Anxiety

Anxiety
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Anxiety Disorders

Overview

Topics

Objectives

  1. Explain to a patient the biological purpose of anxiety, signs/symptoms of anxiety and when anxiety symptoms become disordered anxiety
  2. Summarize the neurotransmitter systems and general brain systems that are involved in anxiety pathways
  3. Construct a patient work-up that points out risk factors for developing an anxiety disorder, potential alternate causes for anxiety symptoms and helpful lab investigations
  4. Distinguish between the different anxiety disorders including relative prevalence, symptomology and diagnostic criteria
  5. Compose goals of therapy for anxiety treatment in collaboration with a patient
  6. Explain the common non-pharm treatment modalities and their role in therapy to a patient
  7. Recommend pharmacologic treatment options to a HCP based on a patient case, incorporating guidelines, clinical judgement and patient-specific factors
  8. Create efficacy and safety endpoints specific to a patient
  9. Recommend a medication switching plan based on pharmacological and patient factors
  10. Discuss medication considerations for special populations and patients with specific comorbidities

Study Materials



Case: AP

Annapura is a 31 year old cis-female who comes to your pharmacy with a prescription for sertraline. She does not have any drug coverage and is not currently working— She graduated highschool but could never afford college or university, though she never had the marks to get into either. She tried working but could never hold down a job. When asked why she is on sertraline, she states she has been depressed and anxious for as long as she can remember. She has never tried any other agents and has been doing psychotherapy monthly for about 5 years through a social worker who charges a sliding scale.

Anxiety is “normal”

  • characteristics of normal
    • Emotional response to real or perceived threat
    • Normal human emotion
    • Transient in nature
    • Allows person to respond to a threat

Anxiety becomes disordered when it interferes with functioning

  • for example:
    • social, occupational, affects school

Types of Anxiety

  • types:

    ❖ General Anxiety Disorder (GAD)

    ❖ Social Anxiety Disorder (SAD)

    ❖ Panic Disorder (PD)

    ❖ Post Traumatic Stress Disorder (PTSD)

    ❖ Obsessive Compulsive Disorder (OCD)

    ❖ Phobias

Pathophysiology

Multiple biochemical systems involved:

  • biochem systems:

    • Norepinephrine (NE):
      • stimulatory neurotransmitter
    • γ-aminobutyric acid (GABA):
      • inhibitory neurotransmitter

    ❖ Serotonin (5-HT)

    • Corticotropin-releasing factor (CRF):
      • is involved in sympathetic nervous system, hence stimulatory
    • Glutamate:
      • stimulatory
    • Dopamine:
      • generally stimulatory
    • Cholecystokinin:
      • in the amygdala , interacts with other neurotransmitters, specifically with dopamine, can induce/reduce

Noradrenergic Model

  • model:

    Week%202%20Anxiety%20Disorders%20dc947af773774c339e03b4bad7f736c6/Untitled.png

    • when there’s increased sensitivity of receptors from downregulation, this is when anxiety becomes pathological

GABA-Receptor Model

  • model:

    ❖ GABA is major inhibitory neurotransmitter

    ❖ GABA has strong modulatory effects on:

    ◦ NE

    ◦ 5-HT

    ◦ DA

    ❖ GABA binds GABA-A to reduce neuronal excitability

    • inability of GABA to relax the body/person, which contributes to anxiety

    Week%202%20Anxiety%20Disorders%20dc947af773774c339e03b4bad7f736c6/Untitled%201.png

    • GABA helps modulate release of CRF, and acting on anterior pituitary

Serotonin Model (exam)

  • model:

    • Serotonin is inhibitory neurotransmitter that acts:
      • on neurons in raphe nucleus (mid brain)
      • These neurons project throughout the brain (cortex, amygdala, hippocampus, limbic system) → widespread effects
    • Theory: More serotonin activity

      ◦ Reduces NE activity in LC

      ◦ Reduces hypothalamic release of CRF

      ◦ Inhibits defense/escape response via periaqueductal grey area (PAG)

    • Conflicting effects of serotonin (5-HT) on anxiety

      ◦ Acute increase of 5-HT induces anxiety

      ◦ 5-HT1A receptor partial agonists reduce 5-HT activity and can be helpful for anxiety

      • so, reduction of serotonin activity can be helpful

Epidemiology

❖ Lifetime prevalence up to 34%

❖ Women > men

❖ Develop before age 30

❖ 40% untreated (have pathological anxiety → diagnosed)

❖ 60-80% have at least 1 other psychiatric disorder

>50% have more than 1 comorbid anxiety disorder; 30% have 3 or more comorbid anxiety disorders

❖ 1.7-2.5 times increased risk of suicide attempts

Lifetime Prevalence: don’t memorize % but know most/least common, relative prevalence & distinction between panic attack vs panic disorder

❖ Phobia 12%

  • individual phobia: afraid of snakes, clowns (specific thing)

❖ SAD 10%

❖ PTSD 9%

❖ GAD 6%

❖ Panic disorder 5%; Panic attack 28%

❖ OCD 1.5%

❖ Agoraphobia 1.4%

Psychiatric Comorbidities

  • comorbidities:

    ❖ > 1 anxiety disorder

    ❖ Mood disorders (depression, bipolar disorder)

    ❖ ADHD

    ❖ Schizophrenia

    ❖ Dementia

    ❖ Substance use disorder

Etiology

  • interaction/combination factors:

    Week%202%20Anxiety%20Disorders%20dc947af773774c339e03b4bad7f736c6/Untitled%202.png

  • Genetic: twin studies, adoption studies, family hx

  • Neurobiological adaptations: signaling in their brain may change, which may cause them to develop anxiety disorder

Risk Factors

  • etiology could be a direct cause, but risk factor is like a correlation

    ❖ Loneliness

    ❖ Low education

    ❖ Adverse parenting

    ❖ Chronic physical illnesses (e.g CV disease, diabetes, asthma, obesity, etc…)

    ❖ Other psychiatric disorders

Case: AP

Annapurahas been experiencing depression and anxiety for as long as she can remember. She has been diagnosed with various anxiety disorders and depression by her GP. She is unsure of her diagnoses but she thinks she probably has panic disorder, PTSD, depression and ADHD.

She says she experienced trauma as a child but she never told her parents about it because they were never around and she always had to fend for herself as they worked many jobs to make ends meet. She has a brother who has bipolar disorder and generalized anxiety disorder. Her parents have never been diagnosed with anything but “they have a lot of mental problems”.

  • Points to consider from the case?
    • women > men, she fits criteria
    • symptoms dev before age 30
    • untreated for some time, until now
    • she dx depression, various anxiety disorder, 1+ anxiety disorders
    • stressful event as a child; adverse event of parenting
    • brother has GAD, which may suggest genetic but not necessarily

Symptoms of Anxiety

Not a comprehensive list

Symptom Type

Physical

Psychological

  • Examples of Symptoms

    GI upset, chest pain, chills, dizziness, nausea, paresthesia, sweating, tachycardia, trembling, blushing, stumbling over words, muscle tension, irritability, fatigue, sleep disturbance, restlessness

  • psycho

    Avoidance, fear of losing control/dying, fear of judgment, feeling on edge, excessive worrying, depersonalization, derealization

Dissociation:

  1. depersonalization: feel disconnected from yourself, but feel in your surroundings
  2. derealization: feel like yourself, but feel disconnected from surroundings

Anxiety Screening Questions

❖ In the past 2 weeks, how much have you been bothered by:

◦ Feeling nervous, anxious, frightened, worried, on edge?

◦ Feeling panic or being frightened?

◦ Avoiding situations that make you anxious?

❖ Different anxiety disorders have different screening questions

◦ Often a part of a general psychiatric evaluation

Differential Diagnoses

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  • Cardio:
    • HR or chest pain, can make CV ilness feel like anxiety
  • Endo:
    • hyperthyrodism: increase HR → feel/trigger anxiety
    • vitb12/folate def: anemia, not enough O2 distributed in body, heart can be compensating by increasing HR makes it feel like anxiety
  • Poor pain control:
    • patient can be/feel anxious, BP increases and other vitals become abnormal
  • COPD exacerbation:
    • not enough O2, heart compensating which feels like anxiety

Drug Induced Causes of Anxiety

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Useful Scales

❖ Hamilton Anxiety Rating Scale (HAM-A)

❖ Beck Anxiety Inventory (BAI)

❖ General Anxiety Disorder Assessment (GAD-7)

❖ Yale-Brown Obsessive Compulsive Scale (Y-BOCS)

❖ Clinical Global Impression (CGI) ←general general scale, good often used to determine the improvement/or not of a person’s functioning, regardless of which mental health disorder they’re being followed for

What to think about when selecting a scale/tool…

  • Think about:

    ◦Screening tool vs. improvement tool

    ◦Validated?

    ◦Applicable to your patient and setting?

    ◦Why/how tool was developed?

Baseline Investigations

  • Vitals:

    BP, HR, RR, O2

  • Labs:

    ◦ CBC (incl. Hb)

    ◦ TSH

    ◦ Electrolytes

    ◦ Fasting glucose

    ◦ Fasting lipid profile

    ◦ Liver enzymes

    ◦ Urine tox screen: helps to determine if person anxious because of illicit drug taken

Case: AP

PMHx:

  • Asthma
  • Hx of anemia –Used to take iron but GP says she does not require anymore

Labs:

  • Last 1 month ago-Unremarkable (CBC, TSH, liver panel, Cr)
  • Hb = 131 g/L, ferritin = 103, B12= 220 pmol/L

Medications:

  • Salbutamol 100 mcg PO QID PRN –Uses approx. once monthly
  • Vitamin D 1000 units PO daily

→ at this point, it can be concluded that she’s experiencing primary anxiety

Types of Anxiety

❖ General Anxiety Disorder (GAD)

❖ Social Anxiety Disorder (SAD)

❖ Panic Disorder (PD)

❖ Agoraphobia (lumped in w/ panic disorder)

❖ Phobias

❖ Post Traumatic Stress Disorder (PTSD)

❖ Obsessive Compulsive Disorder (OCD)

General Anxiety Disorder

  • Persistent symptoms most days for?
    • at least 6 months (if <6mo they DON’T have the disorder)
  • Unrealistic or excessive?
    • anxiety/worry about a number of events/activities
  • At least __ psychological or physical symptoms
    • 3

❖ Symptoms not a part of another psychiatric illness

  • may have another anxiety disorder/substance use disorder that may conflating → whether it’s GAD or cocaine use

Social Anxiety Disorder

  • Marked fear of?
    • one or more social situations (fear of scrutiny)← key!

❖ Fear is out of proportion with social situation; Usually provokes immediate panic attack

  • Duration?
    • For at least 6 months or longer

SAD vs agoraphobia: a person may be avoiding a situation, example avoiding the mall, vs going to the mall meeting friends and worried how friends would perceive them

anxiety when presenting in front of a class or at work, but socially perfectly fine, no issues in smaller groups

or the opposite, presenting fine, ok in smaller groups, in larger groups get nervous and worried how they are judged

Panic Disorder

  • Series of unexpected?
    • panic attacks (abrupt surge of fear/discomfort)
  • Panic attacks followed by?
    • 1 month of persistent concern of recurrence or maladaptive change in behaviour
    • maladaptive:
      • had a panic attack while speaking to a certain colleague at work for at least 1 month after if they’re avoiding going to work/avoiding meetings
  • At least ___ physiologic/physical [symptoms]() during attack
    • 4
    • person may have a panic attack, but NOT a panic disorder
    • people may have panic attacks but not worried affecting daily life

What is a Panic Attack?

  • Panic attack?
    • An abrupt surge of intense fear or intense discomfort that reaches a peak within minutes, and includes
      • ≥4 of the following symptoms:
        1. Palpitations, pounding heart, or accelerated heart rate
        2. Sweating
        3. Trembling or shaking
        4. Sensations of shortness of breath or smothering
        5. Feelings of choking
        6. Chest pain or discomfort
        7. Nausea or abdominal distress
        8. Feeling dizzy, unsteady, light-headed, or faint
        9. Chills or heat sensations
        10. Paresthesias (numbness or tingling sensations)
        11. Derealization (feelings of unreality) or depersonalization (being detached from oneself)
        12. Fear of losing control, going crazy, dying

Agoraphobia

  • Fear of at least 2 of:
    • Public transportation, open spaces, being in shops/theatres/cinemas, standing in line or being in a crowd, being outside of home
  • Fear/avoidance of above situations due to thoughts of no escape
  • Above situations almost always provoke?
    • anxiety
  • Deal with above situations with?
    • avoidance, requirement of companion or endurance with fear
  • Fear/anxiety is out of proportion of danger posed by situation
  • Persistent for how long?
    • Fear/anxiety is persistent, typically more than 6 months

Phobia

  • Persistent fear of?
    • specific object or situation
  • Object/situation actively?
    • avoided
  • Fear/anxiety is out of proportion to actual threat

Post Traumatic Stress Disorder

  • Exposure to situation involving?
    • definite or threatened death or serious injury, sexual violence, possible harm to self/others
      • could have been a witness as well and fulfil the criteria
  • Sx for at least?
    • 1 month
  • May be accompanied by derealization or depersonalization ← dissociation
  • Symptomology for diagnosis:

    • Symptom Type

      • Intrusion (at least 1)

        • examples

          Week%202%20Anxiety%20Disorders%20dc947af773774c339e03b4bad7f736c6/Untitled%205.png

      • Avoidance (at least 1)

        • examples

          Week%202%20Anxiety%20Disorders%20dc947af773774c339e03b4bad7f736c6/Untitled%206.png

      • Cognition/mood (at least 2)

        • examples

          https://i.imgur.com/0B8s3Gv.png

      • Hyperarousal (at least 2)

        • examples

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    • Full Table

      Week%202%20Anxiety%20Disorders%20dc947af773774c339e03b4bad7f736c6/Untitled%208.png

Obsessive Compulsive Disorder

  • Obsessions and/or compulsions (usually both)
  • Severe enough to cause distress or time consuming (>1 hour/day) or significant impairment in social/occupational functioning

Obsession

  • Recurrent, persistent idea, thought, impulse, image that is experienced as intrusive and inappropriate and produces marked anxiety
  • Attempt to ignore/suppress thoughts/urges/images or wholly consumed by them

Compulsion

  • Repetitive behaviour to respond to obsession and is applied rigidly
  • Behaviour aimed at reducing anxiety/distress but not connected in a realistic way

OCD Related Disorders

  • Body dysmorphic disorder
    • person feels unhappy with their body, even if standards say otherwise; 1 scar can cause problems
  • Hoarding disorder
    • mostly compulsive; cannot walk in a house, or functioning is disruptive, throwing out is intolerable
  • Trichotillomania (hair pulling disorder)
    • inability to control pulling hair, so bad that may results in lack of hair in head
  • Skin picking disorder

Case: AP

Annapura has been experiencing depression and anxiety for as long as she can remember. She remembers being a teenager who would go to her family gatherings, and took homework to avoid talking to her cousins, aunts and uncles. She always felt uncomfortable making conversation with them and was afraid of what they thought of her. This pattern has continued into adulthood where she finds it difficult to attend work social events.

She has been seeing a psychotherapist and has become more aware and vocal about being sexually assaulted as a child by a relative, though she doesn’t remember what happened. She frequently has nightmares about this event and often has difficulty sleeping. She has always felt that she deserved this because she was a naughty, rambunctious child. She doesn’t really have any hobbies or friends and doesn’t find anything really brings her joy. Also, she thinks She may have ADHD because she is always on edge and can never focus on one task.

She states she has had panic attacks before at random times, though she isn’t afraid of having any and her behaviour hasn’t changed because of this.

  • afraid of being criticized by family members and avoiding them → alluding to SAD
  • sexually assaulted by a relative as a child, so probably why she’s avoiding
  • trauma:
  • PTSD, intrusion thoughts, nightmare, avoiding family members
  • nothin bring her joy, no friends
  • pt has at least 1 sx of hyperarousal
  • talk about panic attack, because she is not afraid of getting a panic attach after 1 month of having panic attack, so no need to be treated for panic disorder

Goals of Therapy

  • Reduce severity, duration, frequency of symptoms
  • Reduction of symptoms on a scale by 25-50%
    • in drug therapy, time to effect will help determine when improvement occurs
  • Improve functioning
  • Prevent recurrence
    • relapse is common in many psychiatric issues
  • Improve quality of life

  • Duration of therapy: 12-24 months

Guideline

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Non-PharmacologicaI Treatment

  • Avoid stimulants (caffeine, nicotine), alcohol (depressant, but withdrawal anxiety can ensue)
  • Patient education, encouragement to face fears
  • Psychological tx (group and individual)
    • Exposure-based and other cognitive behavioral therapy (CBT) protocols
    • Mindfulness-based cognitive therapy (MBCT)
    • Self-directed/minimal intervention formats (→ online modules)
  • PTSD specific:

Mindfulness

  • Many techniques
  • A few examples:
    • Body scan: how does parts of body feel, head, shoulders, torso, etc.
    • Mindful breathing: box breathing
    • Mindful seeing: “can you name/count anything blue in room”
    • Raisin exercise

all these exercise gets person into the “now” present because thoughts are all over the place

Non-pharm vs Pharm

  • Psychotherapy and pharmacotherapy equivalent efficacy for the treatment of most disorders (for exam purposes)
  • Evidence for combination therapy varies; No routine combination of CBT and pharmacotherapy as initial treatment

Medications Role in Therapy

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agorophobia is lumped in with panic disordes, as per guidelines and DiPiro

Treatment Options

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  • pregabalin/gabapentin: most important
  • prazosin used in nightmares

SSRI/SNRIs

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  • often resolve sooner than 2 weeks, and happens with each subsequent dose increase, however, if a pt hasn’t experienced these from the get-go they are unlikely to experience these SE with subsequent dose increase
  • BDZ used in caution esp. those with substance use order; used liberally in hospitals, but more caution in community
  • long term SE can be managed by adding another medication like bupropion, or switching to another agent with less potential, ie mirtazapine, or a different SSR/SNRI
  • if pt with GI bleed, on anitplatelet, and have stomach upset, may suggest addition of PPI + monitor

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The FDA “Black Box” Warning on Antidepressant Suicide Risk in Young Adults: More Harm Than Benefits?

SSRI/SNRIs and Serotonin Syndrome

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Serotonin Syndrome with Antidepressants and Triptans

❖Orlovaet al., 2018 –Low rate of serotonin syndrome with co-prescription

❖Serotonin syndrome occurs through overactivity at 5-HT2A

❖Triptans act on 5-HT1B and 5-HT1D

  • so there is no reason to prevent a patient to be on both

SSRI/SNRIs and SIADH

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SSRI/SNRI Discontinuation Syndrome

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  • paresthesia: some people call them “brain zaps” esp with venlafaxine

SSRIs

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SNRIs

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TCAs

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MAOIs/RIMAs

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Tyramine

Tyramine and MAOIs

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  • normal circumstances, person not taking a MAOi or RIMA, tyramine is broken down by MAO A and B, there will be NE activity but regulated, not excessive.

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With irreversible MAO A and B inhibitors:

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Tyramine and RIMAs

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  • competitive inhibitor on MAO A only (moclobemide), tyramine able to knock off moclobemide from MAO A receptor
  • MAO B is still breaking down tyramine

    Week%202%20Anxiety%20Disorders%20dc947af773774c339e03b4bad7f736c6/Untitled%2032.png

  • therefore, NE activity is NOT in excess, so not increased risk of hypertensive crisis

  • be careful of high doses!!

Mirtazapine

❖Brand name: Remeron

❖Not 1st line

❖Tetracyclic antidepressant -Antagonizes many receptors: alpha-2 adrenergic receptors, 5-HT2, 5-HT3, H1

❖ADR: Weight gain, sedation, QTc prolongation

❖Lower incidence of sexual side effects

❖Black box warning for suicidality

Bupropion

❖Brand name: Wellbutrin (Zyban for smoking cessation)

❖Not 1st line (has good SE profile, but not rigorously studied like other meds)

❖NDRI –Norepinephrine and Dopamine Reuptake Inhibitor

❖XL or SR formulation (SR is usually Zyban)

❖ADR: Agitation, insomnia, anorexia, reduced seizure threshold

❖May be added on to help with erectile dysfunction (has no libido or lack of orgasm SE)

❖Black box warning for suicidality

Vortioxetine

❖Brand name: Trintellix

❖Not 1st line

❖5-HT reuptake inhibitor, 5-HT1A agonist, 5-HT3 antagonist

❖ADR: Nausea, dizziness, diarrhea/constipation, dry mouth, dyspepsia, flatulence, sexual dysfunction at lower doses → higher doses there’s significant risk fo sexual dysfunction

❖Black box warning for suicidality

Antidepressants and Mania

❖“Treatment emergent affective switch” = TEAS

❖Increased risk to switch into mania

❖Can oppose antidepressant with mood stabilizer/antipsychotic

❖TCAs >> SNRI > SSRI, bupropion

Switching Antidepressants

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Switch Rx: www.switchrx.com

Benzodiazepines

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Buspirone

❖2nd line –No robust evidence for long term therapy, delayed onset of effect (>=2 weeks), therefore cannot be dosed PRN, must be standing at least BID

❖Partial 5-HT1A agonist

❖Dose BID-TID; Relatively short T1/2

❖ADR: dizziness, drowsiness, and nausea

❖Not used much in practice

Anticonvulsants

❖Gabapentin and pregabalin (Lyrica) most frequently used

❖1st and 2ndline in some anxiety disorders

❖Dosed multiple times daily

❖ADR: Dizziness, drowsiness, peripheral edema, vision changes, ataxia

Atypical Antipsychotics

❖2nd or 3rd line

❖Antagonize various receptors: D2, 5-HT2, alpha-1, alpha-2, H1

❖ADR: Weight gain, diabetes and other metabolic effects, sedation, EPS (extrapyramidal symptoms)

Prazosin

❖Reduces trauma nightmares, improves sleep quality

❖Alpha-1 blocker (traditionally for hypertension); Reduces NE activity in the LC

❖ADR: Dizziness, hypotension, tachycardia, nausea, headache

❖Studied mostly in Veterans at doses up to 20 mg per day; Lower doses in practice

❖Start at 1 mg PO QHS and titrate to effect/tolerability

Medications Role in Therapy

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Case: AP

Was sertraline sufficient?

  • for her 2 diagnoses, SAD & PTSD, yes, would take 2 weeks to start working, 4 weeks for full effect, assuming sufficient dose

Annapura comes to you to pick up her prescription refill and states that the medication is not working. She is taking sertraline 25 mg PO daily. She experienced nausea when she started the medication so she did not escalate the dose as recommended by her GP.

  • keep in mind, it has to be an effective dose to work
  • with nausea it goes away within 2 weeks after each dose escalating the doe, can take gravol
  • encourage to increases the dose to 50mg, 100mg and max 200mg

Bottom Line for Medications

❖SSRI/SNRIs are typically first line for all of the anxiety disorders; mostly due to their advantageous SE profile

❖Start low, go slow (wait long enough and pt at a high dose enough before determining tx failure)

❖Consider comorbidities

❖Wait long enough and ensure high enough dose before considering a failure

❖Identify efficacy and safety endpoints -Provide realistic expectations (gravol prn)

❖ADRs often resolve –Ask the patient to be patient

❖If 1st line agent does not work, try another 1st line agent; Then base on clinical picture

❖Observe washout periods and tapering strategies

Special Populations and Specific Medical Comorbidities

❖Elderly

❖High blood pressure

❖Hx of GI bleed and/or on antiplatelet

❖Pregnancy and lactation

❖Bipolar Disorder

❖Substance use

References

❖Dipiros, 11thEd –Chapters 89 (Anxiety), 90 (PTSD, OCD)

◦Chapter 89: Melton ST, Kirkwood CK.Anxiety Disorders: Generalized Anxiety, Panic, and Social Anxiety Disorders.In:DiPiroJT, Yee GC, Posey M, Haines ST, Nolin TD, EllingrodVeds.Pharmacotherapy: A Pathophysiologic Approach, 11eNew York, NY: McGraw-Hill;

◦Chapter 90: Gardner KN, Bostwick JR, Crouse EL. Posttraumatic Stress Disorder and Obsessive-Compulsive Disorder.In:DiPiroJT, Yee GC, Posey M, Haines ST, Nolin TD, EllingrodVeds.Pharmacotherapy: A Pathophysiologic Approach, 11eNew York, NY: McGraw-Hill;

❖Goodman and Gilman 13thed, Chapter 15 (Depression and Anxiety)

◦O’Donnell JM, BiesRR, Shelton RC.Drug Therapy of Depression and Anxiety Disorders.In:Brunton LL, Hilal-DandanR, KnollmannBC.eds.Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13eNew York, NY: McGraw-Hill;

❖DSM-5: Section II (Diagnostic Criteria and Codes) –Anxiety, Obsessive-Compulsive and Related Disorders, Trauma-and Stressor-Related Disorders

◦American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.

❖Stahl, S. M. (2013).Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications(4th ed.). Cambridge University Press.

❖Tomb, DA (Ed). Psychiatry. 7thEd. Chapter 8 -Anxiety Disorders. Lippincott Williams & Wilkins; 2008.

❖Canadian Guidelines: Katzman, M.A., Bleau, P., Blier, P. et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry (2014) 14(Suppl 1): S1. https://doi.org/10.1186/1471-244X-14-S1-S1 ❖Friedman, RA. Antidepressants’ Black-Box Warning —10 Years Later. M.D. N EnglJ Med 2014; 371:1666-1668

❖Gitlin, M.J. Antidepressants in bipolar depression: an enduring controversy.IntJ Bipolar Disord6,25 (2018). https://doi.org/10.1186/s40345-018-0133-9

❖Gross P. Clinical management of SIADH.Therapeutic Advances in Endocrinology and Metabolism. 2012;3(2):61-73. doi:10.11772042018812437561.

❖Jacob, S and Spinler, S. Hyponatremia Associated with Selective Serotonin-Reuptake Inhibitors in Older Adults. The Annals of pharmacotherapy. 2006 40. 1618-22. 10.1345/aph.1G293.

❖OrlovaY, Rizzoli P, LoderE. Association of coprescriptionof triptanantimigraine drugs and selective reuptake inhibitor or selective norepinephrine reuptake inhibitor antidepressants with serotonin syndrome [published online February 26, 2018]. JAMA Neurol. 2018. doi:10.1001/jamaneurol.2017.5144. 4

❖Sansone, RA and Sansone, LA. Serotonin Norepinephrine Reuptake Inhibitors: A Pharmacological Comparison Innov Clin Neurosci. 2014 Mar-Apr; 11(3-4): 37–42