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174 Cards in this Set
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Defn mental health
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The successful performance of mental function, resulting in productive activities, fulfilling relationships with others, and the ability to adapt to change and cope with adversity
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defn anxiety
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An emotional state commonly caused by the perception of real or perceived danger that threatens the security of an individual -> normal response!
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defn anxiety disorder
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Persistent, severe anxiety symptoms and/or irrational fears that significantly impair normal daily functioning -> pathological anxiety
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5 types of anxiety disorders
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Generalized Anxiety Disorder (GAD)
Panic Disorder Social Anxiety Disorder (SAD) Posttraumatic Stress Disorder (PTSD) Obsessive-Compulsive Disorder (OCD) |
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epidemiology of anxierty disorders
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Prevalence
30 million adults; 16% Americans annually 13% children annually Females > males Cost Direct + indirect costs Increased health care utilization Cardiovascular, cerebrovascular, GI, respiratory disorders Onset Most common before age 30 Comorbid conditions 55% have concurrent disease state Major depressive disorder most common Eating disorder, HTN, Irritable bowel, migraines |
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Etiology and pathophysiology of anxiety disorders
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Genetics and inheritance
Increased risk with family history 3 fold increase for SAD OCD risk of 11-12% with first degree relative Environmental factors Early life trauma increases risk Endocrine abnormalities following trauma History of child abuse risk GAD, SAD, PTSD, and panic d/o Stressful life events may trigger vulnerabilities Biological contributions Noradrenergic GABA Serotonin An integrated view Biological vulnerability + psychological vulnerability + experiences |
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generalized anxiety disorder
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Annual prevalence rate of 2.5%
Average age of onset is 21 years Cardinal feature: unrealistic or excessive anxiety and worry Accompanied by at least 3 physiological or physical symptoms Symptoms most days > 6 months Symptoms cause significant distress and impairment in functioning Not secondary to medical cause or drug/medication |
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cardinal feature of GAD
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unrealistic or excessive anxiety and worry
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clinical presentation of GAD
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Psychological and cognitive symptoms
Excessive anxiety Worries that are difficult to control Feeling keyed up or on edge Poor concentration Physical symptoms Restlessness Fatigue Muscle tension Sleep disturbance Irritability Impairment Social, occupational, or other important functional areas Poor coping ability |
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GAD chronic course of illness
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Chronic course of illness:
High relapse rate GAD exacerbated/precipitated by stressors Many patients develop a secondary mental health disorder |
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Panic disorder
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Annual prevalence rate of 1.7%
Spontaneous attacks involving intense fear Overwhelming sense of doom Fear of dying or losing control At least 4 physical symptoms Followed by 1 month of persistent concerns about having another attack |
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panic disorder impact of QoL
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Significant impact on QOL
Social and work impairment High lifetime risk of suicide Agoraphobia (35-50%) – anxiety about being in places or situations from which escape might be difficult or embarrassing 90% of those with agoraphobia have had panic attacks |
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symptoms of panic attack
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Psychological and cognitive symptoms
Depersonalization Derealization Fear of losing control Fear of going crazy Fear of dying Physical symptoms Abdominal distress Chills Chest pain Feeling of choking Dizziness or lightheadedness Hot flashes Palpitations Nausea Parethesias Sweating Shortness of breath Tachycardia Trembling or shaking |
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social anxiety disorder
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Annual prevalence rate of 3.7%
Intense, irrational, persistent fear of being negatively evaluated Blushing most common physical symptom Interferes with normal functioning and/or causes significant distress |
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presentation of SAD
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Fears
Being scrutinized by others Being embarrassed or humiliated Some Feared Situations Addressing group of people Eating or writing in front of others Interacting with authority figures/strangers Speaking in public Use of public toilets Physical symptoms Blushing Butterflies in stomach Diarrhea Sweating Tachycardia Trembling Generalized: Wide range of situations Non-generalized: 1-2 specific situations |
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post traumatic stress disorder
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Annual prevalence rate of 3.7%
increase reports with recent world events Exposure to traumatic event required for diagnosis At least one re-experiencing symptom (flashback) At least 3 avoidance symptoms Avoids reminders of the event At least 2 symptoms of increased arousal Falling or staying asleep, anger, concentration Symptoms >1 month, distress/impairment in functioning |
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presentation of PTSD
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Re-experiencing symptoms
Recurrent, intrusive, distressing memories of trauma Recurring, disturbing dreams of the event Feeling that event is recurring (flashbacks) Physiologic reaction to reminders of trauma Avoidance symptoms Avoidance of conversations about the trauma Avoidance of thoughts/feelings about trauma Avoidance of activities that are reminders of event Avoidance of people/places that arouse recollections Inability to recall important aspect of the trauma Anhedonia Estrangement from others Restricted affect Sense of foreshortened future Hyperarousal syptoms Decreased concentration Easily startled Hypervigilance Insomnia Irritability/angry outbursts Acute: Sx < 3months Chronic: Sx > 3 months |
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PTSD prognosis
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1/3 of patients have poor prognosis
Treated patients -> average duration = 36 mo Untreated patients -> average duration = 5y 20% of patients attempt suicide |
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obsessive compulsive disorder
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Annual prevalence of 1.5-2.5%
Obsessions Recurrent, persistent idea, thought, impulse or image that is intrusive, inappropriate and causes anxiety Contamination, doubts, need for order Compulsions Repetitive behavior or act performed in response to obsession to relieve the anxiety associated with obsession Cleaning, counting, checking |
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presentation of OCD
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Obsessions
Repetitive thoughts (feeling contaminated, etc) Repetitive images (gruesome, or sexually explicit pictures) Repetitive impulses (need for symmetry or specific order) Compulsions Repetitive activities (hand washing, checking, etc) Repetitive mental acts (counting, repeating words, etc) |
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nonpharm therapy for anxiety disorders
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Stress management, meditation, exercise
Psychotherapy Cognitive Behavioral Therapy (CBT) Effective for GAD, Panic d/o, SAD, PTSD, OCD Often treatment of choice for mild symptoms Gold standard for OCD: expose to stimuli (the obsession), refrain from compulsion |
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short term goals of therapy for OCD
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Short term
decrease severity, frequency, duration of symptoms Improve functioning |
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Long term goals of therapy for OCD
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Long term
Remission with minimal or no symptoms No functional impairment |
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SSRIs for anxiety disorders
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Considered first line for ALL anxiety disorders
Established efficacy: GAD, panic disorder, SAD, PTSD, OCD Give treatment trial of at least 8 weeks Side effects usually mild and short lived Somnolence or insomnia, headache, nausea Paroxetine more sedating Fluoxetine, sertraline more stimulating Sexual dysfunction with all agents **Start low and go slow |
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SNRI: venlafaxine
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Effexor (immediate release)
Dosage forms: 25, 37.5, 50, 75, 100mg tablets Dose 37.5mg BID/TID, increase by 75mg every week to max of 225mg Effexor XR (extended release) Dosage forms: 37.5, 75, 150mg capsules Dose 37.5-75mg QD initially, increase by 75mg every week to maximum of 225mg |
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SNRI: duloxetine
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Cymbalta (delayed release)
Dosage forms: 20, 30, 60mg capsules Dose: 20mg BID initially, titrate up to 60mg daily (once daily or 30mg BID) Also has indications for diabetic peripheral neuropathy and major depressive disorder |
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antidepressant TCAs for anxiety disorder
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Imipramine, clomipramine, amitriptyline
Higher side effect burden vs. other antidepressants (i.e. “SLUD”) Clomipramine is the only TCA used in OCD |
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benzodiazepines for anxiety disorders
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Effective for acute anxiety symptoms (somatic and autonomic)
Effective for GAD, panic disorder, SAD Not useful for PTSD or OCD Use as a bridge to treat acute anxiety symptoms while SSRI begins to work, then discontinue!!! |
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side effects BZDs
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Side effects most commonly related to CNS depression
Sedation, psychomotor impairment, ataxia Tolerance to drowsiness Impairment of memory, recall |
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potential abuse w/ BZDs
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Potential for abuse/physical dependence
Abuse is rare, use caution in those with polysubstance or alcohol abuse Physical dependence will occur |
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w/drawal of BZDs
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Discontinuation: withdrawal
Anxiety, insomnia, irritability – common Hallucinations, seizures – rare TAPER |
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Buspirone (Buspar), what is it used for?
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to treat GAD
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Buspirone (Buspar)
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Second-line agent for GAD only
Initial dose: 7.5mg BID Titrate by 5mg/day every 2-3 days Usual therapeutic dose: 30-60mg/day Max benefit: 4-6 weeks Potential benefits Lacks abuse potential, physical dependence, or withdrawal Lack of potentiation of alcohol, or other sedative hypnotics |
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Acute situational anxiety
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“Performance Anxiety”
Beta-blockers Blunt the peripheral autonomic symptoms of arousal (e.g. tachycardia, sweating, blushing, tremor) Propranolol 10-40mg 1 hr prior to event Test dose at home Benzodiazepines generally not recommended |
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4 important points when choosing BZDs
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half life
active metabolites how metabolized lipophilicity (time to onset) |
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3 key components to insomnia
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1. Sleep Disturbance
Difficulty falling or staying asleep Non-restorative sleep 2. Impaired functioning Fatigue, malaise, daytime sleepiness Concentration or memory difficulty, vocational dysfunction Mood disturbances, anxiety over sleep lost 3. Adequate opportunity for sleep |
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Primary insomnia
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all other causes of not sleeping are ruled out
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secondary insomnia
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adjustment(shift changes)
inadequate sleep hygeine psychiatric disorder medical condition substance/drug |
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Secondary insomnia:
Drug classes that can cause it |
anticonvulsants
antidepressants beta blockers bronchodilators decongestants oral corticosteroids stimulants *also caffeine, alcohol and elicit drugs |
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anticonvulsants that can cause secondary insomnia
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lamotrigine
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antidepressants that can cause secondary insomnia
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bupropion
fluoxetine venlafaxine |
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beta blockers that can cause secondary insomnia
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propanolol
metoprolol |
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bronchodilators that can cause secondary insomnia
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theophylline
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decongestants that can cause secondary insomnia
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phenylpropanoloamine
pseudoephedrine |
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oral corticosteroids that can cause secondary insomnia
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prednisone
dexamethasone |
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stimulants that can cause secondary insomnia
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methylphenidate
dextroamphetamine modafinil pemoline |
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common medical conditions that can cause secondary insomnia
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Restless Leg Syndrome (RLS)
Pain Nocturnal Cough/Dyspnea Heart failure, COPD Menopause → hot flashes GERD, BPH sleep apnea psychiatric disorders: BP D/O (mania), schizophrenia, psychosis, depression/anxiety |
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when should you refer insomnia to primary care physician?
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secondary insomnia medical conditions all require referral
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things TO initiate to help secondary insomnia sleep hygeine
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Regular sleep-wake cycle
Comfortable, quiet, dark room Relaxing routine before bedtime Exercise routine bedroom for sleep/intimacy |
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things to AVOID in secondary insomnia poor sleep hygeine
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Use of alcohol, caffeine, nicotine, especially before bedtime
Late, heavy meals Daytime napping “Clockwatching” |
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treatment process for insomnia
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1. Rule out secondary causes of insomnia
2. Identify previous therapy 3. Non-pharmacological therapy should drive treatment plan 4. Pharmacological therapy to reinforce good habits |
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goal of nonpharm therapy in insomnnia
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modify behavior and change thought processes
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pharmacotherapy treatment drug classes
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1. GABA receptor agonists:
Benzodiazepines Non-benzodiazepines Valerian root 2. H1-receptor antagonists: Tricyclic antidepressants Trazodone, Mirtazapine Antihistamines Quetiapine 3. Melatonin receptor agonists: Ramelteon OTC melatonin |
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principles of pharmacotherapy for insomnia
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1. Anything that binds to the benzodiazepine-receptor is a Class-IV controlled substances
2. Hypnotic agents (except eszopiclone, remelteon, zolpidem CR) are approved for short-term use. Nightly use for > 4 months is not uncommon 3. Hypnotic agent selection should be dictated by duration of action, mechanism, side effect profile, and co-morbid conditions No current guidelines for drug selection 4. Use agent to help change behavior and thought processes |
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MOA BZDs for insomnia
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Mechanism: non-selective agonist binding at different GABAA receptor subtypes (α-1, α-2, α-3, or α-5 subunits)
-->Sedation, anterograde amnesia, anticonvulsant activity, anxiolysis, muscle relaxation, ethanol potentiation |
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side effects of BZDs for insomnia
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Alteration of sleep architecture
Residual daytime sedation Cognitive and psychomotor impairment Anterograde amnesia Rebound insomnia Withdrawal symptoms when discontinuing Tolerance to sedative effects (tachyphylaxis), physiologic dependence use caution in the elderly |
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non BZDs for insomnia
(the Z hypnotic agents) |
zolpidem (ambien)
zaleplon (sonata) eszopiclone (lunesta) |
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MOA of the 3 Z hypnotics
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Mechanism: selectively agonize the GABA receptors
More selective for the α-1 subunit of the GABAA receptor Although eszopiclone not selective (alpha 1, alpha 3) Lack of anticonvulsant and muscle-relaxant properties and potentially less effect on the sleep cycle |
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why were the 3 Z hypnotics developed?
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to minimize the side effects associated with the use of BZDs
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ambien vs ambien CR
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ambien:
Immediate release Sleep onset Half-life = 2.5 hr ambien CR: 2 layer release (IR and XR) Sleep onset or maintenance Half-life = 2.8 hr Now has 6-month data ***they were found to be nearly similar, almost identical plasma concentrations ambien CR has slightly larger AUC |
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describe eszopiclone (lunesta)
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S-isomer of the hypnotic agent zopiclone, which has been available in other countries for over 20 years
Similar onset, but longer half-life (5-7 hours) than other non-benzodiazepines, likely making it better for sleep maintenance FDA-approved for long-term use with studies up to 6 months showing no evidence of tolerance |
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describe zaleplon (sonata)
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Ultra-short elimination half-life of 1 hour
Lack of daytime sedation, less psychomotor impairment or memory impairment Dose appropriately – 10mg has been shown to decrease sleep latency to sleep persistence Doses up to 20mg per night may be considered Take before going to bed or after lying in bed and having difficulty sleeping (up to 4 hours before wake time) Middle of the night dosing evaluated |
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OTC insomnia therapy: valerian root
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Mechanism unknown, effects at GABA receptors have been suggested
Dose: range from 1.5 to 3gm of actual herb or root (400-900mg of extract) Generally regarded as safe, but hepatotoxicity has been reported Do not use in patients with liver dysfunction Avoid use with other sedating drugs including benzodiazepines |
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how is H1 associated with sedation?
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H1 binding associated with muscarinic (anticholinergic) and adrenergic binding
Commonalities: Next day “hangover” effect Weight gain Anticholinergic side effects (“SLUD”) Tachyphylaxis |
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what is the goal of sedation through H1 receptor binding?
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to identify a new drug or dose of existing drug that will bind histamine, but not other receptors
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what is an example of a new drug that binds only H1 receptors?
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TCA with antidepressive maintenance dose of 150-300mg per day
High affinity for histamine receptors; low-affinity for muscarinic, serotonin, norepinephrine, and alpha receptors Recent trials evaluating doxepin 1, 3, and 6mg (low dose= H1 binding only) |
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TCAs in insomnia treatment
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Nortriptyline, amitriptyline, doxepin
All provide sedation through binding to H1-receptors Effective for inducing sleep continuity, daytime sedation is significant Disadvantages: side effects - dry mouth, dry eyes, constipation, urinary retention, dizziness upon standing ***use caution in the elderly |
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side effects of TCAs
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dry mouth, dry eyes, constipation, urinary retention, dizziness upson standing
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trazodone in insomnia treatment
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Sedation through H1-receptor binding improves sleep continuity
Popular choice for insomnia in patients prone to substance abuse Frequently used in SSRI- and bupropion-induced insomnia at doses of 25-75mg Side effects: serotonin syndrome, oversedation, dizziness, priapism (1:6,000 men) Minimal data to support its use |
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which receptor does trazodone work on?
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H1 receptor binding
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mirtazepine (Remeron) in insomnnia treatment
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Mirtazapine (Remeron®)
7.5mg, 15mg, 30mg, 45mg tablets Sedation and weight gain are more prominent at lower doses High affinity for H1-receptors and has also been shown to increase melatonin Good choice for thin, depressed elderly patient with insomnia |
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which drug option is the best for a thin elderly person with insomnia?
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mirtazepine
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atypical antipsychotics in insmonia treatment
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Quetiapine, ziprasidone, risperidone, olanzapine, aripiprazole
Side effects: EPS, dry mouth, orthostasis |
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why/when are atypical antipsychotics used for insomnia
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when comorbid psychiatric illness exists (not primary care)
also b/c more selective for histamine |
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antihistamines used to treat insomnia
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diphenhydramine
doxylamine |
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use of antihistamines in insomnia treatment
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Diphenhydramine and doxylamine
Both FDA-approved for insomnia treatment Other 1st-generation antihistamines could work Sedation through H1 receptor binding Anticholinergic side effects limit use in elderly Constipation, dry eyes, dry mouth, urinary retention, confusion Found in several OTC sleep-specific aids Unisom®, Tylenol PM®, Advil PM® ****use caution in the elderly |
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what drug is a melatonin agonist?
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ramelteon (Rozerem)
Mechanism: high affinity for M1 and M2 melatonin receptors to aid sleep promotion and maintain the circadian rhythm Highly metabolized by the liver (1.8% reaches bloodstream) |
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advantages of ramelteon
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Not a controlled substance, does not produce residual effects (memory impairment, daytime sedation), long-term use acceptable
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warnings for ramelteon
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Warnings:
Do not use with Luvox® (fluvoxamine) or in liver failure Can cause increased prolactin levels (cessation of menses, decreased libido, galactorrhea in females) Lack of good clinical data – role currently undefined No trials evaluating it compared to current hypnotic agents |
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herbal melatonin agonists?
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melatonin supplement
Hormone from the pineal gland to maintain sleep/wake cycle Dosing ranges from 0.3mg to 5mg Normal daytime concentration: 2-10 pg/ml, Normal nighttime concentration: 100-200 pg/ml Too much can cause daytime sleepiness, impaired mental and physical performance, and hyperprolactinemia Adjustment Insomnia (shift work, jet lag) Avoid use with warfarin, fluvoxamine, liver dysfunction, seizure disorder, or in children |
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key points for insomnia
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The diagnosis of insomnia requires a sleep disturbance plus impaired functioning with adequate opportunity to sleep
Secondary causes of insomnia must be evaluated, identified, and treated Pharmacotherapy must be used to reinforce non-pharmacologic therapy Patient age and co-morbidities, and duration of action, side effect profile, and cost of medication should drive selection |
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antianxiety sedative defn
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BZDs for anxiety disorders
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antidepressents
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mood elevating agents
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mood stabilizing drugs
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lithium
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antipsychotic/neuroleptic drugs
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used to treat psychosis and mania
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psychotropic drugs
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acting on the mind
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mood vs affect
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mood: sustained/persistent emotional state (climate)
affect: emotional display from moment to moment (weather) |
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types of depression
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reactive (most common)
major depression(endogenous) bipolar(manic depressive) |
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reactive depression features
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Loss (life events)
illness, drugs (antihypertensives, alcohol, hormones), senility >60% cases Symptoms: depression, anxiety, tension, guilt. May respond spontaneously |
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major depression features
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Precipitating life events do not explain the level of depression. Unresponsive to changes in life. May occur at any age (childhood-old age). Biologically determined (family history
25% of all cases. Core syndrome plus “vital” signs: abnormal:abnormal sleep, motor activity, libido, appetite. Responds to antidepressants, ECT. Recurs through life |
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bipolar depression features
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Characterized by episodes of mania. Cyclic; mania alone is rare. Depression alone is occasional. Usually observe mania-depression
10-15% of cases. May be misdiagnosed as endogenous. Lithium stabilizes mood. Mania may require antipsychotic drugs also. Depression managed with antidepressants |
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older drugs to treat depression
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Tricyclic compounds (e.g. imipramine, amitriptyline)
Monoamine Oxidase Inhibitiors (MAOIs) (e.g. tranylcypromine) |
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newer drugs to treat depression
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Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. fluoxetine, fluvoxamine)
Atypical drugs (e.g. bupropion, trazodone, mirtazapine |
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NE reuptake inhibitors (TCAs)
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amytriptyline
desipramine maprotiline |
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SSRIs
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fluoxetine
venlafaxine fluvoxamine |
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atypical antidepressents
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bupropion
mirtazepine nefazodone trazodone |
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MAOIs
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phenelzine
tranylcypromine selegiline |
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SNRIs
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venlafaxine (5HT>NE)
amitriptyline (NE>5HT) |
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atypicals that block 5HT uptake
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trazodone
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how do heteroceptor mechs work with SSRIs and TCAs?
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SSRIs increase NE
TCAs increase 5HT |
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structure activity relationship of TCAs
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THREE ring structure that resembles phenothiazine antipsychotics...
antihistamin structure |
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structure activity relationship of SSRIs
why advantageous compared to TCAs |
Major drawback of older drugs (TCAs) is “multiple or diverse” pharmacological actions e.g. antihistamine, anticholinergic, alpha receptor blockade etc
SSRIs are more selective ( for serotonin vs NE |
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structure activity relationship of MAOIs:
hydrazide vs. nonhydrazide |
Hydrazide structure: e.g. phenelzine, isocarboxazid (no longer marketed)
Non hydrazide structure: e.g. tranylcypromine Older MAOIs inhibited both MAOB and MAOA Newer drugs e.g. Deprenyl inhibits MAOB not MAOA |
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ADME TCAs
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Significant 1st pass metabolism
High protein binding High lipid solubility Large volumes of distribution (Vd) Metabolism: Phase I: ring structure (CYP1A2, CYP3A4) and aliphatic side chain, Phase II: glucuronide conjugation Active metabolites of some agents |
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ADME SSRIs
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Venlafaxine has a short elimination t1/2 ~5 hr
CYP3A4 Bioactivation: Fluoxetine has an active metabolite, norfluoxetine with t1/2 of 7-9 d Inhibition of drug metabolizing enzymes (**P450) CYP2C9-Fluvoxamine CYP2C19-Fluvoxamine CYP2D6-Fluvoxamine, fluoxetine, sertraline CYP3A3/4- Fluvoxamine, nefazodone |
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ADME atypical drugs
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Active metabolites
trazodone, nefazodone, bupropion into amphetamine-like compounds Some have extremely short t1/2 t1/2 of nefazodone is 3 hr t1/2 of trazodone is 6 hr |
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ADME MAOIs
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Measuring MAO activity (inhibition) is a better predictor of drug effect than drug levels
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biogenic amine theory of depression
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Biogenic Amine Theory Depression results from decreased amine (NE, 5HT) dependent synaptic transmission I.e. decreased availability of amines.
According to this hypothesis, depression can be alleviated by drugs that increase the availability of NE and 5HT This can be achieved by Inhibition of MAO, an enzyme that degrades monoamines Inhibiting neurotransmitter re-uptake e.g. TCAs Based on mechanism of reserpine action: Reserpine depletes amines (catecholamines, 5HT) and produces depression May explain action of major antidepressant classes: TCA, MAOIs, SSRIs increase NE/5HT neurotransmission |
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drawback of biogenic amine theory
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NE and 5HT levels increase immediately following MAOIs and TCAs. However, a person suffering from depression may not experience significant relief for as long as 6 to 8 weeks.
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supersensitivity theory of depression
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Supersensitivity Theory (up-regulation)
Supersensitivity is a compensatory response of the postsynaptic neuron when it receives too little stimulation by agonists. The neuron tries to make up for a lack of stimulation by increasing receptor responsiveness. Over time, the postsynaptic neuron may also compensate for lack of stimulation by synthesizing additional receptor sites. This process is known as up-regulation. This hypothesis proposes that depression is the result of a adaptive changes (supersensitivity and up-regulation) in receptor sites, which results from too little stimulation by monoamines, i.e., a deficiency of NE and 5HT in the cleft. Chronic administration of TCAs or MAOIs alters the responsiveness and/or the number of postsynaptic receptor sites |
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serotonin only hypothesis of depression
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Based on the effects of drugs known as selective 5HT reuptake inhibitors, or SSRIs.
Serotonin-only Hypothesis emphasizes the role of 5HT in depression and downplays NE. |
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drawbacks to serotonin only hypothesis of depression
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Does not explain why there is a delay in onset of clinical relief
Does not explain the role of NE in depression |
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permissive hypothesis of depression
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Suggests that mood is controlled by a balance of NE and 5HT, not by absolute levels of these neurotransmitters or their receptors.
According to this hypothesis, the control of emotional behavior results from a balance between 5HT and NE. The Permissive Hypothesis suggests that low levels of 5HT permit abnormal levels of NE to cause depression or mania. If 5HT cannot control NE, and NE falls to abnormally low levels, the patient becomes depressed. On the other hand, if the level of 5HT falls and the level of NE becomes abnormally high, the patient becomes manic. |
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epidemiology of depression
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Lifetime incidence of 12% (men) and 20% (women)
Highest rates among adults 25-44 years old ~8-18% have a first degree relative with h/o depression More common in populations with a great burden of medical care (e.g. nursing homes, hospitals, those suffering from multiple medical conditions) |
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pathophysiology of depression
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Monoamine-deficiency – lack of, or lack of response to serotonin and norepinephrine
Agents that increase these can treat depression Depleting these in humans can cause a relapse of depression (but not an initial episode) People with depression may have serotonin receptors that are less sensitive Dopamine may also play a role Frequent depression in Parkinson’s disease Bupropion – inhibits the reuptake of dopamine Dopamine-agonists may be effective |
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what is the MAIN reason for depression
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monoamine deficiency
serotonin and NE |
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things needed for diagnosis of depression
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depressed mood
Depressed mood Diminished interest or pleasure Weight loss, gain (appetite) Insomnia or hypersomnia Psychomotor agitation or retardation Fatigue or loss of energy Feelings of guilt/worthlessness Concentration difficulty Thoughts of death Suicidal ideation |
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requirements for depression diagnosiss
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Symptoms present daily for at least 2 weeks
Clinically significant distress or impairment Social, occupational, or other functioning Not due to a substance or medical disorder Not better accounted for by bereavement Not a manifestation of bipolar disorder |
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clinical rating scales for depression
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NOT for diagnosis, screening tools to identify and assess severity along with treatment effect
Hamilton Rating Scale for Depression (Ham-D) Filled out by the health care professional Mild (10-13), Mild-moderate (14-17) Moderate-severe > 17) Beck Depression Inventory Filled out by the patient Mild (<15), Moderate (15-30), Severe (> 30) |
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what are clinical rating scales for depression used for?
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NOT diagnosis
they are used for screening to identify and assess severity along with treatment effect |
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what must all patients with depression be screened for?
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suicide
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why screen for suicide?
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8th leading cause of death in the U.S.
Detailed plan with the intention and ability to carry it out indicates a high risk of suicide Suicidal ideation is a medical emergency Change in personality, decision to make a will or give away possessions, purchase of a gun or toxic substance Suicide risk may increase in a person recovering from depression Use caution with antidepressant and quantity you choose |
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what are conditions to rule out for depression
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Hypothyroidism, anemia
Influenza, mononucleosis Electrolyte imbalances Psychiatric disorders Alcoholism, anxiety disorders, schizophrenia Bipolar disorder |
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what baseline exams should depression patients have?
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All patients should have a physical exam, mental status exam, CBC, thyroid function test, and electrolyte panel
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drug classes that can precipitate/worsen depression
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antihypertensives
hormone therapy acne therapy dopamine antagonists |
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antidepressant options
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Selective Serotonin Receptor Inhibitors (SSRI’s)
Tricyclic antidepressants (TCA’s) Serotonin-Norepinephrine Reuptake Inhibitors (SNRI’s) Miscellaneous: Trazodone Bupropion Mirtazapine Atypical Antipsychotic - Abilify® (aripiprazole) Monoamine Oxidase Inhibitors (MAOI’s) |
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SSRIs for depression
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Mechanism
selective reuptake inhibition of serotonin First-line therapy Similar or superior efficacy to others Lower side effects, safer, convenient dosing Generally choose cheapest available Recognize differences between agents |
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which SSRI has longest half life
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fluoxetine
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which SSRI is most activating?
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fluoxetine
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which SSRI is most sedating?
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paroxetine
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TCAs for depression MOA
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Mechanism: block the reuptake of NE and 5-HT
Also bind to α1, histamine-1, and muscurinic receptors (anticholinergic side effects) |
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tertiary vs secondary amine TCAs
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Tertiary cross the blood-brain barrier (BBB) and therefore have more CNS side effects
More sedation, confusion, anticholinergic side effects (SLUD) Amitriptyline most common tertiary TCA Nortriptyline most common secondary TCA |
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how are TCAs used for depression?
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2nd or 3rd line therapy for monotherapy
Good efficacy, but high rate of side effects Use extreme caution in the elderly SLUD, confusion Main use is augmentation or in patients who have certain co-morbid conditions Neuropathic pain, depression with insomnia May be superior for severe or melancholic depression |
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MOA SNRIS
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selective serotonin and norepinephrine reuptake inhibition
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side effects of SNRIs
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Bind α1 and ß1 receptors
Increased HR, BP (HTN), tremor, agitation Dizziness Stimulation of noradrenergic receptors in the sympathetic nervous system net reduction in cholinergic tone “Pseudoanticholinergic” – dry mouth, constipation, urinary retention |
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venlafaxine
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Effexor (immediate release)
Dosage forms: 25, 37.5, 50, 75, 100mg tablets Dose 37.5mg BID/TID, increase by 75mg every week to max of 225mg Effexor XR (extended release) Dosage forms: 37.5, 75, 150mg capsules Dose 37.5-75mg QD initially, increase by 75mg every week to maximum of 225mg |
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high/low dose venlafaxine
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37.5 BID/TID
max 225 mg/day XR: 37.5/day max 225 mg/day |
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duloxetine
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Cymbalta (delayed release)
Dosage forms: 20, 30, 60mg capsules Dose: 20mg BID initially, titrate up to 60mg daily (once daily or 30mg BID) Also has indications for diabetic peripheral neuropathy and generalized anxiety disorder |
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duloxetine high/llow dose
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20BID
Max 60 mg/day |
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desvenlafaxine
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Pristiq® (desvenlafaxine)
Venlafaxine -2D6->desvenlafaxine Has greater NE reuptake inhibition Easier to dose, more predictable response 50mg daily, 100mg tablet available |
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trazodone
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Mechanism
Block 5-HT reuptake & 5-HT2a & 5-HT2c receptors Also block histamine-1 and α1 receptors Higher doses needed to block reuptake and receptors – difficult to tolerate Dosage forms: 50, 100, 150, 300mg tablets Dose: 50-150mg TID initially, increase by 50mg weekly to maximum of 400mg Commonly used at low dose in SSRI- or buproprion-induced insomnia |
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trazodone high/low dose
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50-100 TID
Max 400 mg/day |
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bupropion
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Mechanism
Weak inhibitor of norepinephrine and dopamine uptake, no effect on serotonin Lowers the seizure threshold, especially in bulimic patients Contraindicated in bulimic and anorexic patients Immediate release higher incidence, may be due to peak concentrations Can be added to SSRI Does not cause sexual dysfunction |
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dosing for bupropion
IR, SR, XL |
Dose:
Wellbutrin: 100mg BID x 3 days, then 100mg TID (max = 450mg TID-QID) Wellbutrin SR: 150mg QD x 3 days, then 150mg BID (max = 200mg BID) Wellbutrin XL: 150mg QD x 3 days, then 300mg QD (max = 450mg QD) |
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mirtazapine
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Mechanism:
Enhances the release of 5-HT/NE by blocking α2-adrenergic autoreceptors and 5-HT2A/5-HT2C Little affinity for α1 or muscurinic High affinity for histamine-1 receptors Sedation, weight gain (appetite increase), and dry mouth are more prominent at lower doses useful for thin, depressed geriatric pt. w/ insomnia |
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mirtazapine high/low dose
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7.5 QHS
max 45 mg |
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MAOIs
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Phenelzine, tranylcypromine
Non-selective for MAOA and MAOB Mechanism: Inhibit the monoamine oxidase (MAO) enzyme to increase NE, 5-HT, and DA Last resort for treatment of depression, and only prescribed by those with experience using them Side effects: hypotension and anticholinergic Wait 2 weeks after stopping other antidepressants (5 weeks for fluoxetine) Wait 2 weeks when switching from MAOI *Last resort for depression |
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MAOIs serotonin syndrome
medication restrictions |
Amphetamines
Appetite suppressants Buspirone Carbamazepine Decongestants Pseudoephedrine Phenylpropanolamine Dextromethorphan Levodopa Methylphenidate Methyldopa Sumatriptan Tryptophan Other antidepressants Cyclobenzaprine Ephedrine Dopamine *not all inclusive, screen all medications |
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three phases of pharmacotherapy for depression
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Acute: achieve remission, 6-12 weeks
Continuation: keep symptoms in remission using full-dose therapy, 6-12 months Maintenance: long-term therapy for those at high risk for relapse (prior episodes, strong family history) |
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adequate trial for depression pharmacotherapy
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Full therapeutic doses for 6-8 weeks and in some cases up to 12 weeks (if no response, failure)
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response defn
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Usually defined as a 50% reduction in symptoms
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remission defn
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A return to normal mood and normal functioning
Use Ham-D (< 6 is remission) or other clinical rating scale to monitor for response and remission If a drug has given a response, you can possibly obtain remission by adjusting the dose or augmenting the therapy |
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considerations in agent selection initial depression therapy
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Cost, dosing convenience
Co-morbidities (e.g. depression with insomnia) Side effect profile Previous response to therapy, family members response to therapy Drug-drug/drug-disease interactions Prefer SSRI’s as first-line therapy |
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antideprresant drug selection for peripheral neuropathy
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duloxetine, TCA, venlafaxine
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antidepressant drug selection for insomnia
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mirtazapine, TCA, trazodone
paroxetine, citalopram, escitalopram |
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antidepressant drug selection for concurrent anxiety
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SSRIs that cause more sedation, paroxetine, citalopram, escitalopram
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antidepressant drug selection for erectile dysfxn
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bupropion, mirtazapine, duloxetine
b/c no 5HT effects |
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STAR D Trial
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Outpatients with non-psychotic major depressive disorder eligible for medication as first step
Not achieving remission or not tolerating a step gave eligibility for next step Goal: Identify what it takes to achieve remission in patients with depression Sponsored by the NIH 1st large study providing guidance on which therapy to choose and why Previously, algorithms based on expert clinical opinion |
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level 1 STAR D Trial
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Level 1: All received citalopram
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level 2 STAR D Trial
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Level 2: those who did not have remission or did not tolerate citalopram had several options
Switch: cognitive therapy, venlafaxine XR, sertraline, or bupropion SR Augment: add cognitive therapy, bupropion SR, or buspirone Participants could decline all 3 augmentation, all 4 switch, either or both cognitive, or all except cognitive therapy |
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results STAR D Trial Level 1
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Level 1
1/3 had remission and ½ had a response Mean citalopram dose = 55mg, ~12 weeks treatment |
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results STAR D Trial level 2
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Level 2
Switch: Bupropion SR, Sertraline, Venlafaxine XR ¼ had remission, ¼ had response Not significantly different – all considered acceptable Augment: Citalopram + bupropion SR or buspirone 1/3 had remission, 1/3 had response Bupropion SR was better tolerated and may have better reduction than buspirone |
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what are steps 3-4 used for in STAR D trial?
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reserved for psychiatrists or those highly experience with depression
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Star D Switch therapy
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Switch therapy
Citalopram was discontinued without a tapering or washout period Bupropion SR 150mg x 7, 200mg x 20, 300mg x 14, 400mg Sertraline 50mg x 14, 100mg x14, 150mg x 35, 200mg Venlafaxine 37.5mg x 7, 75mg x 7, 150mg x 14, up to 375mg |
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Star D augmentation therapy
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Augmentation therapy
Bupropion SR 200mg x 14, 300mg x 14, 400mg Buspirone (indicated for generalized anxiety) 15mg x 7, 30mg x 7, 45mg x 21, 60mg |
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Star D conclusions
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Conclusions
Switching therapy or augmenting therapy are both viable options for initial failure |
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suggested algorithm based on Star D Trial
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1. Initiate SSRI as first line therapy, if appropriate
2. If response, but not remission, augment with bupropion SR (preferred) or buspirone 3. If no response, switch to sertraline, venlafaxine XR, or bupropion 4. After these steps, refer to a psychiatrist |
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options for resistant depression
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Augment SSRI
Low dose TCA (25-50mg of most) Low-medium dose mirtazapine (15-30mg) Augment antidepressant Lithium (blood level goal of 0.6-1.0 mEq/L) Thyroid hormone (50-75mcg triiodothyronine) Add atypical antipsychotic Add stimulant (e.g. methylphenidate) Add anticonvulsant (lamotrigine 100-200mg) Switch to an MAOI ****Reserve for psychiatrists or those highly experienced with depression |
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Treatment duration acute phase
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May require hospitalization if suicide risk or psychosis with risk to self and others
Generally 6-12 weeks Goal: obtain remission Start low dose, titrate to max tolerated Augment or switch, if necessary |
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Treatment duration maintenance phase
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Maintenance phase:
Continue therapy for 12-36 months or indefinitely to prevent relapse High risk patients Multiple episodes of depression Previous suicidal risk Chronic major depression or dysthymia (low-grade depression) Strong family history of resistant depression |
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high risk patients in need of maintenance depression treatment
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High risk patients
Multiple episodes of depression Previous suicidal risk Chronic major depression or dysthymia (low-grade depression) Strong family history of resistant depression |
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blackbox warning
serotonin and suicide |
FDA Black Box Warning for all antidepressants
Risk of suicidality in children, adolescents, and adults younger than 25 years Clearly warn the patient and family about risk Patient Medication Guide distributed with each new prescription and refill Risk appears greatest in the first few weeks of therapy Monitoring: Weekly visits for first 4 weeks Biweekly until 12 weeks As clinically indicated beyond 12 weeks |
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serotonin syndrome symptoms
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hyperreflexia, tremor, clonus, diaphoresis, agitation, HTN, increased bowel sounds (diarrhea), mydriasis
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role of the pharmacist in depression
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Serotonin Syndrome
How do I identify it? When should I call the physician when a drug interaction seems possible? Patient counseling Onset of effect Side effect profile Therapeutic recommendations Selection of least expensive product Choosing agent given side effects |