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296 Cards in this Set
- Front
- Back
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Presentation in Adults of adhd
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Male to female ratio closer to 1:1
Hyperactivity is less overt because better compensation Adult symptoms Attention span dysfunction Limited/problematic time management skills Poor frustration control Sleep dysfunction (i.e., insomnia) Motivational dysfunction Talk too much, too fast unimportant tasks become more important |
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Differential Diagnosis in adults
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Psychiatric disorders
Depression Bipolar I disorder Generalized anxiety (GAD) Long-term alcohol or marijuana abuse Antisocial personality disorder Medical conditions Hyperthyroidism Petit mal and partial complex seizures Hearing deficits Sleep apnea Medication side effects or interactions Traumatic brain injury (TBI) Note: many of these may be comorbid with ADHD |
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screening tool for adhd
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a serious of questions
that is very easy to administer and provides a physician an opportunity to address adhd with the patient |
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General Principles of treatment of adhd in children
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“It takes a village…”
Must collaborate with parents, teachers, pediatrician, other healthcare providers Behavioral therapy Pharmacotherapy is mainstay Should recognize and treat as a chronic condition Per parent reports, 60-80% persist from childhood into adolescence takes a group effort |
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is adhd treated as and acute or chronic disorder
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chronic
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Non-Pharmacologic Treatment of adhd for children
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Behavioral therapy
Psychotherapy Cognitive behavioral therapy (CBT) Psychosocial interventions, e.g., biofeedback Parenting strategies Immediate and frequent feedback More powerful consequences Strive for consistency Use incentives before punishment Plan ahead for problem situations |
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Treatment Algorithm of adhd in children
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Summary:
Stage 1 – Stimulant Treatment Amphetamine vs. mixed-salts amphetamine Stage 2 – Alternative Stimulant (if failed the 1st one) Stage 3 – Atomoxetine Combine atomoxetine and stimulant or can just use atomoxetine Stage 4 – Antidepressant treatment* Stage 5 – Alternative Antidepressant* Stage 6 – Alpha agonists* stages 4, 5, and 6 need to be preformed by a specialist |
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Treatment Clinical Pearls in children of adhd
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About 85% of children will respond to a stimulant
if given systematic trials Medication side effects are often transient Continue x 2 weeks to see if they resolve |
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Background for treatment of adhd in adults
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Treatment extrapolated from treatment of children
Behavioral therapy may play a role Risks for and concern with side effects may differ |
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Stimulant Use in Adults for adhd
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Most commonly used medication for treatment of
ADHD in adults Improve focus and concentration – improve daily cognitive function Improved driving demonstrated Appear less effective in adults vs. children Response rates appear lower extrapolate from children to adults |
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Concerns with Stimulant Use for adhd
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Addicting nature of ADHD
Potential for long-term use Possibility of multiple co-morbidities Cardiovascular side effects Increased heart rate and blood pressure (not typically a problem in children, more so in adults with comobid conditions or strong family history) Potential for cardiac arrest, arrhythmias, stroke |
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Suggested Algorithm for treatment of adults for adhd
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Adult with ADHD – concern with stimulant therapy?
Yes: Non-stimulant trial No: Stimulant trial |
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FDA Approved Agents for adhd
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Stimulants
Methylphenidate Dextroamphetamine Dexmethylphenidate Mixed amphetamine salts Non-stimulants Atomoxetine Selective norepinephrine reuptake inhibitor |
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what do stimulants target to treat adhd
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Dopamine & norepinephrine
effects: •Improve attention •Sustain focus •Increase impulse inhibition |
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Non-FDA Approved Agents for adhd
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Antidepressants<br /> Bupropion<br /> Imipramine<br /> Nortriptyline<br /> Alpha agonists<br /> Clonidine<br /> Guanfacine<br /><br />•Not as much evidence<br />•More side effects<br />•Less efficacious<br />•2nd line agents<br /><br />for the treatment of stages 4,5, and 6
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lant Medications for adhd
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First-line therapy
C-II controlled substances All are equally efficacious Patient-specific factors may dictate product chosen Doses are not weight-based Start with low doses, titrate up to effect |
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SE of stimulants
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Side Effects
Anorexia Insomnia Stomach aches HA Tachycardia Irritability Linear growth suppression |
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moitoring for stimulants
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Height, weight, BP, pulse
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is insomnia a bigger problem with LA or IR stimulants
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LA
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why do you monitor weight with stimulants
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because they cause anorexia
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Stimulant Medications black box warning
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Methylphenidate hydrochloride should be given cautiously to
emotionally unstable patients, such as those with a history of drug dependence or alcoholism, because such patients may increase dosage on their own initiative.” don't use as first line in patients with substance abuse porblems |
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Stimulant Medications and CV risk
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Sudden death has been reported in association with CNS
stimulant treatment at usual doses in children & adolescents having structural cardiac abnormalities or other serious heart problems. A careful history & physical exam is recommended before prescribing these medications. If potential risk is identified, further cardiology evaluation is recommended. death mainly occured inpatients with underlying heart conditins that they did not know about need a baseline EKG and appropriate screening |
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stimulant contraindications
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Marked agitation, anxiety, and tension
Glaucoma Hypersensitivity to active or inactive ingredients Motor tics Tourette’s Syndrome Cardiovascular disease MAOI use Do not use a stimulant medication within 14 days of discontinuing the MAOI |
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are seizures are absolute contraindications for stimulant use
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no, relative because stimulants can decrease seizure threshold so use with caution
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Stimulation Medications:
Addressing Side Effects insomnia |
Switch from long-acting to intermediate or short-acting
For IR, decrease or D/C afternoon dose Adjunctive medication: clonidine, trazodone, anti-histamine |
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Stimulation Medications:
Addressing Side Effects Tic development |
Switch to another stimulant or to atomoxetine
Stimulant + α-agonist for tics |
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Stimulation Medications:
Addressing Side Effects Appetite suppression/weight loss |
Give high-calorie meal when stimulant effects are low
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with all Side Effects of stimulants
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Regular follow-up and monitoring
BP, HR, height, weight, mood changes, other |
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Metadate® CD
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Diffucaps: biphasic release 30% IR, 70% ER
Can be sprinkled on food |
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Ritalin® LA
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SODAS: spheroid oral drug absorption system
50% IR, 50% ER |
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Focalin® XR
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Also employs SODAS technology (50/50)
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Adderall® XR
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50% IR, 50% ER – PK profile similar to IR Adderall given BID
this makes it easy to switch between IR and LA because the have similar pk but LA is QD |
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Concerta®
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OROS (Osmotic Release Oral System)
Immediate release occurs in the outer covering, followed by an 8-hour release through the osmotic pump the push compartment expands with water and the IR is released first and then the LA so it has a quick onset in addition to LA allows for a smoother drug concentration throughout the day In theory, this prevents abuse… |
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COncerta copared to methylphenidate
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M: has more peaks and troughs because doesd TID
C: much smoother drug concentrations of a single dose of concerta |
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Daytrana®
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Not approved for use in adults
Begin with 10mg patch QAM, titrate up by 5mg QAM every week – Do not cut! (destroys release mechanism) Apply to the hip 2 hrs prior to needed effect, remove 9 hrs after application (don't apply to other areas because don't know the absorption profile) |
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Daytrana® advantages and disadvantages
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Advantages
Convenient Good for kids who can’t or won’t take oral meds Disadvantages Needs to be applied for 2 hrs for effect to manifest 1st peak – 2-3 hrs, 2nd peak – 6-8 hrs 9 hr application provides at least 12 hrs of coverage SE incidence increases if used > 9 hrs Application site is easily accessible by child Contact sensitization can occur |
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once you get the contact sensitization due to Daytrana® what does this result in
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there is a cross sensitivity to all other stimulants so it elminates the majority of treatment options for adhd
that is way daytrana is a last option |
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Vyvanse® (lisdexamphetamine)
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FDA-approved in February 2007 in children and
adults 20, 30, 40, 50, 60, and 70 mg capsules Amphetamine pro-drug bound to l-lysine Hydrolysis releases dextroamphetamine slowly Potentially lower abuse: Less reinforcement, less euphoria, later peak effect $$$$$ |
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Vyvanse® (lisdexamphetamine)
Clinical Pearls: |
Clinical Pearls:
Was designed by manufacturer to shift market share from Adderall XR to new product Claims of lower abuse potential likely not valid Cannot be snorted or injected, but can still be abused orally Still C-II controlled substance No advantage with regard to efficacy, side effects, convenience, or cost |
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Controlled Substance
Schedule II |
High potential for abuse
Currently accepted medical use Use may lead to severe psychological or physical dependence |
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Legal Dispensing C-II
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Misuse & Diversion
10-yr longitudinal study of youths with ADHD 22% had misused stimulants, 11% had diverted it Misuse of stimulants as “study-enhancing drugs” |
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Red Flags for Diversion
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Continuously escalating doses
Infrequent user (e.g., 1 rx every 6 mos.) ↑ symptoms of psychosis Palpitations, syncope, SOB Lost prescriptions or pill count disagreement “Emergency supply” requests Requests for immediate-release only |
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Vyvanse® (lisdexamphetamine)
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FDA-approved in February 2007 in children and
adults 20, 30, 40, 50, 60, and 70 mg capsules Amphetamine pro-drug bound to l-lysine Hydrolysis releases dextroamphetamine slowly Potentially lower abuse: Less reinforcement, less euphoria, later peak effect $$$$$ |
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Vyvanse® (lisdexamphetamine)
Clinical Pearls: |
Clinical Pearls:
Was designed by manufacturer to shift market share from Adderall XR to new product Claims of lower abuse potential likely not valid Cannot be snorted or injected, but can still be abused orally Still C-II controlled substance No advantage with regard to efficacy, side effects, convenience, or cost |
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Vyvanse® (lisdexamphetamine)
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FDA-approved in February 2007 in children and
adults 20, 30, 40, 50, 60, and 70 mg capsules Amphetamine pro-drug bound to l-lysine Hydrolysis releases dextroamphetamine slowly Potentially lower abuse: Less reinforcement, less euphoria, later peak effect $$$$$ |
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Vyvanse® (lisdexamphetamine)
Clinical Pearls: |
Clinical Pearls:
Was designed by manufacturer to shift market share from Adderall XR to new product Claims of lower abuse potential likely not valid Cannot be snorted or injected, but can still be abused orally Still C-II controlled substance No advantage with regard to efficacy, side effects, convenience, or cost |
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Controlled Substance
Schedule II |
High potential for abuse
Currently accepted medical use Use may lead to severe psychological or physical dependence |
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Controlled Substance
Schedule II |
High potential for abuse
Currently accepted medical use Use may lead to severe psychological or physical dependence |
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Legal Dispensing C-II
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Misuse & Diversion
10-yr longitudinal study of youths with ADHD 22% had misused stimulants, 11% had diverted it Misuse of stimulants as “study-enhancing drugs” |
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Legal Dispensing C-II
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Misuse & Diversion
10-yr longitudinal study of youths with ADHD 22% had misused stimulants, 11% had diverted it Misuse of stimulants as “study-enhancing drugs” |
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Red Flags for Diversion
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Continuously escalating doses
Infrequent user (e.g., 1 rx every 6 mos.) ↑ symptoms of psychosis Palpitations, syncope, SOB Lost prescriptions or pill count disagreement “Emergency supply” requests Requests for immediate-release only |
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Vyvanse® (lisdexamphetamine)
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FDA-approved in February 2007 in children and
adults 20, 30, 40, 50, 60, and 70 mg capsules Amphetamine pro-drug bound to l-lysine Hydrolysis releases dextroamphetamine slowly Potentially lower abuse: Less reinforcement, less euphoria, later peak effect $$$$$ |
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Red Flags for Diversion
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Continuously escalating doses
Infrequent user (e.g., 1 rx every 6 mos.) ↑ symptoms of psychosis Palpitations, syncope, SOB Lost prescriptions or pill count disagreement “Emergency supply” requests Requests for immediate-release only |
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Vyvanse® (lisdexamphetamine)
Clinical Pearls: |
Clinical Pearls:
Was designed by manufacturer to shift market share from Adderall XR to new product Claims of lower abuse potential likely not valid Cannot be snorted or injected, but can still be abused orally Still C-II controlled substance No advantage with regard to efficacy, side effects, convenience, or cost |
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Controlled Substance
Schedule II |
High potential for abuse
Currently accepted medical use Use may lead to severe psychological or physical dependence |
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Legal Dispensing C-II
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Misuse & Diversion
10-yr longitudinal study of youths with ADHD 22% had misused stimulants, 11% had diverted it Misuse of stimulants as “study-enhancing drugs” |
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Red Flags for Diversion
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Continuously escalating doses
Infrequent user (e.g., 1 rx every 6 mos.) ↑ symptoms of psychosis Palpitations, syncope, SOB Lost prescriptions or pill count disagreement “Emergency supply” requests Requests for immediate-release only |
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Legal Dispensing C-II
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“Post-dating” by prescriber constitutes refilling
and is not considered acceptable Can prescribe more than 1-month at a time Date appropriately! Should be evaluating height, weight, BP/HR at periodic intervals C-II requires a new, signed prescription with every fill Appropriately log C-II dispensing |
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Colorado Prescription Drug Monitoring Program
(Colorado PDMP) |
Tracks prescribing and dispensing of controlled
substances Bi-weekly updates Tracks patient name, address, insurance/cash, prescriber, drug, quantity, fill date, pharmacy utilized interns cannot sign up |
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Atomoxetine (Strattera®)
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FDA-approved in children and adults
Norepinephrine reuptake inhibitor 2nd line therapy for ADHD in children – less effective than Concerta and Adderall XR Not a controlled substance Given 1-2 times daily (2nd dose in evening) Very expensive if given BID (> Daytrana®) Slow onset of therapeutic effect (2-4 weeks) Consider 1st line if active substance abuse disorder, severe side effects from, or contraindications to stimulants slow onset so counsel patient |
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Atomoxetine (Strattera®)
Side Effects: |
GI distress, sedation, and decreased
appetite |
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Warnings of Atomoxetine (Strattera®)
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Case reports of severe liver disease
Suicidal ideation in children and adolescents |
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Bupropion (Wellbutrin, Wellbutrin SR/XL)
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2nd or 3rd line therapy for ADHD (also used for those
who cannot take stimulants) Antidepressant that is effective for inattention and impulsivity Insomnia, agitation, weight loss Too high of doses (> 400mg) can induce seizures Do not use in those with history of seizure disorder or anorexia May not have pill sizes small enough for those < 25 kg |
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Tricyclic Antidepressants (TCA’s)
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2nd or 3rd line therapy for ADHD (also used for those who cannot
take stimulants) Imipramine and nortriptyline are most common Monitoring: Baseline ECG, obtain plasma level once on a stable dose to ensure it’s not in the toxic range “TCA’S” – side effects mnemonic Thrombocytopenia, Cardiac, Anti-cholinergic, Seizure Anti-cholinergic side effects: Dry eyes/mouth, urinary retention, constipation |
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Alpha agonists
Clonidine & Guanfacine |
Prescribed for ADHD itself, for comorbid aggression, or to
combat side effects of tics/insomnia If discontinuing, gradually taper over 1-2 weeks to avoid rebound hypertension Side effects: Bradycardia, hypotension, rebound hypertension Sedation that resolves over 2-3 weeks |
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Conclusions of ADHD
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ADHD is characterized differently in children
compared to adults. In the absence of contraindications, stimulants are safe and 1st-line therapy but must be routinely monitored. Stimulants are C-II’s and pharmacists must prevent misuse and abuse. Both stimulants & non-stimulants are available for treatment of ADHD and are both selected and modified given patient-specific characteristics |
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What is Bipolar Disorder?
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Also called manic-depressive disorder
Consists of recurring episodes of mood disorders from the spectrum of mania to depression Each mood is classified as either manic, hypomanic, depressive, or mixed |
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Depressive Episode for bipolar disorder The following criteria are met for 2 or more weeks
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1 of the following must be met:
depressed mood apathy/loss of interest four or more of these are required weight/appetite changes sleep distribances psychomotor (agitation, retardation) fatigue guilt/worthlessness executive dysfunction suicidal ideation |
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Manic Episode for bipolar disorder dDSM-IV symptoms dimensions of manic episode
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The following criteria are met at least once a week:
elevated/expansive mood irritable mood 3 or more of these must be met: weight/appitite changes increased goal directed activity or agitation risk taking decreased need for sleep distractible/concentration more talkative pressured speech flight ot ideas/racing thoughts |
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Mixed Episode of bipolar
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Rapid alternation of mood
And… DSM-IV manic and depressive episodes occurring simultaneously for at least one week |
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Hypomanic Episode
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Presence of manic symptoms, but not enough to meet criteria for a full manic episode per DSM-IV guidelines
Symptoms lasting at least 4 days Generally, symptoms are less severe |
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Bipolar I
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History of a full manic episode
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Bipolar II
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Major depression and hypomania, no history of mania
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Rapid Cycling bipolar disorder
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More than 4 episodes per year
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Cyclothymia for bipolar disorder
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Persistent alternation between dysthymia and hypomania
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Epidemiology of bipolar disorder
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Affects anywhere from 1-3% of the population
Found in all cultures and ethnicities Equal prevalence among genders Men are more likely to present with an initial manic episode Women are more likely to present with an initial depressive episode |
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Genetic Influence on bipolar disorder is compelling
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Evidence in adoption and twin studies
First-degree relatives of individuals with bipolar disorder have an increased risk of 4% to 24% of having bipolar disorder Some of these studies have been criticized for being small, but results have been very consistent |
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Age of Onset
of bipolar disorder |
Most typical age of onset is in the late teens or early twenties
Some patients have initial episode in early childhood (0.3% to 0.5% of bipolar patients diagnosed at age 10 or less) After age 50, the prevalence of new onset bipolar disorder is thought to decrease Time interval between episodes increases with age However, older adults constitute a similar percentage of psychiatric admissions when compared to young adults |
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Course of Illness of bipolar disorder
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Highly variable from individual to individual
Episode duration depends on severity of illness and whether patient receives treatment Some trends that do exist… >90% of individuals who experience a manic episode will have futures episodes Most manic episodes occur immediately before or after a major depressive episode Psychotic symptoms can occur with any episode type and may present days or weeks after onset 75% of patients return to normal functioning between episodes; remaining 25% have chronic symptoms Differentiating bipolar mood disorder (BMD) from major depressive disorder (MDD) is of critical importance! |
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Consequences of BMD
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All-cause mortality increased, largely due to chronic medical disorders and suicide
Associated with morbidity – severity linked with number of episodes Debilitating to social and occupational functioning Significant economic burden (direct and indirect costs exceed $45 billion per year) |
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Trimonoaminergic Neurotransmitter System: Serotonin, Norepinephrine, and Dopamine and bipolar disorder
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Many symptoms of mood disorders are thought to be due to dysfunction in the trimonoaminergic neurotransmitter system in various areas of the brain
All known pharmacological treatments for mood disorders regulate one or more of these neurotransmitters |
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Serotonin: bipolar disorder
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Regulates aggression, anger, appetite, body temperature, metabolism, mood, sexuality, sleep, and vomiting
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Ne and BMD
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Regulates alertness, arousal, and influences on the reward system
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Da and BMD
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Regulates attention, behavior, cognition, inhibition of prolactin production, learning, mood, motivation, motor activity, reward, and sleep
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glutamate and the monoamines and BMD
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Is an excitatory neurotransmitter that enhances the monoamines
Over-activity of glutamate resulting in dysfunctional neurotransmission Mania… Excitotoxicity resulting in cell death and Depression! Passage of sodium through voltage-sensitive sodium channels (another target for mood stabilizers) may increase glutamate production |
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Gamma-aminobutyric acid (GABA) and the monoamines
and BMD |
Inhibitory neurotransmitter that decreases the effects of the monoamines
Produces anticonvulsant effect May also account for antimanic effects of drugs that boost GABA Also implicated in managing anxiety disorders |
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Theories on the Pathophysiology of Mood Disorders To complicate your life…
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There are many neurobiological pathways and systems involved
A “bipolar storm” of neurotransmitters and chaotic neurotransmission may be a better reflection of what is actually occurring at the synapse However, the current practice of psychopharmacology directs treatment based on the matching of symptoms to neurotransmitter systems that may be “out of tune” |
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depressed mood is caused by
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5HT
NE DA |
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apathy/loss of interest caused by
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NE
DA |
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suicidal tendency caused by
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5HT
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sleep distribances caused by
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5HT
NE DA |
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fatigue caused by
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NE
DA |
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executive dysfunction caused by
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NE
DA |
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psychomotor (retardation and agitation) caused by
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5HT
NE DA |
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weight/appetite changes caused by
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5HT
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gulit/worthlessness caused by
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5HT
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elevated/expansive mood
irriitable mood caused by |
5HT
NE DA |
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inflated self esteem/grandiosity, more talkative pressured speech, flight of ideas/racing thoughts casued by
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5HT
NE DA |
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decreased need for sleep caused by
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NE
5HT DA |
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distractible/concentration casued by
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NE
DA |
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increased goal directed activity or agitation caused by
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5HT
DA |
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primary goals of treatment fo BMD
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Resolve acute symptoms
Prevent future episodes Improve overall function and QOL |
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secondary goals of treatment fo BMD
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Minimize adverse events
Increase response to treatment Promote adherence |
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place in therapy of lithium for BMD
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Introduced for BMD in 1970’s
Indicated for acute mania and for maintenance therapy for BMD Proven to prevent future manic episodes and reduce risk of suicide in patients with depression May be less effective than VPA or carbamazepine for mixed episodes and rapid cyclers Requires 2 – 3 weeks of therapeutic plasma levels to be considered an adequate trial 1st line therapy |
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MOA of lithium
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Not completely understood
Downstream signal transduction cascade targets Monovalent cation, thus competes with Na, K, Ca, and Mg Affects neurotransmitter availability |
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litium monitoring
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Requires close monitoring
Narrow therapeutic index Dosed to achieve plasma concentration of 0.8 mEq/L – 1.2 mEq/L Levels greater than 1.2 mEq/L are associated with increased adverse events and toxicity Levels maintained at 0.8 mEq/L or greater associated with lower relapse rates |
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Pretreatment workup
for lithium |
Baseline EKG, CBC with differential, electrolytes, thyroid function test (TSH, T3, T4), creatinine, pregnancy test, urine analysis, weight
Maintenance laboratory tests every 6 - 12 months (CBC, electrolytes, thyroid function tests, and creatinine, lithium level) Lithium plasma concentrations needed 4 - 5 days post initiation or when dose is adjusted, and when clinically indicated |
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pk of lithium
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Renally excreted, no hepatic metabolism
Half-Life: ~24 hours Steady State concentration at 4 - 5 days Empiric dosing still best model for dosing and predicting levels 300mg daily dose will produce a serum concentration of 0.2 – 0.4 mEq/L Other models not as effective |
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dosing of lithium
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300mg BID initially; titrated up by 300mg/week based on symptom control, tolerability, and serum concentration
Children require higher levels due to increased clearance |
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formulations of lithium
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Li CO3 tab – 300mg
Li CO3 capsule – 150mg, 300mg, 600mg Li CO3 slow release – Lithobid® 300mg Li CO3 sustained release – Duralith® 300mg Li CO3 controlled release – Eskalith® CR 450mg Li citrate syrup – 300mg/5ml |
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drug interactions with lithium
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Increase [Li]
ACE-inhibitors, diuretics (thiazides have biggest effect), and NSAIDs alter fluid/electrolyte balance and/or decrease renal perfusion Decrease [Li] Caffeine and theophylline increase renal perfusion Lithium-associated neurotoxicity Calcium-channel blockers, carbamazepine, antipsychotics, and methyldopa |
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life style considerations with litium
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Alcohol, high sodium foods, exercise, extreme heat
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SE of lithium
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First seen: leukocytosis, GI upset (dose related), confusion, cognitive disturbances, polyuria, polydipsia, weight gain, muscle spasms, tremor
Later seen: alopecia, renal function decline, thyroid function decline, tremor, acne, metallic taste FDA pregnancy category D drug |
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Lithium overdose and toxicity
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[Li] 1.5 – 2.0 mEq/L. Mild toxicity: impaired concentration and memory, tremor, N/V, fatigue, weakness
[Li] 2.0 – 2.5 mEq/L. Moderate toxicity: worsening tremor, altered mental status, increased deep tendon reflexes [Li] 2.5 mEq and greater. Severe toxicity: seizures, coma, arrhythmias, death Treatment: discontinue lithium, monitor vitals, supportive care with fluids and electrolytes, dialysis if [Li] >3.5 mEq (possible rebound) |
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Anticonvulsants
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Valproate
Carbamazepine Oxcarbazepine Lamotrigine Topiramate Gabapentin Zonisamide Tiagabine Levetiracetam Riluzole* |
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place in therapy of valproate and BMD
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Effective in acute mania and in preventing relapse of mania
Very useful in rapid cyclers, mixed episodes, medically induced mania Less effective than Li in classic mania Little effect on depressive symptoms 1st line therapy |
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MOA valproate in BMD
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Mechanism of Action – Not completely understood
Blocks the effects of glutamate Enhances GABA activity Interferes with voltage-sensitive sodium channels Effect on downstream signal transduction cascade |
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PK and dosing for valproate and BMD
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Empiric dose strategy: 250mg TID (BID) titrated up based on symptom control, tolerability, and plasma level
Loading dose strategy: 20mg/kg/day given in divided doses Helpful in acute mania Target level achieved faster with this method Regardless of dosing strategy, a valproate level between 60 – 100 mcg/ml is desired 60-70 mcg/ml minimum better acute mania control Upper limit: 125 mcg/ml. Rarely higher (150 mcg/ml). |
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MOA valproate in BMD
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Mechanism of Action – Not completely understood
Blocks the effects of glutamate Enhances GABA activity Interferes with voltage-sensitive sodium channels Effect on downstream signal transduction cascade |
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SE valporate
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GI upset, N/V, sedation, dizziness, tremor, diarrhea are common
Reduced GI and CNS symptoms with divalproex Weight gain Alopecia occurs in ~12% of patients ~25% of patient can have mild thrombocytopenia Monitor for epistaxis and easy bruising Black Box Warning Pancreatitis, hepatotoxicity, teratogenicity FDA pregnancy category D drug |
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carbamazepine place in therapy for BMD
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Effective for acute treatment of mania
Limited data assessing its efficacy as a maintenance treatment in BMD May be more effective than Li in mixed episodes, rapid cyclers, atypical BMD Studies suggest potential modest effect on depressive symptoms, but these treatments were in combo with Li Generally considered a 2nd line agent |
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MOA valproate in BMD
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Mechanism of Action – Not completely understood
Blocks the effects of glutamate Enhances GABA activity Interferes with voltage-sensitive sodium channels Effect on downstream signal transduction cascade |
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MOA carbamazepine
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Not completely understood
Interferes with voltage-sensitive sodium channels Indirectly reduces glutamate Enhances GABA activity |
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PK and dosing for valproate and BMD
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Empiric dose strategy: 250mg TID (BID) titrated up based on symptom control, tolerability, and plasma level
Loading dose strategy: 20mg/kg/day given in divided doses Helpful in acute mania Target level achieved faster with this method Regardless of dosing strategy, a valproate level between 60 – 100 mcg/ml is desired 60-70 mcg/ml minimum better acute mania control Upper limit: 125 mcg/ml. Rarely higher (150 mcg/ml). |
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PK and dosing for valproate and BMD
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Empiric dose strategy: 250mg TID (BID) titrated up based on symptom control, tolerability, and plasma level
Loading dose strategy: 20mg/kg/day given in divided doses Helpful in acute mania Target level achieved faster with this method Regardless of dosing strategy, a valproate level between 60 – 100 mcg/ml is desired 60-70 mcg/ml minimum better acute mania control Upper limit: 125 mcg/ml. Rarely higher (150 mcg/ml). |
|
|
SE valporate
|
GI upset, N/V, sedation, dizziness, tremor, diarrhea are common
Reduced GI and CNS symptoms with divalproex Weight gain Alopecia occurs in ~12% of patients ~25% of patient can have mild thrombocytopenia Monitor for epistaxis and easy bruising Black Box Warning Pancreatitis, hepatotoxicity, teratogenicity FDA pregnancy category D drug |
|
|
SE valporate
|
GI upset, N/V, sedation, dizziness, tremor, diarrhea are common
Reduced GI and CNS symptoms with divalproex Weight gain Alopecia occurs in ~12% of patients ~25% of patient can have mild thrombocytopenia Monitor for epistaxis and easy bruising Black Box Warning Pancreatitis, hepatotoxicity, teratogenicity FDA pregnancy category D drug |
|
|
carbamazepine place in therapy for BMD
|
Effective for acute treatment of mania
Limited data assessing its efficacy as a maintenance treatment in BMD May be more effective than Li in mixed episodes, rapid cyclers, atypical BMD Studies suggest potential modest effect on depressive symptoms, but these treatments were in combo with Li Generally considered a 2nd line agent |
|
|
carbamazepine place in therapy for BMD
|
Effective for acute treatment of mania
Limited data assessing its efficacy as a maintenance treatment in BMD May be more effective than Li in mixed episodes, rapid cyclers, atypical BMD Studies suggest potential modest effect on depressive symptoms, but these treatments were in combo with Li Generally considered a 2nd line agent |
|
|
MOA carbamazepine
|
Not completely understood
Interferes with voltage-sensitive sodium channels Indirectly reduces glutamate Enhances GABA activity |
|
|
MOA carbamazepine
|
Not completely understood
Interferes with voltage-sensitive sodium channels Indirectly reduces glutamate Enhances GABA activity |
|
|
Dosing / Pharmacokinetic carbamazepine
|
200mg BID initially, titrated up by 200mg based on symptom control, tolerability, and plasma levels
Patients sensitive to CNS SE’s or who have mild-moderate renal impairment, initiate dose at 100mg BID May give larger portion of TDD dose at night to minimize sedation Desired response occurs with trough levels between 8 – 12 mcg/ml More side-effects are present with level >15mcg/ml May need to dose adjust in first few months as a result autoinduction |
|
|
Drug interactions
carbamazepine |
Hepatically metabolized as a substrate of the CYP3A4 isoenzyme
Increased carbamazepine levels with CYP3A4 inhibitors Azoles, macrolides, cimetidine, various protease inhibitors, fluoxetine, nefazodone Induces many CYP isoenzymes Can decrease concentration and efficacy of antipsychotics, antidepressants, contraceptives, thyroid replacement, warfarin, phenytoin |
|
|
SE carbamazepine
|
Adverse effects
Up to 60% of patients have CNS SE’s Sedation, dizziness, ataxia, vision change Hyponatremia Stevens-Johnson Syndrome Black Box Warning Aplastic anemia Agranulocytosis FDA pregnancy category C |
|
|
Place in therapy
of Oxcarbazepine for BMD |
Prodrug of eslicarbazepine, which is structurally similar to carbamazepine
Possible antimanic properties comparable to Li and haloperidol 2nd line agent for acute mania and depression associated with BMD Few controlled studies to support its use Several small studies suggest its use as an adjunct therapy for acute mania, and as an adjunct therapy for depressive symptoms Oxcarbazepine is better tolerated than carbamazepine |
|
|
MOA Oxcarbazepine
|
Not completely understood
Interferes with voltage-sensitive sodium channels Indirectly reduces glutamate Enhances GABA activity |
|
|
dosig of oxcarmazapine for BMD
|
Dosing – 300mg BID, can titrate up to 600mg BID based on response
Adverse effects – HA, dizziness, blurred vision, SJS, SIADH Less side-effects, weight gain, and CYP450 3A4 drug interactions than carbamazepine No autoinduction, but does increase metabolism of contraceptives |
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|
lamotrigine palce in therapy fro BMD
|
Indicated for maintenance therapy in bipolar I disorder
Although not FDA indicated for treatment of bipolar depression, studies suggest LTG is superior to Li in prolonging time to intervention for a depressive episode Starting to replace antidepressants as first-line for bipolar depression given growing concern about antidepressants inducing mania, causing mood instability, and increasing suicidality in bipolar disorder Good choice for patients with bipolar II disorder who primarily experience depressive episodes Shares some overlapping mechanistic actions with carbamazepine, but LTG is not approved for acute mania Can take 2-4 months to achieve desired effect |
|
|
drug interactions of lamotrigine
|
Increases [LTG]
Valproic acid Decreases [LTG] Carbamazepine, phenobarbital, phenytoin |
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|
MOA lamotrigine
|
Not completely understood
May act to reduce the release of glutamate Not clear whether this action is secondary to blocking the activation of VSSCs or to some additional synaptic action Reduction of excitatory glutamatergic neurotransmission could explain unique clinical profile as a treatment and stabilizer Shares some actions on VSSCs with certain anticonvulsants (e.g. CBZ) that are apparently effective for the manic phase of bipolar disorder Has a relatively unique profile of effectiveness for the depressed phase and for preventing the recurrence of depression |
|
|
SE lamotrigine
|
Common: HA, N/V, dizziness, ataxia, somnolence, blurred vision, diplopia, rash
Life-threatening: Steven-Johnson syndrome Rare but highly related to dosing rate, which is why a slow titration schedule is essential Important to counsel patients about SJS, and instruct them to immediately contact physician at first sign of a rash Black box warning FDA pregnancy category C drug |
|
|
pk of lamotrigine
|
Hepatic metabolism: glucoronosyltransferase; negligible metabolism through CYP P450 system
94% renally excreted Half-life: 22-38 hours With concomitant valproate half-life increases to ~59 hours With concomitant enzyme inducers the half-life decreases to about 15 hours |
|
|
dosing of lamotrigine for BMD
|
Slow titration schedule: 25mg/day for the first 2 weeks, then increase to 50 mg for 2 weeks, then 100 mg/day for 1 week; further dose increases should be made by increments of 100 mg/week
If used in combo with CBZ: initial dose is 50 mg/day for 2 weeks with upward titration in increments of 50 mg/week every 1-2 weeks If added to VPA: initial doses of 25 mg every other day should be used for 2 weeks and then 25 mg/day for 2 weeks; subsequent titration may occur in increments of 25 mg/week up to a target dose of 100-150 mg/day |
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|
place in therapy of topiramate for bmd
|
No proven efficacy in BMD
Used as an adjunctive therapy May be useful for weight gain secondary to other mood stabilizers, insomnia, anxiety Being tested for treatment of substance abuse disorders |
|
|
MOA topiramate
|
Enhances GABA
Reduces glutamate function Interferes with voltage-sensitive sodium and calcium channels |
|
|
dose and pk of topiramate
|
25mg/day initially, titrated up to 400mg/day
Dosed BID, despite long half-life 70% renal elimination, minimal hepatic |
|
|
SE of topiramate
|
Cognitive issues, sedation, weight loss, renal stones, metabolic acidosis
“Dopamax” |
|
|
Pharmacotherapy: Miscellaneous Anticonvulsant Agents for BMD
|
Gabapentin
Proven NOT to be useful in BMD Zonisamide No convincing evidence Tiagabine Generally not useful Levetiracetam Generally not useful Riluzole Some promising results in bipolar depression, unipolar depression, and anxiety disorders May be similar to lamotrigine (blocks VSSC and decreases glutamate) Research in progress Expensive Frequent liver function abnormalities Developed for amyotrophic lateral sclerosis (ALS), some anticonvulsant properties in pre-clinical models |
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|
Pharmacotherapy: Antipsychotics for BMD
|
Typical antipsychotics
Haloperidol Chlorpromazine Many others Atypical antipsychotics Olanzapine Quetiapine Risperidone Paliperidone Ziprasidone Aripiprazole Clozapine |
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|
Pharmacotherapy: Typical Antipsychotics for BMD
|
In clinical practice…
Can help symptoms of mania D2 dopamine antagonist High rates of extrapyramidal symptoms (EPS), though this varies with affinity for the D2 receptor D2 blockade related to control of mania/psychosis Anticholinergics can relieve this SE Major reason for medication non-adherence Risk of tardive dyskinesia Other adverse effects Autonomic, cardiac, anticholinergic (as anticholinergic effects increase, EPS decrease) |
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|
Pharmacotherapy: Atypical Antipsychotics for BMD use in clinical practice
|
Proven effective in the treatment of mood disorders and psychosis
D2 dopamine antagonist 5HT2A antagonist (reduces glutamate hyperactivity, disinhibits NE and DA release in the prefrontral cortex) Beneficial to mood and reduced SE’s compared to typicals Degree of EPS and anticholinergic SE’s vary between agents Class warnings Increased risk of death in elderly patients with dementia Cardiac risks Increased risk of suicide in depressed patients Less EPS, but notable cardiometabolic side-effects (varies with each agent) |
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|
Olanzapine (Zyprexa)
for bmd |
Effective in acute mania, preventing recurrence of mania, and in the treatment of bipolar depression
Used as a monotherapy or in combination with other mood stabilizers The use of 2 more antipsychotics has never been proven effective, though is commonly practiced 5 – 20 mg daily dose Has notable cardiometabolic side-effects and is very sedating (anticholinergic) High affinity for the D2 receptor Possible EPS Injectable, zydis, and long-acting depot (Relprevv) formulation available |
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|
Quetiapine (Seroquel)
for bmd |
Effective in acute mania and in the treatment of bipolar depression
Used as monotherapy or in combination with other mood stabilizers 300 – 800 mg daily dose (QHS) Has notable cardiometabolic side-effects and is very sedating (anticholinergic) Low affinity for D2 receptor little (to no) EPS Only available in oral form, no real benefit from XR formulation over IR formulation |
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|
Risperidone (Risperdal) for bmd
|
Effective in acute manic and mixed episodes
Usually in combination with another mood stabilizer 1 – 6 mg daily dose divided BID Has some cardiometabolic risks (though is not anticholinergic), can potentially cause EPS (high affinity for D2 receptor), and elevates prolactin levels Available as a rapid disintegrating tab, and as a long acting depot injectable (Risperdal Consta) Palperidone (Invega) is the active metabolite of risperidone – thought to have less drug interactions and to produce more stable blood levels Thought to have similar efficacy/SE profile to risperidone 6 – 12 mg daily dose (typically given once daily) Invega Sustenna now available (long-acting depot) |
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|
Ziprasidone (Geodon)
for bmd |
Effective in management of acute mania and mixed episodes, with or without psychotic symptoms
40 – 160 mg daily dose divided BID with food Lacks cardiometabolic side-effect profile, but has potential to cause EPS Risk of QTc prolongation Risk over-stated, all antipsychotics have potential to cause QTc prolongation Potential baseline EKG for at risk patients Available as an injectable |
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|
Aripiprazole (Abilify) for bdm
|
Effective for acute manic / mixed episodes, preventing relapse of mania, and as an adjunctive therapy in the treatment of major depressive disorder
New studies show all atypicals may be effective as adjunct to antidepressants in treating depression Is a dopamine D2 partial agonist Potential to induce mania in some patients 15 – 30 mg daily dose for schizophrenia/mania (more blockade) 2.5 – 5 mg daily dose when used as adjunct therapy for MDD (more agonism) Also acts as partial agonist on 5HT1A receptor Little to no cardiometabolic effects, but can cause notable EPS Injectable formulation available |
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|
Clozapine (Clozaril) for bmd
|
To be discussed in greater detail by someone else!
Last line therapy, though potentially the most efficacious antipsychotic Adverse effects often preclude its use and therapy requires constant monitoring Agranulocytosis Significant cardiometabolic risks Seizures |
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|
Pharmacotherapy: Special Circumstances for bmd
|
Pregnancy
No guidelines for FDA pregnancy category C Most antipsychotics are category C Clinical judgment required to determine best course of action Rapid behavioral control Injectable antipsychotics Injectable benzodiazepines Do not use injectable benzos with injectable olanzapine – reports show increase in mortality Consider giving prophylactic anticholinergic if agent known to cause EPS is given IM volume limit is ~2.1 mL |
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|
Can Antidepressants make you bipolar?
|
Antidepressants can be destabilizing, often resulting in mania, hypomania rapid cycling, mixed states, and even suicidal ideation
Activate already up-regulated systems in the trimonoaminergic pathway A careful differentiation between depression and BMD disorder must be made to avoid consequences of “unmasking” Antidepressant can be used in bipolar disorder on base-by-case basis No formal recommendation about antidepressant use for patients who have BMD, are at risk for BMD, or who have activation with an antidepressant Antidepressant monotherapy generally to be avoided Some treatment algorithms suggest antidepressants in combination with mood stabilizers (controversial) |
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|
Psychopharmacolgy in Clinical Practice bmd
|
Directs treatment based on the matching of symptoms to neurotransmitter systems that may be “out of tune”
No right answers Logical approach to symptoms using psychopharmacology Symptoms change, evolve, disappear – drug therapy should reflect this Some helpful treatment algorithms and tools… |
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|
Bipolar Mood Disorder in Summary
|
Varying severity
Dynamic Cognitive behavioral therapy is a necessary and integral part of treatment Adherence and its implications Life stressors play a large role Substance use and abuse can have major effect Associated with negative health outcomes |
|
|
A brief histoy of adhd
|
Features of ADHD first identified in the 19th
century Fidgety Phillip by Heinrich Hoffman First described as a disorder of children with unruly behavior and hyperactivity Called “hyperkinetic syndrome” and “hyperactive reaction of childhood” 1976: recognized ADD/ADHD occurs in adults 1980: DSM classified ADD/ADHD 1987: DSM-IIIR identified adults |
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|
Etiology & Epidemiology of adhd
|
Genetics
40-50% chance of developing if child has at least one parent with ADHD 75-90% concordance rate among monozygotic twins Non-genetic Fetal alcohol syndrome, lead poisoning, meningitis, TBI Perinatal stress, maternal smoking, low birth-weight Epidemiology (US) 3-9% of children/adolescents affected 3-5% adults 2006: 5 million stimulant rx’s (3.5 million for children) things that affect the CNS can cause adhd a lot of children with adhd have sympotoms that manifest into adulthood in children males are 3x more likely than females in adults males to females is 1/1 |
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|
Pathophysiology adhd
|
Dysregulation of the central noradrenergic (NA)
networks NA system modulates attention, alertness, vigilance, and executive function NA activation affects the performance of attention, including maintenance of arousal Structural/functional abnormalities in prefrontal structures and basal ganglia Impaired executive function Difficulties with response inhibition |
|
|
Neurotransmission in adhd
|
dopamine:
IMPROVES ATTENTION Focus Vigilance Information acquisition On-task behavior NE: INCREASES INHIBITION Behavioral Cognitive Motor Shifting, distractibility |
|
|
DSM-IV Criteria (I) in children
|
Inattention (A)
Does not give close attention to details/makes careless mistakes Trouble keeping attention on tasks or play activities Does not seem to listen when spoken to Does not follow instructions & fails to finish work Trouble organizing activities Avoids/dislikes/won’t do things require sustained attention Often loses things needed for tasks or activities Easily distracted Forgetful in daily activities Hyperactivity (B) Fidgets, squirms Leaves seat when expected to sit Runs or climbs inappropriately Trouble with quiet playing or leisure activities “On the go” or acts as if “driven by a motor” Talks excessively Impulsivity (B) Blurts out answers before the question is finished Trouble waiting one’s turn Interrupts or intrudes on others Need 6 + in the A and/or B categories persisting ≥ 6 months |
|
|
3 domains of adhd that are evaluated to diagnos
|
Inattention (A)
Hyperactivity (B) Impulsivity (B) |
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|
DSM-IV Criteria (II-V) in children
|
Some symptoms that cause impairment were present
before age 7 Some impairment from the symptoms is present in 2+ settings (e.g., home and school) Clear evidence of significant impairment in social, school, or work functioning Do not occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or other psychotic disorder. These symptoms are not better accounted for by another mental disorder. |
|
|
at what age are diagnosis factors more indicative of adhd
|
7
after that it may be comorbid illnesses that are more associated with addolescents So before 7 years old it is more indicative of adhd |
|
|
does the child have to have symptoms of adhd in multiple or singualr settings to be diagnosed with ahhd
|
multiple
school, home, daycare |
|
|
3 Types of ADHD
|
ADHD, Combined (80%)
A + B symptoms for past 6 months ADHD, Predominantly Inattentive (10-15%) A symptoms (but not B) for past 6 months ADHD, Predominantly Hyperactive-Impulsive (5%) B symptoms (but not A) for past 6 months NOTE: Male to female ratio 3:1; males more likely to be diagnosed as hyperactive, females more likely to be diagnosed as inattentive. |
|
|
Differential Diagnosis of adhd
|
Mental Health Disorders*
Anxiety disorders Mood disorders Oppositional defiant disorder Conduct disorder Medical Disorders Hyperthyroidism Fetal alcohol syndrome Medication effects (e.g., antihistamines) Environment-related Issues Abuse or neglect Severely dysfunctional family dynamic Many of these are comorbid with ADHD |
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|
Impact of ADHD going forward
|
Symptoms in adulthood
Impaired academic performance and employment Less schooling, lower standardized scores, more failures Lower job status, poor performance Increased risk of anti-social personality disorder (acting out due to frustrations of adhd and they don't know how to control their issues) Unlawful behaviors, deceitfulness, irritability or aggressiveness (e.g., physical fights) Reckless disregard for safety, consistent irresponsibility Substance abuse risk Less for those who use stimulant medications and greater potential for those who are not treated with stimulants |
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|
what type of adhd is more likely to affect young girls
|
inatentive
|
|
|
what type of adhd is more likely to affect young boys
|
hyperactivivty
|
|
|
what makes adhd hard to diagnois
|
18-35% of patients have comorbid conditions
adhd happens in conjunction with a lot of metal health disorders |
|
|
DSM-IV Criteria (I) for adults
|
Inattention (A)
Does not give close attention to details/makes careless mistakes Trouble keeping attention on tasks or play activities Does not seem to listen when spoken to Does not follow instructions & fails to finish work Trouble organizing activities Avoids/dislikes/won’t do things require sustained attention Often loses things needed for tasks or activities Easily distracted Forgetful in daily activities Hyperactivity (B) Fidgets, squirms Leaves seat when expected to sit Runs or climbs inappropriately Trouble with quiet playing or leisure activities “On the go” or acts as if “driven by a motor” Talks excessively Impulsivity (B) Blurts out answers before the question is finished Trouble waiting one’s turn Interrupts or intrudes on others the hyperactivity and implusivity in decreased in adults because they are better able to cope DSM-IV criteria best describe pediatrics Adult presentations often more subtle Need 6 + in the A and/or B categories persisting ≥ 6 months |
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|
DSM-IV Criteria (continued) in adults
|
Present before age 7
Debate over whether age 12 is a better cut-off… (it is difficult to remember if they had symptoms or not and most people could remember at the cut off of 12 better) Some impairment from the symptoms is present in 2+ settings (e.g., school, family, peer relationships) Do not occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or other psychotic disorder Are not better accounted for by another mental disorder (e.g., mood disorder or anxiety disorder) Clear evidence of clinically significant impairment in social, academic, or occupational functioning. other disorders have to ruled out before a diagnosis is made for adhd |
|
|
Utah Criteria for ADHD in
Adults |
Childhood history consistent with ADHD
Adult symptoms: Hyperactivity and poor concentration 2 of the following: Affective lability Hot temper Inability to complete tasks & disorganization Stress intolerance Impulsivity |
|
|
do the symptoms of hypomanic episodes meet the fill criteria
|
no
|
|
|
is there equal prevalence among genders with bmd
|
yes
|
|
|
is there a strong genetic component associated with bmd
|
yes
|
|
|
what is the age of typical onset of bmd
|
18-26
|
|
|
differentiating bmd from _______ disorder is of critical importance
|
major depressive disorder
|
|
|
what NT are decreased in BMD and causse a depressed mood
|
5HT
Da Ne |
|
|
what 2 NT are decreased and cause apathy/loss of interest
|
NE
Da |
|
|
what is 1st line therapy for bmd
|
lithium
increases apporpriate stimulation and maintains function of neurons and preserves brain function |
|
|
can lithium be used long term
|
no because over time the kidneys become lithiumized
|
|
|
pregnency category of lithium
|
D
|
|
|
is lithium efficaciuos for both the mania and depression of bmd
|
yes, it balances the over and underactivity
|
|
|
why do you give a patient a baseline EKG prior to starting lithium for bmd
|
to ensure electrolytes are ok
if there is a low concentration of Na and the charges are not balanced the body will hold onto lithium |
|
|
what is the half life of lithium once SS is reached
|
24 hours regardless of formulation
|
|
|
a daily dose of _______ will produce a serum concentration of ________
|
300 mg/day
0.2-0.4 mEq/L |
|
|
what is a typical starting dose of lithium and what concentration does it produce
|
600 BID
0.4-0.8 mEg/L |
|
|
do children require a higher or lower dose of lithium than adults
|
a higher does due to increased CL
|
|
|
explain the inportance of hydration and lithium
|
patients need to stay hydrated or it will result in more SE (immediatly)
dehydration causes the body the body to hold on to lithium and the serum concentrations will increase if the patient is not peeing they are not excreting lithium |
|
|
what is the drug interaction between ACE, ARBs and NSAIDs on lithium
|
they all constrict the efferent vessels and decrease renal profussion therefore the body retains lithium
|
|
|
what is the drug interaction between diuretics and lithium
|
diuretics decrease the electrolytes in the body and as a result the body holds on to lithium to maintain the charge balance
|
|
|
what is the result of drinking a ton of water and lithium
|
lithium will be flushed from the body
|
|
|
what SE of lithoum are concentration related
|
confusion
congnitive distribances tremor |
|
|
what is the possible rebound of lithium after being flushed from the body
|
Li is cleared from the body however it is in the tissues and can leach out so can increase toxicity
|
|
|
how does lithium interfer with cardiac function
|
interfers with cations and cardiac conduction
|
|
|
lethal dose (LD 50) of lithium
|
#35 of the 300 mg tablets results in a serious OD
|
|
|
is valproate efficacius for the depression asspect of bmd
|
no
it controls impulsivity, anger and aggression |
|
|
what are valproates affects on glutamate
|
it blocks its effects therefore decreasing the excititory impluses
also it interfers with the voltage gated Na channels decreasing glutamate even more |
|
|
what is the desired serum concetration of valpraate
|
60-100 mcg/ml
60-70 mcg/ml minimum for better acute mania control upper limit: 125 mcg/ml, rarely higher than 150 mcg/ml not a NTR |
|
|
is thrombocytopenia dose dependent with valproate
|
yes and react when the platelets have decreases by 50%
|
|
|
pregnancy category of valproate
|
D
|
|
|
carbamazepine is an _______ and ______ for CYP 3A4
|
inducer
substrate |
|
|
half life of lamotrigine
|
22-38 hours
|
|
|
if the patient stops taking lamotrigine for 5 or more days what should they do when they restart
|
slowly titrate the dose due to SJS
|
|
|
A Da antagonist treats what asspect of bmd
|
mania
|
|
|
A 5HT (2a) antagonist treats what asspect of mania
|
decrease glutamate hyperactivity and helps with mood disorders, increases cognition
|
|
|
when a antipsychotic has little affinity for the D2 receptor what SE is avoided
|
EPS
|
|
|
what helps with EPS
|
anticholinergics can be given to decrease the EPS
|
|
|
how do anticholinergics decrease EPS
|
they decrease D2 to prevent movement disorders
|
|
|
the ________ the affinity for a D2 receptor the more ________ symptoms
|
greater
EPS |
|
|
long term use of anticholinergics SE
|
weight gain
increased risk of DM because of insulin resistance |
|
|
does Ziprasidone (Geodon) have any anticholinergic affects
|
no so lots of EPS
|
|
|
do not use injectable _________ wih injectable _________ has been shown to increase mortality and is contraindicated
|
benzos
olanzapine |
|
|
MOA of antidepressants
|
Inhibition of NT re-uptake of inhibition of NT breakdown--> initial increase in synaptic NT levels--> adaptive changes in NT receptors/transporters--> antidepressant effect
|
|
|
antidepressant affect correlates with
|
the desensitization
|
|
|
is a transporter more or less selective than a receptor
|
less
|
|
|
building block of NE
|
tyrosin
|
|
|
initially how does the synapse try to regain homeostatis after a TCA is administered
|
the alpha 2 receptor is activated on the presynaptic neuron and it decreases biosynthesis of NE so there is less released
|
|
|
how is the majority of action terminted in the synapse
|
by the reuptake of the NT
|
|
|
When TCAs are chronically administered what happens
|
the alpha 2 receptor becomes desensitized over 2-3 weeks and then the NE levels begin to increas and the drug becomes therapeutic
|
|
|
what is the building block of 5HT
|
tryptophan
|
|
|
when chronically administer SSRI what happens
|
initally leads to the activation of alpha 2 receptor which is autoinhibitory
then over 2-3 weeks it becomes desensitized |
|
|
rate limiting step of NE
|
tyrosine hydroxylase
|
|
|
rate limiting step of 5HT
|
tryptophan hydroxylase
|
|
|
TCAs pharmacologic properties
|
NE, 5HT (not DA) reuptake inhibition leads to increased NE or 5HT levels in the synapse
|
|
|
MAOIs pharmacologic properties
|
Blockade of MAO inhibition leads to increased neurotransmitter levels in the synapse
|
|
|
SSRIs pharmacologic properties
|
Block 5HT reuptake
|
|
|
atypical antidepressants pharmacologic properties
|
(e.g. mirtazapine, nefazodone, trazodone bupropion)
Antagonists of 5HT2A or 5HT2C receptors Some inhibit a2 autoreceptors (antidepressant effect) (getting rid of the feedback inhibition), H1 (sedative) |
|
|
Pharmacological properties of TCAs (generally termed as NE Reuptake Inhibitors)
|
CNS effects
Mood, sleep, behavior Autonomic system Cardiovascular system |
|
|
Receptor Effects of TCA/NE uptake inhibitors
|
Direct actions on a1>>a2, but not b1 receptors
Indirect effects via a2 autoreceptors Autoreceptors normally limit NE release (negative feedback) This (a2 receptor mediated negative feedback) mechanism is activated by TCAs (via increased synaptic NE). This is an attempt by the synapse to maintain functional homeostasis. Repeated (chronic) TCA exposure results in desensitization of a2 receptors. Over a period of days to weeks, the production and release of NE returns to, or exceeds baseline levels. |
|
|
do TCA block NE or 5HT to a greater extent
|
Blockade of NE>5HT, not DA transport (via transporters)
|
|
|
chronic exposure of TCAs and the receptors
|
(REMEMBER: CHORNIC EXPOSURE TO AGONISTS DOWNREGULATE RECEPTOR NUMBERS; ANTAGONISTS UPREGULATE)
Chronic TCA: Post-synaptic b adrenergic receptors are gradually downregulated (this is true for several classes of antidepressants-MAOIs, SSRIs, electroshock treatment). Post-synaptic a1-adrenergic receptors (initially partially blocked by TCAs) remain available over weeks to respond to NE. This may be the basis of antidepressants action of TCAs. |
|
|
Other receptor effects (TCAs/NE reuptake inhibitors)
|
Blockade of postsynaptic a-adrenergic, muscarinic (cholinergic) and histaminergic receptors (cause of many side effects)
Enhanced stimulation or responsiveness of postsynaptic 5HT (1A) receptors may contribute to antidepressant action Adaptive changes: Altered sensitivity of muscarinic ACH, GABA, glutamate receptors |
|
|
Summary of Receptor Effects of
TCAs and NE uptake inhibitors |
Block the uptake of NE>5HT, but NOT dopamine transporters
Antidepressant action associated with Downregulation of postsynaptic b receptors Desensitization of presynaptic a2 receptors Maybe increased sensitivity of postsynaptic 5HT1A receptors |
|
|
Pharmacological properties of TCAs/NE Reuptake Inhibitors CNS (Normal subjects)
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CNS (mood, behavior):
Single dose in normal subject: sleepy, quiet, BP falls, light headed, often unpleasant anticholinergic effects (dry mouth, blurred vision). Mostly “unpleasant” or “unhappy” feeling Repeated doses in normal subject: Worsening of above effects, difficulty concentrating, thinking |
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Pharmacological properties of TCAs/NE Reuptake Inhibitors CNS (depressed subjects)
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Mood, behavior
Sedative or antianxiety effect within a few days Mood elevation occurs over a period of time (2-3 weeks). Therefore not prescribed as “as-needed” basis. Dulling of affect rather than euphoria |
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does tolerance develop to the sedation se of antidepressants
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yes
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Pharmacological properties of TCAs/NE Reuptake Inhibitors CNS (depressed subjects)
Sleep |
Sedative/hypnotic, histamine receptor- blocking property (may be useful in depressed people with sleep disturbances)
Tolerance develops to sedative effect Hangover Decrease the number of awakenings, increase stage 4 sleep, decrease REM (which is often increased in depressed people) sleep cycles are normalized |
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Pharmacological Effects of TCAs ANS
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Anticholinergic (antimuscarinic) effect (blurred vision, dry mouth, constipation, urinary retention)
Trazodone-like drugs have fewer anticholinergic effects Antiadrenergic (a 1 adrenergic receptor antagonism)-postural hypotension removing the bodies ANS control of BP (overtime develop tolerance ) |
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Pharmacological Effects of TCAs CV
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Lower blood pressure
Postural hypotension (a1 antagonism) Direct cardiotoxicity, conduction defects and ventricular arrhythmias etc bind to cardiac tissue (remember they are lipophil, large Vd) |
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Pharmacological properties of SSRIs
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Receptor effects (pharmacodynamics)
CNS effects Mood, sleep, behavior no ANS or CV affects |
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MOA of SSRI
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inhibition of 5HT reuptake-->initial increase in synaptic 5HT levels--> adaptive changes in 5HT receptors/transporters-->antidepressant effect
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Stimulation of 5HT receptors
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5HT3 causes GI (nausea, vomiting) and sexual side effects (delayed or impaired orgasm)
5HT2C causes agitation or restlessness activating all subtypes which causes SE |
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Autoreceptor mechanisms of SSRI
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Autoreceptors that normally limit 5HT release e.g. 5HT1D on terminals, are activated by increased 5HT resulting from blockade of reuptake by SSRI. This is an attempt by the synapse to maintain functional homeostasis.
Repeated (chronic) SSRI exposure results in desensitization and downregulation of autoreceptors (especially 5HT1D at nerve terminals). Over a period of days to weeks, the production and release of 5HT returns to, or exceeds baseline levels. when lose feedback inhibition get more NT when desensitized |
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what receptor are desensitized with SSRIs
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5HT 1d on the presynaptic neuron which causes loss of feedback inhibition providing the antidepressant effect
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Chronic exposre of SSRI causes the receptors to....
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Gradual downregulation of postsynaptic 5HT receptors (especially 5HT2A)
5HT2A heteroceptors (5HT receptors on NE neurons) normally inhibit NE release (tonic inhibition of NE release by 5HT). After chronic SSRI and 5HT2A receptor downregulation, this inhibitory effect is reversed leading to enhanced NE release. Adaptive changes similar to TCA/NE uptake inhibitors |
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. Pharmacological properties of SSRIs CNS
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Improvement in mood takes 2-3 weeks, may produce insomnia
sedation less common for SSRIs (e.g. fluoxetine, venlafaxine, citalopram) in comparison with TCAs, trazodone, mirtazapine insomnia is associated with SSRIs because they do not bind the H1 receptor |
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Pharmacological properties
Atypical Antidepressants |
Some have effects on both NE and 5HT neurotransmission (include some older tertiary amine TCAs e.g. Amitriptyline, clomipramine, doxepin and imipramine). Also can include Venlafaxine, duloxetine and milnacipram (mixed effects on both NE and 5HT transport).
Some include drugs that affect dopamine (e.g. bupropion) |
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trazodone and nefazadone affects
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5HT2A receptor antagonists (nefazodone, trazodone). Trazodone also inhibits cerebral a1 receptors and H1 histamine receptors.
Some have effects on neurotransmitter reuptake (e.g. Trazodone inhibits 5HT reuptake) |
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mirtazapine and mianserine affects
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5HT2A, 5HT2C, 5HT3 antagonists (Mirtazapine, mianserine). Mirtazapine also decreases the effectiveness of inhibitory a2 heteroceptors on 5HT neurons.
Alpha2 adrenergic autoreceptors (Mirtazapine) H1 histamine receptors (Mirtazapine) |
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Pharmacological properties of MAO Inhibitors
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2 types of MAOs: A and B
MAO-A metabolizes NE, 5HT, tyramine (more effective in depression) MAO-B more selective for dopamine (more effective in Parkinson’s disease) Selegeline (antiparkinson’s drug) (MAO-B), Phenelzine and tranlycypromine (MAO-A & MAO-B) |
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MAO-A metabolizes
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NE, 5HT, tyramine (more effective in depression)
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MAO-B more selective for
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dopamine (more effective in Parkinson’s disease)
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MAOIs increase synaptic NT levels by inhibiting _____________ via MAO
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NT degradation
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Summary of mechanisms of antidepressants
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Inhibition of NT reuptake, increase in synaptic NT levels, transmission, receptor effects.
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Summary of Pharmacological actions of antidepressants
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NE/TCAs: Receptor effects (NE>5HT, downregulation of bR, desensitization of a2, adaptive), CNS effects, autonomic system, cardiovascular system.
SSRIs: 5HT selective, increase 5HT effects, desensitization of 5HT1D, adaptive changes MAOIs: inhibition of MAO, Atypicals:some block both NE & 5HT transport, some block 5HT receptors as well |
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Adverse Effects During life stages of antidepressants
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Most antidepressants are generally safe during pregnancy
Most antidepressants secreted in breast milk Cardiotoxicity and seizures in children with higher doses of tricyclics (desipramine) Geriatrics patients: side effects of tricyclics (dizziness, postural hypotension, constipation, edema, tremor) |
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do antidepressants enter breast milk
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yes they are lipophilic
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Mechanism of postural hypotension
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Tricyclics- a1-adrenergic antagonism
MAOI- formation of false neurotransmitters MAOI--> MAO inhibition--> Tyramine build-up--> octopamine (false NT) formation, which is released form the neuron instead of NE but has no affect |
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SE of antidepressants (N/V, CV, and geriatrics)
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Nausea, vomitting and sexual side effects with SSRIs due to 5HT3 receptors
Cardiotoxicity with tricyclics may be due to tissue accumulation Geriatrics patients: side effects of tricyclics (dizziness, postural hypotension, constipation, edema, tremor) |
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SE of antidepressants Genital-urinary tract
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(Trazodone): urine retention, priapism, possibly leading to impotence, decreased libido
unwanted ED which can lead to impotence and decreased libido activation of the cerebral alpha1 receptors |
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Tolerance and physical dependence of antidepressants
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Tricylics-some tolerance to sedative and autonomic effects with continued use. Occasionally physical dependence
SSRIs-tolerance to initial nausea |
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Drug Interactions with antidepressants
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Binding of tricyclics with plasma proteins
Reduced by competition with phenytoin, aspirin, aminopyrine, scopolamine and phenothiazines. Interference with metabolism Barbiturates, carbamazepine, cigarette smoke increases hepatic metabolism of tricyclics by inducing CYP enzymes Inhibitors of P4502D6 (paroxetine and fluoxetine) interfere with desipramine, nortriptyline |
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Serotonin syndrome
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(hyperthermia, muscle rigidity, myoclonus etc) can occur with combination of fluoxetine (and some other SSRIs) with MAOI. Presumably due to excessive synaptic 5HT levels.
Other combinations: trazodone and St. John’s wort acute sensitivity to inhibitors overdose associated with co-administration so abnormally high concentrations of 5HT |
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Hypertensive crises with MAO inhibitors and foods containing tryramine
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Interaction discovered by an alert pharmacist (Blackwell)
Drug interaction with food (aged cheeses, beer, wine, pickled herring, snails, chicken livers, large amounts of coffee, canned figs, broad beans, chocolate etc). Tyramine present in some foods usually metabolized by gut MAO. With MAOIs, tyramine builds up, displaces catecholamines leading to hypertensive crisis. false NT builds up tyromine displaces NE from the vesicles so you get a large burst of NE |
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Contraindications
TCAs |
Hypersensitivity to drugs,
MAOIs (within 14 d of therapy), thyroid drugs, history of seizures |
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Overdose symptoms (some) TCAs
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Restlessness, seizures, coma, depressed respiration, hypothermia, hypotension, antimuscarinic, cardiac arrhythmias
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Overdose symptoms
MAOIs |
similar to TCAs) Agitation, hallucinations, hyperreflexia, convulsions, hypo/hypertension.
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Contraindications MAOIs
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Foods containing tyramine, avoid with amphetamines, ephedrine etc, ginseng.
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Overdose symptoms SSRIs
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Agitation, restlessness, seizures, nausea, vomitting.
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Contraindications SSRIs
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Hypersensitivity to drugs,
MAOIs (within 14 d of therapy), high risk of suicide, history of seizures, CV disease etc. |
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atypical antidepressant overdose syptoms
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Similar to SSRIs and cardiotoxicity
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overdose symptoms of atypical antidepressants
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Agitation, restlessness, seizures, nausea, vomitting.
Similar to SSRIs and cardiotoxicity |
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atypical antidepressants contraindications
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Concurrent use with MAOIs,
St. John’s wort |
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theraputic uses of antidepressants
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Major Depression: clinically significant depression of mood and impairment of function. Overlap with anxiety disorders including panic disorders, social anxiety disorder, phobias, generalized anxiety disorder, posttraumatic stress disorder and OCD.
Panic disorder Enuresis Chronic pain Bipolar disease Other: eating disorders, attention deficit disorder, premenstrual dysphoria (PMDD). |
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Which injectible cannot be combined with Ativan?
(Gold test question) |
Zyprexa (olanzapine)
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What is the MOA of anticonvulsants in bipolar disease
(gold test question) |
•Blocks effects of glutamate
•Enhances GABA activity •Interferes with voltage-sensitive Na and Ca channels •Effect on downstream signal transduction cascade |
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What OTC's are safe for people on Lithium(gold test question)
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APAP, Sulindac, ASA, nasal sinus rinse; NOT pseudoephedrine, no stimulants
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4.Who's affected by bipolar disorder (T/F)? (epidemiology question) (gold test question)
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•Found in all cultures and ethnicities
•Equal prevalence among genders: men are more likely to present with an initial manic episode and women are more likely to present with an initial depressive episode |
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What labs/tests do you need before giving Lithium?
(gold test question) |
Baseline EKG, CBC with differential, electrolytes, thyroid function test (TSH, T3, T4), creatinine, pregnancy test, urine analysis, weight
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What makes Lamictal (lamotrigine) such a good mood stabilizer vs. other anticonvulsants? (gold test question)
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•For bipolar depression – used as 1st line
•May act to reduce the release of glutamate •Reduction of excitatory glutamatergic neurotransmission could explain unique clinical profile as a treatment and a stabilizer •Shares some actions on VSSCs with certain anticonvulsants (carbamazepine) that are apparently effective for the mania phase of bipolar disorder •Has a relatively unique profile of effectiveness for the depressed phase and for preventing the recurrence of depression •Does not induce mania •Does not increase suicidality •Well tolerated |
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What is a reasonable recommendation for someone who is on an anti-psychotic and experiences extrapyramidal symptoms (EPS)? (gold test question)
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Take a medication with anticholinergic properties such as a 1st generation antihistamine - diphenhydramine
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What is not a consequence of long-term Lithium therapy? gold test question()
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No Suicide or Depression, No liver disease
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What is a consequence of long-term Lithium therapy? gold test question
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•Alopecia
•Renal fxn decline/failure •Thyroid fxn decline •Tremor •Acne •Metallic taste |
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Which antipsychotic is most like Zyprexa (olanzapine)? (gold test question)
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let me know if you find dthe answer to this I have
seroquel- noteable cardiometabolic SE and very sedating (weight gain, DM risperidone- cardiometabolic (not anticholinergic) and high affinity for D2 receptors geodon- no cardiometabolice SE, but high affinity of D2 receptors |
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What MOA do all atypical antipsychotics (olanzapine, quetiapine, risperidone, paliperidone, ziprasidone, aripiprazole, clozapine) have in common? (gold test quetion)
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•D2 dopamine antagonist
•5HT2A antagonist (reduces glutamate hyperactivity, disinhibits NE and DA release in the prefrontal cortex) •New studies show all atypical may be effective as adjunct to antidepressants in treating depression •All proven effective in the treatment of mood disorders and psychosis |
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11. Short Answer: New patient on Anti-depressant worried about getting bipolar from it, how do you counsel? (gold test question)
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•Antidepressant can be destabilizing, often resulting in mania, hypomania rapid cycling, mixed states, and even suicidal ideation - active already up regulated systems in the trimonoaminergic pathway
•A careful differentiation between depression and bipolar mood disorder must be made to avoid consequences of “unmasking” •Antidepressants can be used in bipolar disorder on a case-by-case basis |
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12. Short answer: Various lifestyle factors and how they affect lithium: (dehydration, alcohol, salt, analgesics) (gold test question)
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Decreased renal perfusion via EtOH ingestion, dehydration, exercise, low sodium diet, extreme heat, NSAIDs, ACEi, diuretics (mainly thiazides): ↑ [Li]
Increased renal perfusion via high sodium diet, hydration: ↓ [Li] |
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13. Short answer: What are the signs and symptoms of Lithium toxicity? (gold test question)
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•Mild: impaired concentration and memory, tremor, N/V, fatigue, weakness
•Moderate: worsening tremor, altered mental status, increased deep tendon reflexes •Severe: seizures, coma, arrhythmias, renal failure, death |
