment Guidelines Part 1

Psychotherapy

Optimize Dose Augment/switch

Antidepressants started but with residual symptoms

American Psychiatric Association (APA), 2010

Depression Treatment Guidelines Part 2dk;ldWhat if side effect are an issue?

Reduce dose/switch Use pharmological to minimize side effects

APA, 2010

Guide To Switching Antidepressants

Soreide, K.K., Ward. K.M., & Bostwick, J.R., (2017). Strategies and Solutions for Switching Antidepressants Medications. Table 3. Guide to Switching Antidepressants. Retrieved from https://www.psychiatrictimes.com/strategies-and-solutions-switching-antidepressant-medications/page/0/1

Approximate Common Antidepressant Dose Conversions* Drug Approximate Equivalent Dosage (mg)

SSRIs

Citalopram 20

Escitalopram 10

Fluoxetine 20

Paroxetine 20

Setraline 50

SNRIs

Duloxetine 30-60

Venlafaxine 37.5-75

Atypical Agents

Bupropion XR 24 hrs 150

Mirtazapine 15

Serotonin Modulators

Trazadone 100https://ahpnetwork.com/wp-content/uploads/2017/09/Switching-Scenarios.pdf *Equivalent doses are approximated and may vary based on patient-specific factors such as sensitivity to medication side

effects and concomitant medications.

Treatment Guidelines Part 3dk;ldIf full-dose trial antidepressant monotherapy

fails to provide remission, consider

Switch in class Switching to psychotherapy

dk;ldSwitch antidepressants/refer to mental health

Switching classesAPA, 2010

Texas Medication Algorithm Project For Depression§Stage 1: Antidepressants monotherapy with SSRI, SNRIs, mirtazapine, and bupropion

•Stage 1A: Partial responders receive and adjunct with a different mechanism to action (add bupropion, mirtazapine, buspirone to a SSRI/SNRI)

•Stage 2: Failure to stage 1 treatment, change med to different class/refer to mental health

•Stage 2A: Partial responders receive an adjunct with bupropion, mirtazapine, buspirone, an SSRI or SNRI

•Stage 3: Refer to mental health/combine treatment for those who fail to respond to stage 2

- SSRI/SNRI + bupropion/mirtazapine; SSRI + TCA; SSRI + atypical antipsychotic

General Anxiety Disorder• The presence of excessive anxiety and worry about a variety of

topics, events, or activities.

• Worry occurs more often than not for at least 6 months and is clearly excessive and not easily controlled

• Psychological symptoms: Excessive anxiety, uncontrolled worry, feeling on edge, poor concentration, restlessness, irritability, impaired social or occupational functioning

• Physical symptoms: Fatigue, muscle tension, difficulty sleeping

DSM 5 Criteria:

1. The presence of excessive anxiety and worry about a variety of topics, events, or activities. Worry occurs more often than not for at least 6 months and is clearly excessive.

2. The worry is experienced as very challenging to control. The worry in both adults and children may easily shift from one topic to another.

3. The anxiety and worry are accompanied with at least three of the following physical or cognitive symptoms (In children, only one symptom is necessary for a diagnosis of GAD):

• Edginess or restlessness

• Tiring easily; more fatigued than usual

• Impaired concentration or feeling as though the mind goes blank

• Irritability (which may or may not be observable to others)

• Increased muscle aches or soreness

• Difficulty sleeping (due to trouble falling asleep or staying asleep, restlessness at night, or unsatisfying sleep)

APA, 2017

Management of GAD•Use a patient centered approach

- Communicate realistic expectations

- Treatment preferences/prior treatment/adverse effects

- Treatment adherence key goal of therapy

•Tailor treatment based on severity, distress and functional impairment/quality of life

•Consider using a GAD diagnostic tool such as General Anxiety Disorder(GAD)-7

- scores: mild = 5, for moderate = 10 and for severe anxiety =15

- 10 or more suggestive of GAD/can be used to track treatment progress

•Screen for suicidality (risk assessment and safety) PTSD and substance use disorder

Treatment Approach to GADStep 1: GAD confirmed

Stepe 1: GAD confirmed- Determine severity and functional impairment (if severe, go to step 3)- Estabilish agreed upon goals

- Counsel on lifestyle changes/refer to BHOP- Provide self-help info on relaxation techniques/refer to BHOP- F/U in 4 weeks

Step 2: Poor or Partial Response in Step 1- If symptoms severe/go to step 3- Refer to mental health for psychotherapy/Support group/mindfulness based interventions-F/U in 2-4 weeks/soon if symptoms are severe

Step 3: Initiate psychotherapy or psychopharmacotherapy- Discuss options for pharmocotherapy /shared decision

- Refer for clinician delivered CBT/applied relaxation therapy- Consider starting SSRI/short term benzos* for severe

symptoms/functional impairment- Alternatives include SNRI, hydroxyzine, Pregabalin, bupropion

- Monitor f/u every 2 weeks, then every 2-3 months- Continue meds for at least 12 mo after response

Kohoe, 2017 * Avoid use in history and current substance use disorder

Treatment Approach to GAD Cont.Step 1: GAD confirmed

Step 4: Modify psychotherapy or pharmacotherapyPoor or partial response in step 3- Reassess for anxiety severity (GAD-7), medication side effects/compliance and psychosocial stressors (relationship/work issues)- Increase number of sessions or add pharmotherapy- If pharmacotherapy inadequate :1. Poor response: change to another SSRI/SSRI2. Partial response: Augment with buspar, hydroxyzine, pregabalin, short course of BZD*, change to another antidepressant, add CBT, depending on patient preference- F/U in 2-4 weeks

Step 5: Modify pharmacotherapyPartial or poor response in Step 4- Partial response: Change to another combo of antidepressant or augmenting agent to used earlier (hydroxyzine/pregablin)- Poor response: Refer to mental health

Kohoe, 2017 * Avoid in history or current substance use disorder

ReferencesAPA. (2017). Diagnostic and statistical manual of mental disorders: Dsm-5. Arlington, VA.

APA (2010). Practice Guidelines for The Treatment of Patients with Major Depressive Disorder. Retrieved from http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines /guidelines/mdd.pdf

Boyer, E.W. & Shannon, M. (2007). Current Concepts: The Serotonin Syndrome. New England Journal of Medicine, 356(23), 2437–2437. doi: 10.1056/nejmx070028

Bhatt, N.V (27 Mar, 2019). Anxiety Disorders Medication. Medscape. Retrieved from https://emedicine.medscape.com/article/286227-medication#5

Foong, A. L., Patel, T., Kellar, J., & Grindrod, K. A. (2018). The scoop on serotonin syndrome. Canadian pharmacists journal : CPJ = Revue des pharmaciens du Canada : RPC, 151(4), 233–239. doi:10.1177/1715163518779096

Bhatt, N.V (27 Mar, 2019). Anxiety Disorders Medication. Medscape. Retrieved from https://emedicine.medscape.com/article/286227-medication#5

Kehoe, W. (2017). General Anxiety Disorder. Neurologic/Psychiatric Care. Retrieved from https://www.accp.com/docs/bookstore/acsap/a17b2_sample.pdf