Transcript Antidepressants and Anti-anxiety Medications for RN

Antidepressants and Anti-anxiety
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
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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):
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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
(5HT, DA, NE)
◦ For example, not enough 5HT 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)
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◦ Drowsiness / fatigue (especially paroxetine and fluvoxamine)
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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
inSanity (mania)
SSRIs: Serotonin Syndrome
Potentially life-threatening clinical syndrome caused by excess serotonin in CNS and peripheral
nervous system
HARM mnemonic
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Hyperthermia
Autonomic instability with delirium
Rigidity
Myoclonus
Rare. Likely to occur only in massive overdose and/or in combination with other serotonergic drugs
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Opioids: tramadol, meperidine, others
5HT-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-HT2a 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-HT2a 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?
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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 CYP450 induction
Still may have some role in anesthesia (thiopental) and seizure disorders (phenobarbital)
Buspirone
Mechanism of action: 5-HT1a 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 x4 days ago. Healing well, no signs of post-op
complications, now in SNF for rehab. She is A+O x4. 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 5mg q4h prn, vitamin D / calcium supplement, hydrochlorothiazide
12.5mg, atorvastatin 80mg, levothyroxine 50mcg, metformin 750mg 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 she 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 x3 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 2mg 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 2mg 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 0.5mg 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?