phar_358_20241002172701 Flashcards
Define bipolar I disorder (BDI)
A distinct period of at least one week of full manic episode: abnormally and persistently elevated mood and increased energy
Define bipolar II disorder (BDII)
A current or past hypomanic episode and a current or past major depressive episode
How do men and women compare in terms of prevalence of bipolar disoder?
Men = Women, but:
- Men have more manic episodes, women more depressive or mixed
True or False? There is a cure to bipolar disorder
False, but full recovery/maintenance is possible
The exact cause of bipolar is _______
unknown
What are 5 risk factors for developing bipolar disorder?
- Drug or alcohol abuse
- Having a first-degree relative
- Period of high stress
- Medical conditions (hyperthyroidism, hormonal changes, CNS disoders, endocrine dysregulation, CVD)
- Major life changes, such as the death of a loved one or other traumatic experiences
Describe the clinical presentation of bipolar
Mood can fluctuate from euthymia where everything is normal, to hypomania –> mania then down to subthreshold depression –> major depression, and back and forth, sometimes achieving a mixed state.
What is kindling theory of bipolar disorder? (2)
- Abnormalities lead to more abnormalities
- Syndromal episodes increase vulnerability to more episodes
What is neurodegeneration?
Persistent neurocognitive deficits, increasing impairment, delayed functional recovery
What is the best predictor of level of functioning in bipolar?
Medication adherence
- ~50% of pts ds/c meds due to adverse effects
What are some comorbid conditions that may worsen existing bipolar or make treatment challenging? (5)
- Anxiety disorders
- Substance use disorder (alcohol is most common)
- ADHD
- PTSD
- Medical comorbidities (e.g., diabetes, dyslipidemia, obesity, CVD)
One of the leading causes of death in bipolar is _______
suicide
(20x higher than the general population)
What are some factors that are associated with suicide attempts in bipolar? (8)
- Female sex
- Younger age of illness onset
- Depressive polarity of 1st illness episode
- Comorbid anxiety
- Comorbid SUD
- Comorbid cluster B personality disorder
- 1st degree family history of suicide
- Previous attempt
True or False? Comprehensive assessment for suicide risk for a bipolar patient should only be done after the initial diagnosis
False - should occur during all BD patient interactions
From the DSM-5, mania is classified as persistently and abnormally elevated mood (irritable or expansive) and energy, with at least 3 of the following changes from usual behaviour: (7)
- Grandiosity or inflated self-esteem
- Decreased need for sleep
- Racing thoughts
- Increased talking/pressured speech
- Distractibility
- Increased goal-directed or psychomotor agitation
- Excessive engagement in high risk behaviours
In the DSM-5 for bipolar, not only do patients need the 3+ specific symptoms they ALSO need to have these 3 things alongside it
- Symptoms occur nearly every day for at least 1 week
- Leads to significant functional impairment OR includes psychotic features OR necessitates hospitalization
- Episode is not due to physiological effects of a substance or another medical condition
What is the DIGFAST mnemonic to help remember the mania symptoms?
Distractibility
Irritability or indiscretion
Grandiosity
Flight of ideas (racing thoughts)
Activity (or energy) increased
Sleep decreased
Talkativeness
True or False? Both manic and hypomanic episodes are required for a diagnosis of BDI in the DSM-5
False
Manic episode is required
Hypomanic or major depressive episodes may occur before or after manic episode but are NOT required for diagnosis
Essentially a hypomanic episode is the same as a manic episode but it is a shorter time period and less severe. What are the diagnostic criteria of one of these episodes? (4)
- Same symptom criteria as manic episode, but only lasting up to 4 days
- Unequivocal change in functioning or mood that is uncharacteristic of the individual and/or observable by others
- Impairment in social or occupational functioning is not severe. Hospitalization not required. No psychosis
- The episode is not due to physiological effects of a substance or another medical condition
What is the main diagnostic criteria of BDII?
Hypomanic episode AND major depressive episode (current or past episodes)
Compare and contrast: BDI vs. BDII - Duration of manic symptoms
BDI ≥7 days
BDII ≤ 4 days
Compare and contrast: BDI vs. BDII - Functional impairment
BDI: necessary
BDII: not necessary
Compare and contrast: BDI vs. BDII - Psychotic features
BDI: necessary
BDII: not necessary
Compare and contrast: BDI vs. BDII - Requires hospitalization
BDI: necessary
BDII: not necessary
Compare and contrast: BDI vs. BDII - History of depression
BDI: - nil
BDII: necessary
What type of scale is the Montgomery-Asberg Depression Rating Scale (MARDS)?
Clinican-rated to assess severity of depression
What type of scale is the Hamilton Depression Rating Scale (HDRS)(HAM-D)?
Clinician-rated to assess severity of depression - gold standard for clinical research
What type of scale is the Young Mania Rating Scale (YMRS)?
Clinician-rated - used in research for screening and assessing severity of mania
What type of scale is the Mood Disorders Questionnaire?
Patient-rated. Used to screen for possible BD. Most specific for identifying BDI
What are 3 challenges in BD diagnosis and treatment?
- Delay to diagnosis
- Misdiagnosis
- Limited clinical trials
Why might there be a delay in diagnosis of BD? (3)
- Average delay 8-12 years
- Often patients do not recall hypomanic symptoms
- More likely to seek help for depression vs. mania
Why might there be misdiagnosis of BD? (3)
- Survey found that 73% of BD pts are initially misdiagnosed
- In 2000 ~30% of pts waiting 10 years for correct dx
- Most often misdiagnosis = depression - consequences include developing hypo/manic episodes and rapid cycling
Why are there limited clinical trials involving BD? (4)
- Heterogenous illness
- Co-morbidities
- Manic symptoms –> impaired judgement –> impaired adherence
- Require longitudinal assessment
ZZ is a 25yo female that presents to the emergency room today. With increased energy, no need for sleep for the past 4 days, pressured speech. Diagnosed with mania. What med on her BPMH is of concern?
a. Pregabalin
b. Prednisone
c. Pindolol
d. Pantoprazole
B
What are 8 goals of therapy for BD?
- Eliminate mood episode with complete remission of symptoms, ongoing. “Acute treatment”
- Prevent recurrences or relapses of mood episodes, ongoing. “Maintenance treatment”
- Improve quality of life and optimize psychosocial functioning, ongoing
- Minimize harm to self and others (including prevent suicide, ongoing
- Maximize adherence and minimize adverse effects of pharmacotherapy, ongoing
- Identify and minimize risk factors for mood episodes, ongoing
- Provide care for comorbid psychiatric, substance use or, medical condition, ongoing
- Provide education to patient and family members, ongoing
For mania, what is the timeline in which we see improvement from medication (response and full benefit)?
- Response = 1-2 weeks
- Full clinical benefit = 3-4 weeks
For depression, what is the timeline in which we see improvement from medication (response and full benefit)?
- Response = 2-4 weeks
- Full clinical benefit = 6-12 weeks
What are some easyish lifestyle changes to recommend a patient (non-pharm therapy) with BD? (5)
- Exercise
- Adequate sleep
- Healthy diet
- Decreased/abstinent substance use
- Decreased caffeine/nicotine/alcohol
What are some other non-pharm options to potentially try for BD patients? (7)
- Bright light - more for depression
- Relapse prevention plan
- Psychoeducation, supportive counselling, biosocial rhythm normalization, psychotherapy (CBT, interpersonal therapy)
- ECT
- Collaborative care
- Case management
- Medication adherence
What are the 3 most commonly used mood stabilizer medications used for BD?
- Lithium
- Valproic Acid/Divalproex
- Lamotrigine
What are the anticonvulsant drugs that can be used for BD? (6). Only 2 of them are really used, so why not use the other 4?
- VPA/Divalproex
- Lamotrigine
- Carbamazepine
- Oxcarbazepine (3 and 4 use is limited by ADEs and drug interactions)
- Topiramate
- Gabapentin (5 and 6 rare used as mood stabilizers due to lack of efficacy & poor tolerability)
What are the indications for lithium? (3)
- BD
- Acute mania treatment
- Prophylaxis/maintenance - Schizoaffective disorder
- Unipolar depression
- Antidepressant augmentation
While the exact mechanism of action of lithium is not fully understood, what are some examples of the multiple effects on cellular functioning it might have? (4)
- Interaction with downstream signaling cascades
- Enhances GABA activity
- Alters Ca-mediated intracellular functions
- Decreases CNS adrenergic activity
Is bioavailability of oral lithium high, medium, or low?
High
True or False? Lithium is almost completely absorbed from the small intestine
True
What is the potential issue with time to peak onset of IR lithium?
Can lead to tremors or nausea, can switch to XR if that’s the case
True or False? Lithium is bound to plasma proteins
False - not bound to plasma proteins
What should you know about lithium’s volume of distribution in the body?
It distributes evenly in the total body water space
What is the t1/2 of lithium in normal renal function?
12-27 hours (typically call it 24 hours for the sake of calculations)
How is lithium eliminated?
95% renally
It’s freely filtered by the glomerulus like Na and K, 80% reabsorbed in the proximal tubules (with sodium)
True or False? Lithium follows non-proportional dose pharmacokinetics?
False - follows linear, dose-proportional PK
What are some causes for decreased clearance of lithium in the body? (4)
- Hyponatremia
- Dehydration
- Renal failure or dysfunction
- Decreased renal blood flow
Should know the therapeutic range of lithium (in mmol/L) in the following populations:
1. Acute mania
2. Maintenance therapy
3. Elderly
- Acute mania = 1.0-1.2 mmol/L
- Maintenance therapy = 0.6-1.0 mmol/L
- Elderly = 0.6-0.8 mmol/L
When are lithium levels taken when doing bloodwork for it?
In what situation would that be different?
- 12 hour post dose level
- Take is STAT if toxicity or non-adherence is suspected
How frequent are lithium levels checked starting from initiation of therapy?
- 5-7 days after starting or changing dose, then q weekly until at stabilized dose for 2 weeks, then q monthly for up to 3 months, then at least q 6 months.
With acute mania, how often is lithium typically dosed?
Initial is 1-2 times per day then try to go with BID
With BD maintenance, once the person is stabilized on lithium they can be given once daily dosing (if able to tolerate it). What are some of the benefits/things to look out for? (4)
- Usually given at night to improve compliance
- Some trials show decrease in urine volume and decreased renal toxicity with once daily dosing
- Pts sensitive to peak related side effects may respond to XR formulations
- When Li changes from multiple daily dosing to once daily dosing, can expect ~10-25% increase in 12h Li level
When CrCl is below __, we have to adjust Li dosing
50mL/min
Can we use Li in acute renal failure?
How about dialysis?
No.
Pts undergoing dialysis should have dose after dialysis
What are 3 things that should be done if Li is at a toxic level?
- Hold dose
- Repeat plasma level next day
- Restart therapy when within target range
Assuming the pt has stable renal function and they are on 900mg of lithium/day and at 0.6mmol/L blood levels, what dosing regimen would we want in order to achieve 1mmol/L?
Because Li PK is linear can do cross multiplication
900mg/0.6mmol/L = Xmg/1.0mmol/L
X = 1500mg
What are some important factors that can decrease lithium levels in the body? (6)
- Pregnancy (contraindicated in 1st trimester anyways)
- Sodium supplement
- Hemodialysis
- Peritoneal dialysis
- Burns
- Caffeine
What are some important factors that can increase Li level in the body? (4)
- Sodium loss
- NSAIDs
- Thiazide diuretics
- ACEis/ARBs
What are some drug interactions to look out for with lithium? (5)
- Diuretics (e.g., furosemide, chlorthalidone)
- Potentially mixed effects - NSAIDS
- Decrease Li clearance, increasing concentration - ACEis
- Antipsychotics
- Risk of additive neurotoxicity - Antidepressants
- Theoretical risk of serotonin syndrome
What are some common side effects of Li to be aware of? (7)
- Increased thirst and urinary frequency (dose-related)
- Fine tremors to hands/arms (usually symmetric and at high frequency and worse with fine motor activity; dose-related)
- Headache, sedation, weakness (dose-related)
- GI upset (nausea, diarrhea) (dose-related)
- Skin changes (acne, psoriasis)
- Alopecia
- Weight gain (avg 4-6 kg in first 2 years)
What are some serious side effects of Li to be aware of? (5)
- Hypothyroidism
- Renal injury: interstitial nephritis, renal failure, end stage renal disease
- Blood dyscrasias (i.e., leukocytosis)
- Bradycardia or conduction abnormalities
- Nephrogenic diabetes insipidus
- Cannot concentrate urine –> polydipsia, polyuria
- Secondary to Li accumulation in collecting tubule
- Li interferes with antidiuretic hormone
- Volume depletion = Li reabsorption = toxicity
Severe Li poisoning may also result in: (10)
- Coma with hyper-reflexia
- Muscle tremor
- Hyperextension of limbs
- Pulse irregularities
- HTN or hypotension
- ECG changes (T wave depression or inversion)
- Peripheral circulatory failure
- Neuroleptic malignant syndrome
- Epileptic seizures
- Acute tubular necrosis (renal failure) can occur
How will the following factors affect Li levels
1. Eating a lot of pretzels after being on a low sodium diet
2. Hot yoga
3. Giving up caffeine after previously drinking 3-4 cups coffee/day
4. Starting naproxen 500mg BID for gout flare
5. 2nd trimester of pregnancy
6. Increasing fluid intake to 15 cups of water/day to help with overall health
- Decrease
- Increase
- Increase
- Increase
- Decrease
- Decrease
What are some counselling points about common side effect manangement of Li?
1. Thirst
2. Nausea
3. Sedation
4. Acne
5. Tremors
- Drink water, hard candies (should subside)
- Take with food; can consider ER formulation if doesn’t subside
- Take at bedtime; don’t drive
- Talk to pharmacist or physician for treatment
- Talk to physician if doesn’t subside
What are 2 indications for valproic acid?
- Seizures
- Generalized tonic-clonic (grand mal), partial onset, absence
- Has broad-spectrum anti-epileptic activity - Bipolar disorder
- Acute mania treatment
- Maintenance (prophylaxis)
The exact mechanism of action of valproic acid (VPA) is unknown, but what are 5 possible mechanisms to know of?
- Inhibition of voltage-gated Na channels
- Increasing action of GABA
- Modulates signal transduction cascades and gene expression
- May effect neuronal excitation mediated by the NMDA subtype of glutamate receptors
- Also effects serotonin, dopamine, aspartate, and T-type Ca channels
True or False? VPA is not very protein bound?
False, it is bound 85-90% to serum albumin
How is VPA metabolized?
Hepatically
4-ene-valproic acid metabolite can cause _____ ________
liver toxicity
What is the t1/2 of VPA?
12-18 hours
What is the therapeutic range for VPA (In umol/L)?
350-700 umol/L
When is VPA sampled and what is the frequency?
Steady state trough level 3-4 days after initial therapy
How does hepatic disease and renal impairment impact VPA dosing?
How about being elderly?
- Hepatic disease - decreased protein binding and clearance. Avoid in hepatic disease b/c unbound conc goes up
- Renal impairment - no dosage adjustment necessary.
- Elderly have decreased protein binding and clearance, use lower initial doses
Is valproic acid and enzyme inhibitor or inducer?
Inhibitor
What antibiotic class can increase VPA levels (drug-drug interaction)?
Macrolides
- Clarithromycin
- Erythromycin
- Telithromycin
What antibiotic class can decrease VPA levels (DDI)?
Carbapenems
- Ertapenem
- Imipenem
- Meropenem
What OTC drug can increase VPA levels?
ASA/salicylates
What is the MOST MAJOR drug-drug interaction to be aware of when it comes to VPA?
Lamotrigine
What are the dose-related side effects of VPA? (5)
GI
1. NVD
CNS
1. Tremors
2. Sedation
3. Ataxia
4. Dizziness
What are the serious (idiosyncratic) side effects of VPA? (3)
- Increased transaminases and LDH
- Hepatotoxicity
- Pancreatitis
What are 3 chronic side effects of VPA?
- Weight gain
- Menstrual disturbances
- Alopecia
True or False? VPA can be used in pregnancy
False - it is teratogenic
What are the 2 indications for lamotrigine?
- Seizures
- Partial seizures (adjunct), absence seizures (monotherapy), generalized tonic-clonic (monotherapy) - BD
- Acute bipolar depression
- Maintenance in BDI or II
What is the MOA of lamotrigine? (2)
- Alters signal transduction via:
- Binding to the open channel conformation of the voltage-gated Na channels
- Reducing release of glutamate (which may be a secondary result of blocking Na channels, rather than an independent effect) - Weak 5-HT3 receptor inhibitory effects
What is the t1/2 of lamotrigine?
25-33h
What are 3 drugs that can induce metabolism of lamotrigine?
- Phenytoin
- Carbamazepine
- Oral contraceptives
What drug can inhibit metabolism of lamotrigine?
VPA
What is the most important dosing principle you need to know regarding lamotrigine? Why?
Slow titration is very very important.
Faster titration can lead to SEVERE skin rashes, such as SJS or necrolysis (leading to end organ failure)
What are the common side effects of lamotrigine? (4)
- Sedation
- Headaches
- Nausea
- Dizziness
What are the less common side effects of lamotrigine? (3)
- Dyspepsia
- Dysmenorrhea
- Anxiety or emotional lability
What are the rare/serious side effects of lamotrigine? (3)
- Risk of SJS (if titrated too quickly)
- Aseptic meningitis
- Hepatotoxicity
What is the MOST MAJOR drug-drug interaction to remember for lamotrigine?
VPA/DVP - can increase lamotrigine level two-fold or more
What is the most important self-monitoring tip to tell a patient regarding lamotrigine?
Self-monitoring for rash. If any signs of skin abnormalities, STOP taking, and seek medical attention. Don’t start any new lotions or creams when starting this med.
Carbamazepine is structurally similar to ____
TCAs
What are 4 indications for carbamazepine?
- Seizures
- Generalized tonic-clonic (grand mal), partial-onset - BD
- Acute mania treatment
- Maintenance - Neuropathic pain (off-label)
- Trigeminal neuralgia
What is the MOA of carbamazepine?
Signal transduction modulation (decrease repetitive action potential firing) and anti-kindling properties
- Blocks voltage-dependent Na channels (at a different recpetor/subunit than VPA)
- Blocks NMDA glutamate receptor and decreases [Ca2+]
- May depress activity in the nucleus ventralis of the thalamus or decrease synaptic transmission
Carbamazepine and ADH. What happens here?
Carbamazepine stimulates the release of ADH and potentiates its action in promoting reabsorption of water
How is carbamazepine metabolized?
Hepatically via CYP enzymes (CYP3A4)
Carbamazepine-10,11-epoxide is the major metabolite of carbamazepine. Why is it important and how is that metabolized?
It is active and has therapeutic and toxic effects.
Is hydrolyzed by CYP1A2
What is the unique thing to remember about carbamazepine metabolism?
It induces its own metabolism via the epoxide-diol pathway (AUTOINDUCTION)
What is the clearance and t1/2 of carbamazepine?
Both are variable due to autoinduction
What is the time of sampling of carbamazepine levels?
Trough within 1 hour prior to dose
What is the frequency of sampling of carbamazepine levels? (2)
- During auto-induction (every 1-2 weeks until on stable regimen)
- Steady state trough (after 5 weeks)
How does hepatic disease and renal impairment impact carbamazepine dosing?
How about being elderly?
- Hepatic disease - not recommended in pts with decompensated liver disease, dose reduction may be needed in pts with stable liver disease
- Renal impairment - no dosage adjustment necessary
- Elderly have decreased hepatic clearance, use initial lower doses and smaller dose increases
What are 4 dosing principles of carbamazepine?
- Initiate slowly due to early long half-life in order to minimize side effects
- Can initiate with any dosage form
- Best to give in divided doses, usually Q12H or Q8H, instead of a single dose
- Dosing best at mealtime
Any time carbamazepine is started or stopped, what must be done?
Why?
Do a drug interaction check.
- Co-administration of CYP3A4 inhibitors and inducers increase and decrease CBZ levels respectively with initiation or dose increase
- CBZ induces multiple enzyme systems too
What are the drug classes that can increase CBZ levels? (3)
- Macrolides (clarithromycin, erythromycin, telithromycin)
- Azoles (itraconazole, fluconazole, ketoconazole)
- CCBs (diltiazem, verapamil)
What are some “other” substances that can increase CBZ levels (3 are drugs, one is non drug)
- Cimetidine
- Grapefruit juice
- Propoxyphene
- Quinine
What is an important class of medications that can be decreased by CBZ?
Anticoagulants - warfarin and DOACs
What are some dose-related side effects of CBZ? (3)
- GI - NV
- CNS - sedation
- CV - tachycardia
What are 3 important serious (idiosyncratic) side effects of CBZ?
- SIADH/hyponatremia
- Blood dyscrasias: leukopenia, thrombocytopenia, eosinophilia
- Rash (10% morbilliform) and hypersensitivity reactions.
What are the contraindications for using CBZ? (5)
1. Concurrent use with clozapine
2. History of hepatic disease
3. CVD
4. Blood dyscrasias
5. Bone-marrow depression
Should be able to list the atypical antipsychotics (6)
(Real Quests Only After Leveling Alts)
- Risperidone
- Quetiapine
- Olanzapine
- Aripiprazole
- Lurasidone
- Asenapine
Atypical vs. typical antipsychotic use in bipolar disorder. Which is used more?
Atypicals - generally have a lower risk of EPS and hyperprolactinemia.
Typicals rarely used in BD
Doses of antipsychotics are lower for BD than for psychosis. Why?
BD patients are more likely to show EPS when treated with comparable doses of antipsychotics compared to patients with psychosis (more likely to go into depression)
What is the consensus to using antidepressants in bipolar as of right now? (4)
- Avoid AD monotherapy without antimanic agent
- Use with caution in people with history of AD-induced mania, mixed features, or rapid cycling
- Ds/c during acute manic episode (taper or abrupt discontinuation if severe mania)
- Consider tapering off once depression symptoms eliminated for 3-4 months
IF going to use an antidepressant in bipolar, then what should be done? (3)
- Avoid TCAs > Avoid SNRIs (higher risk of switching)
- Safest in BDII
- Bupropion > sertraline, then fluoxetine or other SSRIs > venlafaxine - Paroxetine NOT recommended due to level 2 negative evidence in BDII
Following the CANMAT guidelines, what is being assessed if the person has acute mania? (8)
- Risk of aggressive behaviour or violence to others
- Risk of suicide
- Degree of insight
- Ability to adhere to treatment
- Co-morbidities
- Substance use
- Physical conditions & lab tests
- Most appropriate treatment setting (inpatient vs. outpatient)
Following the CANMAT guidelines, what substances should be discontinued if the person is experiencing acute mania? (4)
- Antidepressants
- Stimulants (caffeine, amphetamines)
- Alcohol
- Nicotine (gradual discontinuation)
Following the CANMAT guidelines, what needs to be ruled out before stating the person is experiencing acute mania? (4)
- Prescribed medication
- Illicit-drug use/abuse (treat if present)
- Endocrine disorder
- Neurological disorder
What are 1st line monotherapies for acute mania?
(Just know the meds) (6)
- Lithium
- Quetiapine
- Divalproex
- Aripiprazole
- Paliperidone (dose >6mg)
- Risperidone
What are the 1st line combination therapies for acute mania? (4)
- Quetiapine + Li/DVP
- Aripiprazole + Li/DVP
- Risperidone + Li/DVP
- Asenapine + Li/DVP
What are the patient specific factors for giving a manic patient lithium?
Lithium is preferred over DVP for individuals who display classical euphoric grandiose mania (elated mood in the absence of depressive symptoms), few prior episodes of illness, a mania-depression- euthymia course, and/or those with a family history of BD, especially family history of lithium response
What is the patient specific factors for giving a manic patient DVP?
DVP is equally effective in those with classical and dysphoric mania. It is recommended for those with multiple prior episodes, predominant irritable or dysphoric mood and/or comorbid substance abuse or those with a history of head trauma
When might you add on or switch therapy for a patient with acute mania?
Some therapeutic response is expected within 1-2 weeks after starting a 1st line agent. If no response is observed within 2 weeks with therapeutic doses of antimanic agents, and other contributing factors are excluded, then switch or add-on strategies should be considered
What are some agents that are NOT recommended to use in acute mania? (4)
- Gabapentin
- Lamotrigine
- Omega 3 fatty acids
- Topiramate
What things should be assessed in a patient with BDI depression? (7)
- Severity of depression
- Risk of suicide/self-harm behaviour
- Ability to adhere to treatment
- Psychosocial support network
- Ability to function
- Previous treatments
- Decided appropriate treatment setting:
- Hospital
- Outpatient
What substances should be discontinued if a patient has BDI depression? (5)
- Stimulants
- Nicotine
- Caffeine
- Drugs
- Alcohol
What should be ruled out if a patient is presenting with BDI depression? (2)
- Symptoms due to alcohol/drug use, medications, other treatments
- General medical conditions
What are the first line treatments for BDI depression? (6)
- Quetiapine
- Lurasidone + Li/DVP
- Lithium
- Lamotrigine
- Lurasidone (monotherapy)
- Lamotrigine (adjunct)
What agents are NOT recommended for acute bipolar depression?
Antidepressant monotherapy
- Available trials do not support their efficacy
- Safety concern = mood switching
What is the importance of effective bipolar maintenance treatment early in illness, even after first episode? (3)
- Reverse cognitive impairment
- Preserve brain plasticity
- May lead to improved prognosis and minimization of illness progression
Pharmacotherapy is the foundation to BD maintenance therapy but alone is often ineffective to prevent recurrence. What then should also be done 1st line?
Psychoeducation is the only 1st line psychosocial intervention for maintenance therapy that should be offered to all patients
What should be assessed in a patient on BDI maintenance? (5)
- Medications effective in acute phase (usually effective in maintenance phase)
- Controversial if antidepressants should be continued - History (clinical course, response to previous medications, family history)
- Psychiatric comorbidities
- Predominant illness polarity
- Polarity of most recent illness
What substances should be discontinued if a patient is on BDI maintenance therapy? (5)
- Stimulants
- Nicotine
- Caffeine
- Drugs
- Alcohol use
What should be ruled out when patient present in BDI maintenace? (2)
- Symptoms due to alcohol/drug use, other treatments
- General medical condition
What are the first-line treatment options in BDI maintenance? (9)
- Li
- Quetiapine
- DVP
- Lamotrigine
- Asenapine
- Quetiapine + Li/DVP
- Aripiprazole + Li/DVP
- Aripiprazole
- Aripiprazole OM
When might you add on or switch therapies in BDI maintenance?
If therapy requires adjustment and no acute mania or depression
What is the recommended pharmacotherapy in a BD patient with mixed episodes? (3)
- Discontinue antidepressants
- Monotherapy –> atypical antipsychotic
- Combination therapy –> Li/DVP + atypical antipsychotic
What BD meds should be avoided in pregnancy? (3)
Avoid: DVP/VPA, CBZ
Small increased risk in 1st trimester: lithium
Which BD agent has the least risk/appears to be safe in pregnancy?
Lamotrigine
Can antipsychotics be used in pregnancy?
Least studied, but risk appears neutral for quetiapine, risperidone, aripiprazole, olanzapine
Which BD medication has the most evidence for reducing the risk of suicide in a BD patient? How?
Lithium
Reduces risk of depressive relapse, serotonin-mediated reduction in impulsivity or aggressive behaviour (e.g., toward triggers) and a non-specific benefit from long-term monitoring provided during therapy with lithium
In general, what important roles do we as pharmacists have in treating a BDI patient? (5)
- Screening for presence or history of mania
- Avoiding antidepressant monotherapy
- Patient education
- Appropriate dosing
- Supporting adherence
Secondary Causes of Mania:
What are some medical conditions that can induce mania? (4)
- CNS disorders (brain tumor, strokes, head injuries, etc.)
- Infections (encephalitis, sepsis, HIV, etc.)
- Electrolyte or metabolic abnormalities (Ca or Na fluctuations)
- Endocrine or hormonal dysregulation (Addison’s disesase, Cushing’s, etc.)
Secondary Causes of Mania:
What are some medications/drugs that can induce mania? (7)
- Alcohol intoxication
- Drug withdrawal states
- Antidepressants (MAOIs, TCAs, etc.)
- DA-augmenting agents (CNS stimulants: amphetamine, cocaine; DA agonists)
- Marijuana intoxication
- NE-augmenting agents
- Steroids (anabolic, cortico, etc.)
Secondary Causes of Mania:
What are some somatic therapies that can potentially induce mania? (3)
- Bright light therapy
- Deep brain stimulation
- Sleep deprivation
What is anxiety?
A normal emotion under circumstances of threat and is thought to be part of the evolutionary fight or flight reaction of survival.
When does anxiety become a disorder?
When it is overwhelming and affecting function and quality of life
What are the core symptoms of anxiety? (2)
- Psychological
- Fear/anxiety, worry, apprehension, difficulty concentrating - Somatic (physical)
- Increased HR, tremor, sweating, GI upset
Which circuit in the brain primarily relates to fear?
Amygdala-centered circuit
Which circuit in the brain primarily relates to worry?
Cortico-striato-thalamo-cortical circuit
What are the neurotransmitters that regulate the brain circuits associated with anxiety? (6)
- 5HT
- GABA
- Glutamate
- CRF/HPA
- NE
- Voltage-gated ion channels
GABA _________ activity of neurons
decreases
True or False? Gabapentin and pregabalin work on GABA in the brain
False - despite their names they have no association with GABA, they work on the 𝜶2ẟ subunit of presynaptic N and P/Q voltage-sensitive calcium channel to block release of glutamate when neurotransmission is excessive
What happens with SNRIs and β1 receptors when initially starting the medication?
Symptoms can be worsened at initial dosing with SNRIs but as β1 receptors downregulate, fear/worry improves long term
What are 4 aspects to evaluation of anxiety disorders?
- Gather history
- Review of systems
- Rule out anxiety disorders due to general medical conditions or substance use
- Review substances used (caffeine, OTC use, herbal medications, recreational substances) - Suicidal ideation or intent
What classes of drugs are classified as serotonergic agents? (3)
- SSRIs
- SNRIs
- TCAs
What drugs are classified as 𝜶2ẟ ligand drugs? (2)
- Gabapentin
- Pregabalin
What drugs are classified as selective serotonin agents (5HT1A agonists) (2)?
- Buspirone
- Second generation antipsychotics (SGAs)
What drug is an 𝜶1-1 adrenergic antagonist?
Prazosin
What are unique considerations to remember for bupropion? (2)
- Activating.
- Risk of seizures, avoid if seizure history, head trauma, bulimia, anorexia, electrolyte disturbances
What are unique considerations to remember for buspirone? (3)
- Slow onset, modest efficacy.
- May be helpful to augment therapy in those with partial response to antidepressants.
- Avoid if comorbid depression
What is a unique consideration to remember for citalopram? (2)
- Lower risk for insomnia, agitation, drug interactions compared to other SSRIs.
- Dose dependent risk of QT prolongation
What is a unique consideration to remember for duloxetine? (3)
- May be useful for comorbid pain.
- Compared to SSRIs: increased withdrawal symptoms if not tapered, increased insomnia or agitation.
- Avoid if liver disease or heavy EtOH use.
What are unique considerations to remember for escitalopram? (1)
- Similar to citalopram, except QT risk is controversial
What are unique considerations to remember for fluoxetine? (3)
- More activating than other SSRIs
- Self-tapering due to long half-life
- Drug interactions
What are unique considerations to remember for fluvoxamine? (2)
- Withdrawal symptoms if not tapered.
- Risk for drug interactions due to inhibition of CYP1A2 and CYP2C19
What are unique considerations to remember for hydroxyzine? (2)
- Useful for co-morbid insomnia
- Dose-related anticholinergic effects limit clinical use
What are unique considerations to remember for imipramine? (2)
- Anticholinergic; cardiotoxic in overdose
- Not well tolerated
What are unique considerations to remember for mirtazapine? (3)
- Helpful with comorbid insomnia
- Lower doses are more sedating
- May increase appetite and lead to weight gain
What are unique considerations to remember for paroxetine? (4)
- Compared to other SSRIs, more sedating, less agitation, more constipation, withdrawal symptoms if not tapered.
- May be associated with greater weight gain.
- Concern for drug interactions
- Avoid in pregnancy due to cardiac septal defects
What are unique considerations to remember for pregabalin? (2)
- Sedation and dizziness are common
- Weight gain, especially with long-term use
What are unique considerations to remember for quetiapine? (1)
- Concerns for metabolic ADEs, sedation, EPS
What are unique considerations to remember for sertraline? (1)
- Compared to other SSRIs, insomnia, agitation, dizziness
What are unique considerations to remember for venlafaxine (5)
- Compared to other antidepressants, greater risk for insomnia or agitation as well as increased BP
- Possible benefit for comorbid pain
- Few drug interactions
- Withdrawal symptoms if not tapered
- Better evidence for psychological symptoms (e.g., ruminative worry of GAD)
Ratio of women:men with GAD is x:y
2:1
When is GAD onset usually?
Usually in late adolescence or early adulthood
- Cases in older adults as well
GAD etiology is not really know, but it is likely caused by what?
A combined effect of biological and psychological factors
What are other suspected causes of GAD? (6)
- Medications
- Natural products
- Medical conditions
- Medication withdrawal
- Alcohol, sedatives, benzos - Socioeconomic: poor minority classes
- Stressful event in susceptible person
What are some important drugs to know that are associated with anxiety symptoms? (4)
- Antidepressants - bupropion
- NSAIDs
- Stimulants
- Sympathomimetics - pseudoephedrine, phenylepherine
What are some psychological and cognitive symptoms of GAD? (7)
- Excessive anxiety
- Worries that are difficult to control
- Feeling keyed up or on edge
- Poor concentration
- Restlessness
- Irritability
- Sleep disturbances
What are some physical symptoms of GAD? (6)
- Fatigue
- Muscle tension
- Trembling or shaking
- Feeling of fullness in throat/chest
- Sweating
- Cold, clammy hands
Describe the Generalized Anxiety Disorder Assessment-7 (GAD-7).
That is, how many items, what is it used for, who does it, how long?
- 7-item scale
- Screens for GAD and severity
- Self-rated
- Brief (5 mins)
Describe the Hamilton Anxiety Scale (HAM-A).
That is, how many items, what is it used for, who does it, how long? (6)
- 14-item scale
- Assess severity of anxiety
- Clinician rated
- Brief (10-15 mins)
- Assess response to treatment
- Need trained rater
What are the GAD goals of therapy for an acute episode? (2)
- Decrease severity and duration of anxiety symptoms
- Improve overall function
What are the GAD goals of therapy for long-term goals? (4)
- Remission
- With minimal or no anxiety symptoms
- No functional impairment
- Improve patient QoL
What are the treatment principles to consider for GAD treatment? (3)
- Psychotherapy + pharmacotherapy
- Psychotherapy is least invasive and safest
- Pharm indicated if symptoms severe enough to produce functional disability - Treatment plan depends on severity and chronicity of symptoms, age, medication history, and comorbid medical and psychiatric conditions
- Consider: anticipated ADEs, history of prior response in patient or family member, patient preference, cost
What are some non-pharm treatment options that can be used for GAD? (6)
- Reduce/avoid alcohol, caffeine, nicotine use
- Avoidance of non-prescription stimulants & medications known to induce anxiety
- Exercise
- Psychotherapy +/- counselling (CBT most effective)
- Relaxation techniques
- Biofeedback
What are THE 1st-line treatment options for GAD? (6)
1.SSRI:
- Escitalopram
- Paroxetine
- Sertraline
2. SNRI:
- Duloxetine
- Venlafaxine
3. Pregabalin
What are the 2nd-line treatment options for GAD? (6)
- BZD (short-term use)
- Alprazolam
- Lorazepam
- Diazepam - Bupropion
- Buspirone
- Hydroxyzine
What does current evidence say about what to do when there has been a partial response to drug therapy?
Current data does not provide guidance as to whether it is best to increase to dose, augment, or switch when there has been a partial response to drug therapy
What is the main side effect to know for hydroxyzine?
Anticholinergic, sedation
Should know the important GAD treatment timeframes for SSRIs/SNRIs:
1. Onset of symptom relief
2. Maximal response
3. Treatment duration
- 2-4 weeks
- 12 weeks
- 12-24 months
What is the MOA of benzodiazepines? (3)
- Bind to the benzodiazepine receptors on the GABA neuron
- Leads to an increase in the frequency of opening of the chloride channels by increasing binding affinity for the endogenous ligand GABA
- The shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization
How efficacious are benzos in GAD?
Provides rapid initial relief of anxiety symptoms, but effects may not be significantly different from placebo after 4-6 weeks of treatment
RCT evidence supports the efficacy of which benzos in GAD specifically? (BALD)
- Bromazepam
- Alprazolam
- Lorazepam
- Diazepam
True or False? Clonazepam is not used in GAD
False? So, there are no RCTs evaluating its use in GAD, but it is used extensively in clinical practice.
The short acting benzos include? (3)
- Alprazolam
- Lorazepam
- Bromazepam (maybe, t1/2 is 8-30h which is a huge variation)
The long acting benzos include? (2)
- Clonazepam
- Diazepam
How fast is the onset for the following:
1. Alprazolam
2. Bromazepam
3. Clonazepam
4. Diazepam
5. Lorazepam
- 1-2h
- 1-2h
- 20-60 min
- 30-60 min
- 30-60 min
What are the common side effects of benzos? (5)
- Ataxia
- Dizziness/lightheadedness
- Sedation and residual daytime sleepiness
- Psychomotor impairment
- Agitation, irritability, confusion
What are some of the less common side effects of benzos? (6)
- Anterograde amnesia
- Depression
- Confusion
- Bizarre behaviour
- Hallucination
- Respiratory depression
Touch on benzodiazepine dependence. That is;
1. When might it develop?
2. What doses have a higher risk?
3. What else can increase the risk?
4. Withdrawal?
- Psychological and physical dependence may develop with long-term use
- Risk of dependence increases with higher dose and/or longer use
- Risk further increased with history of AUD or other SUD or personality disorders
- Withdrawal symptoms can occur following discontinuation of therapy with as little as one week of use
What are the LOT drugs (benzos)/why are they used?
Lorazepam, oxazepam, temazepam
Preferred in elderly and liver dysfunction due to no active metabolites
What is a pro and con of long acting benzos?
Pro:
- Good choice for tapering as less risk of withdrawal (i.e., diazepam, clonazepam)
Con:
- More daytime sedation
What is a pro of short acting benzos? What are the 3 cons?
Pro:
- Better hypnotic and sedative properties
Cons:
- More rebound anxiety
- Inter-dose withdrawal
- Anterograde amnesia
What are the benzo withdrawal symptoms? (11)
- Sweating
- Tremor
- Nausea
- Vomiting
- Rebound anxiety
- Increased heart rate
- Insomnia
- Agitation
- Twitching
- Visual/tactile hallucinations
- SEIZURES (onset within 1-2 days after BZD stopped)
To avoid benzo withdrawals, we should taper. Which benzo is best for tapering and what is a conservative tapering schedule we can follow?
Diazepam
Decrease dose by 10-20% q1-2 weeks
What are some precautions to giving benzos to someone? (7)
- SUD (concurrent use with opioids may cause profound respiratory depression, coma, or death)
- Sleep apnea
- COPD
- Elderly
- CNS depression
- Pregnancy (floppy infant syndrome; possible teratogen)
- Clozapine-use
Benzo withdrawal is rarely fatal alone, but may be fatal when taken in combination with _______, _______, ____________
alcohol, opioids, barbiturates
What is the benzo antidote?
Flumazenil
How does flumazenil work as a benzo antidote?
Reverses hypnotic-sedative effect of BZD but clinically use is limited due to risk of causing seizures in BZD dependent patients
For which of the following antidepressant classes would it be especially important to counsel patients that their activity may get worse before it starts to improve?
a. SSRI
b. SNRI
c. SARI
d. 5HT1a agonist
b
Which of the following is a first-line option for GAD?
a. Mirtazapine
b. Quetiapine
c. Buspirone
d. Pregabalin
e. Lorazepam
d
Define panic disorder
Recurrent unexpected panic attacks with at least 1 of the attacks being followed by a month or longer of at least 1 of the following:
- Constant concern about having another attack
- Being anxious about the implications of the attack or its consequences (e.g., losing control, having a heart attack)
- Maladaptive change in behaviour designed to avoid having panic attacks
The ratio of females:males with panic disorder is x:y
2:1
What are the categories of risk factors that can lead to panic disorder? (5)
- Tempermental (i.e., learned behaviours)
- Personality types
- Environmental
- Genetic and physiological
- Medications
What are some comorbidities of panic disorder? (6)
- Other anxiety disorders
- Depression
- Bipolar disorder
- AUD
- Higher rates of suicide atempts and suicidal ideation
- Medical comorbidities
What are the clinical psychological presentations of a panic attack? (5)
- Depersonalization
- Derealization
- Fear of losing control
- Fear of going crazy
- Fear of dying
What are the clinical physical presentations of a panic attack? (13, obvs dont need to memorize every last one of them)
- Abdominal distress
- Chest pain
- Chills
- Dizziness
- Feeling of choking
- Hot flashes
- Palpitations
- Nausea
- Paresthesias
- Shortness of breath
- Sweating
- Tachycardia
- Trembling or shaking
What is the clinical course of panic disorder? (4)
- Panic attacks vary in frequency and intensity
- 1/3 of pts achieve remission
- 1/5 of pts have unremitting & chronic course
- Most pts require long-term treatment to achieve remission, prevent relapse, and reduce risks associated with co-morbidity
What are some predictors of a chronic course of panic disorder? (3)
- Long duration of illness
- Comorbidity with personality, mood, other anxiety disorders
- Excessive sensitivity to physical symptoms of anxiety
What are the 2 standardized rating scales for panic disoder?
- Panic Disorder Severity Scale (PDSS)
- Panic and Agoraphobia Scale (PAS)
What are the non-pharm treatment options for panic disorder? (5)
CBT. Types:
- Applied relaxation
- Exposure through imagery
- Panic managment
- Breathing retraining
- Cognitive restructuring
How effective is non-pharm treatment when compared to pharmacotherapy when it comes to panic disorder? (3)
- Effectiveness comparable to pharmacotherapy
- Limited by lack of availability of trained professionals
- Studies indicate 8-15 sessions needed
What are the 1st line medications for PD? (2 classes, 8 meds total)
SSRIs:
1. Citalopram
2. Escitalopram
3. Fluoxetine
4. Fluvoxamine
5. Paroxetine
6. Sertraline
SNRIs:
1. Duloxetine
2. Venlafaxine
What are the 2nd line medications for PD? (2 classes, 4 meds total)
TCAs:
1. Clomipramine
2. Imipramine
BZDs:
1. Alprazolam
2. Clonazepam
What is the 3rd line med for PD? (1)
MAOI: Phenelzine
True or False? BZDs are useful for treating acute panic attacks?
False - they are not, because the onset of BZDs will typically occur after the panic attack
What is the onset of action of antidepressants in panic disorder? (3 things to know about)
- Most pts with PD are hypersensitive to medication ADEs at initation and this can lead to activation (early worsening of anxiety, agitation, irritability)
- Reduction of panic attack frequency, anticipatory anxiety, and avoidance may start within first 3-4 weeks
- For pts with significant avoidance, full remission may take up to 6 months or longer
What is the onset of action of BZDs in panic disorder?
Onset within hours for autonomic symptoms of anxiety, full benefit may take 4-6 weeks
Should know the important panic disorder treatment timeframes for:
1. Acute treatment duration
2. Maintenance treatment duration
3. Tapering duration
- 1-3 months (alter treatment if no response after 6-8 weeks)
- 12 months
- 4-6 months (taper slowly to reduce risk of relapse)
Females or males, who has a higher rate of social anxiety disorder (SAD)?
Females
What is the epidemiology of SAD? (5)
- Older adults may show concern about disability due to declining sensory functioning (sensory, hearing) or embarrassment about one’s appearance (e.g., tremor from Parkinson’s disease) or functioning due to medical conditions (e.g., urinary incontinence)
- Associated with increased rates of school dropouts; and decreased well-being, employment, workplace productivity, SES, and QoL
- Associated with being single, unmarried, divorced and not having children
- Only ~50% of pts with SAD seek treatment and usually only after 15-20 years of symptoms
- Unemployment is a strong predictor of persistence of SAD
What are the classes of risk factors associated with SAD? (3)
- Tempermental
- Environmental
- Genetic and physiological
What are some comorbidities associated with SAD? (6)
- Females report greater number of social fears and comorbid depressive, bipolar, and anxiety disorders
- Males are more likely to fear dating, have oppositional defiant disorder or conduct disorder, and use alcohol or recreational drugs to relieve symptoms of disorder
- Chronic social isolation may lead to MDD
- Comorbid MDD higher in older adults
- Substances may be used to self-medicate for social fears but symptoms of intoxication or withdrawal may be a source of further social fear
- 70-80% have history of concurrent anxiety, depression, and SUD
What are the classes of signs and symptoms of SAD? (4)
- Fears
- Feared situations
- Physical symptoms
- Types
What are some of the “fears” of SAD? (3)
- Scrutinized by others
- Embarrassment
- Humiliation
What are some of the “feared situations” of SAD? (5)
- Public speaking
- Eating or drinking in front of others
- Interacting with authority figures
- Talking with strangers
- Use of public washrooms
What are the physical symptoms of SAD? (6)
- Blushing
- “Butterflies in stomach”
- Diarrhea
- Sweating
- Tachycardia
- Trembling
What are the types of SAD? (2)
- Generalized: fear and avoidance of a wide range of social situations
- Nongeneralized: fear is limited to one or two situations
Name the 2 standardized rating scales for SAD
- Liebowitz Social Anxiety Scale
- Social Phobia Inventory (SPIN)
What are the non-pharm treatment options for SAD? (2)
- CBT - education, exposure, cognitive restructuring
- Treatment for at least 12 weeks
- Individual treatment more effective than group therapy
- Similar efficacy to pharmacotherapy for acute treatment
- Effects may last for 6-12+ months - Social Skills Training
What are the 1st line treatment options for SAD? (1 non-pharm, 3 classes, 7 meds total)
- CBT
- SSRIs
- Escitalopram
- Fluoxetine
- Fluvoxamine
- Paroxetine
- Sertraline - SNRIs
- Venlafaxine - Pregabalin
What agents are used in SAD only for performance situations?
Beta-blockers, such as atenolol and propranolol
What is the treatment timeframes for SAD for the following:
1. Onset of symptom relief
2. Treatment duration
3. Tapering duration
- 6-8 weeks
- 1+ years (continue for 1 year or longer after response attained)
- 3-4 months
Men vs. women. Who is PTSD more prevalent in?
Women 2x more than men
What is the neuropathophysiology of PTSD?
Insufficient glucocorticoid signaling at the time of trauma results in unopposed sympathetic nervous system activation that enhances the consolidation of the traumatic memory
After trauma, 3 dimensions of PTSD unfold. What are they?
- Re-experiencing the event with distressing recollections, dreams, flashbacks, psychological, and physical distress
- Persistent avoidance of stimuli that might invite memories or experiences of the trauma
- Increased arousal
75-80% of pts with PTSD will have other psychiatric disorders, such as? (Thinking co-morbidities here) (6)
- MDD
- SUD and AUD
- Anxiety disorders (GAD)
- Personality dysfunction
- Bipolar
- Psychosis
PTSD comes with increased rates of medical co-morbidities, such as? (3)
- CVD
- Respiratory disorders
- Autoimmune disorders
True or False? There are no specific screening tools specific to PTSD
False - obviously there are
The core of PTSD treatment is trauma-focused psychotherapy. What does that include? (3)
- Cognitive Processing Therapy
- Prolonged Exposure Therapy
- Eye Movement Desensitization & Reprocessing
What are the limitations to the core treatment of PTSD (trauma-focused psychotherapy)? (3)
- 30-50% of pts have residual symptoms
- High drop out rates
- Resources
What are the 3 goals of pharmacotherapy in PTSD?
- Symptom reduction
- Improve sleep, QoL, participation in non-pharm treatment
- Minimize ADEs and comorbidities
What are the 1st line treatment options for PTSD? (3 classes, 5 meds total)
SSRIs:
1. Fluoxetine
2. Paroxetine
3. Sertraline
SNRIs:
1. Venlafaxine
Prazosin (for trauma related nightmares and to improve sleep)
Which PTSD medication is specifically used for trauma related nightmares and to improve sleep?
Prazosin
What medications are NOT recommended in use to treat PTSD?
Benzos such as alprazolam and clonazepam
What are the important timeframes to remember in the treatment of PTSD?
1. Onset of symptom relief
2. Maximal response
3. Treatment duration
- 2-8 weeks
- 12 weeks+
- 12-24 months
Men vs. women, which has a higher prevalence of OCD?
Females affected slightly more than males
The pathophysiology of OCD is not well understood, but it could possibly be related to abnormalities in: (3)
- Serotonin neurotransmission
- Dopamine transmission (especially in cases with co-morbid tics and Tourette’s)
- Glutamate
The etiology of OCD is unknown, but what are some potential risk factors to be aware of? (5)
- PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections)
- Pregnancy
- Tempermental
- Environmental
- Genetics
What are the comorbidities associated with OCD? (7)
- Males more likely to have comorbidities
- Suicidal thoughts occur at some point in ~50% of patients with OCD, suicide attempts are reported in 25% of patients with OCD
- MDD and bipolar
- Anxiety disorder
- Tic disorder
- A triad of OCD, tic disorder, and attention-deficit/hyperactivity disorder can also be seen in children
- Body dysmorphic disorder, trichotillomania, excoriation occuring more likely in pts with OCD than other disorders
What are some indicators of good prognosis of OCD? (3)
- Good social and occupational adjustment
- Presence of precipitating event
- Episodic nature of the symptoms
What are some indicators of poor prognosis of OCD? (7)
- Acting on compulsions
- Childhood onset
- Bizarre compulsions
- Need for hospitalization
- Comorbid depression
- Comorbid personality disorder
- Delusional beliefs
What are some signs/symptoms of obsessions in OCD? (5)
- Fear of contamination
- Unwanted sexual or aggressive thoughts
- Doubts (e.g., left door unlocked)
- Concerns about throwing away something valuable
- Need for symmetry
What are some signs/symptoms of compulsions in OCD? (5)
- Washing, cleaning
- Checking, praying, “undoing actions,” asking for reassurance
- Repeated checking behaviours
- Hoarding
- Ordering, arranging, balancing, straightening until “just right”
What is the OCD standardized rating scale?
Yale-Brown Obsessive Compulsive Scale (Y-BOCS)
- Clinician-rated
What are the 3 non-pharm treatment options for OCD?
- CBT
- Found to be as effective as pharmacotherapy
- Stronger effects on compulsions vs. obsessions - Deep Brain Stimulation (DBS)
- Surgically implanted device - Radio Frequency Wave Surgery
- Destroy small amount of brain tissue in the corticostriatal circuit
What are the 1st line treatment options for OCD? (3 classes, 8 meds total)
SSRIs:
1. Escitalopram
2. Fluoxetine
3. Fluvoxamine
4. Paroxetine
5. Sertraline
SNRI:
1. Venlafaxine
Adjunct:
1. Aripiprazole
2. Risperidone
What is the 2nd line treatment option for OCD?
Clomipramine
How often is the acute phase of OCD treatment monitored?
Monitor weekly x 4 weeks then biweekly. Once stable, monitor q1-2 months
What are the important OCD treatment timeframes for the following:
1. Onset of symptom relief
2. Maximal response
3. Treatment duration
- 2-4 weeks
- 10-12 weeks
- 1-2 years
What are the 1st generation antipsychotics? (10)
- Chlorpromazine
- Flupent(h)ixol
- Fluphenazine
- Haloperidol
- Loxapine
- Methotrimeprazine
- Perphenazine
- Pimozide
- Trifluoperazine
- Zuclopenthixol
What are the 2nd generation antipsychotics? (8)
- Asenapine
- Clozapine
- Lurasidone
- Olanzapine
- Paliperidone
- Quetiapine
- Risperidone
- Ziprasidone
What are the 3rd generation antipsychotics? (3)
- Aripiprazole
- Brexpiprazole
- Cariprazine
Define schizophrenia
A complex syndrome of disorganized bizarre thoughts, hallucinations, delusions, inappropriate affect, and impaired social functioning
Define psychosis
Presence of gross impairment of reality testing (e.g., lose touch with reality) as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour without apparent awareness on the part of the patient of the incomprehensibility of their behaviour
What is substance induced psychosis (define)?
Hallucinations or delusions development during or within 1 month of substance use/withdrawal
What are some risk factors for schizophrenia? (5)
- Immigrant ethnic groups
- Perinatal/early childhood (hypoxia, maternal infection/stress/malnutrition)
- Urban upbringing
- Cannabis use
- Life stress
Patients with schizo die 10-20 years earlier than the average population. Why? (7)
- Decreased access to care, poor diet
- Decreased exercise
- Increased obesity/diabetes
- Increased smoking 60-90%
- SUD
- Increased CVD - doubles in first year
- Suicide
What are some factors associated with non-adherence of medication for schizo? (11)
- Decreased motivational drive from AP
- Adverse effects
- Poor insight into illness
- Personal attitudes towards treatment
- Stigma
- Financial constraints
- Homelessness
- Substance use
- Lack of support
- Ethnic minority
- Weak therapeutic alliance
What is the pathophysiology of schizophrenia? (3)
- Dopamine dysregulation is the key theory underlying the pathophysiology of the disease
- Serotonin dysregulation also contributes
- Modulates dopamine - Glutamate and GABA also have a role
- Less clearly understood
What are the 4 dopaminergic pathways of the brain?
- Nigrostriatal
- Mesolimbic
- Mesocortical
- Tuberoinfundibular
What is the function of the nigrostriatal dopamine tract? (2)
- Motor coordination
- Posture control
What are the dopamine blocking AP drug effects on the nigrostriatal dopamine tract? (1)
Movement disorders (EPS)
What is the function of the mesolimbic dopamine tract? (5)
- Pleasure
- Reward
- Desire
- Response to stimuli
- Motivational behaviour
Dopamine excess in which dopamine tract in the brain increases positive symptoms of schizo?
Mesolimbic
What are the dopamine blocking AP drug effects on the mesolimbic dopamine tract? (1)
Relief of psychosis (positive symptoms)
What are the functions of the mesocortical dopamine tract? (6)
- Cognition
- Motivation
- Communication
- Social function
- Emotional response
- Problem solving
Dopamine excess in which dopamine tract in the brain increases negative symptoms of schizo?
Mesocortical
What are the dopamine blocking AP drug effects on the mesocortical dopamine tract? (2)
- Akathisia?
- Treatment of negative symptoms and depression? (possibly through 5HT2A blockade)
What is the function of the tuberoinfundibular dopamine tract?
Regulates prolactin release
What are the dopamine blocking AP drug effects on the tuberoinfundibular dopamine tract? (9)
- Hyperprolactinemia
- Gynecomastia
- Galactorrhea
- Amenorrhea
- Hirsutism
- Weight gain
- Osteoporosis
- Sexual dysfunction
- ED
What are the prodromal features of schizophrenia? (5)
- Often recognized retrospectively after the diagnosis has been made
- Reclusive adolescence without close friends (e.g., not involved in school actitivies or teams)
- Not functioning well in occupational, social, and personal activities
- Markedly peculiar behaviour, abnormal affects, unusual speech, bizarre ideas and strange
- Perceptual experiences:
- Preoccupation w/ religion; magical thinking; excessive writing without meaning; sensitivity and irritability when touched by others; unusual sensitivity to stimuli
True or False? There are no specific signs or symptoms that are specific of schizophrenia
True
Define what positive and negative symptoms are
Positive = added experiences
Negative = loss of experiences (sense of emotion seems to be blunted)
What are some examples of positive symptoms (psychosis)? (6)
- Hallucinations (most commonly auditory or visual)
- Suspiciousness/paranoia
- Delusions
- Disturbed thought content
- Bizarre or disorganized behaviour (involuntary movements, mannerisms, catatonia)
- Thought disorder (e.g., tangential speech; thought blocking)
What are some examples of negative symptoms of schizo? (8)
- Apathy
- Social indifference
- Loss of emotional connectedness
- Loss of motivation (avolition)
- Alogia (poverty of speech)
- Flat affect
- Poor self care
- Psychomotor retardation
What are some examples of cognitive symptoms of schizophrenia? (3)
- Memory impairment
- Poor concentration
- Impaired executive function: planning, problem solving
What are some examples of mood symptoms of schizophrenia? (4)
- Dysphoria
- Depression
- Excitement
- Mania
What ARE delusions?
What are some (5) common themes?
- Fixed beliefs that are not amenable to change in light of conflicting evidence
- Common themes:
- Persecutory
- Referential
- Somatic
- Religious
- Grandiose
What ARE hallucinations? (3)
- Perception-like experiences that occur without an external stimuli
- Vivid and clear with the full force and impact of normal perceptions and not under voluntary control
- May occur in any sensory modality but auditory are most common in schizo
What is disorganized thinking (positive symptom of schizo) (2)
- Usually inferred from the individual’s speech
- Loose associations
What is grossly disorganized/abnormal motor behaviour (positive symptom of schizo)? (2)
- May manifest in a variety of ways, ranging from a childlike “silliness” to unpredictable agitation
- Problems may be noted in any form of goal-directed behaviour, leading to difficulties in performing activities of daily living
What is catatonia? (4)
- Marked decrease in reactivity to the environment
- Ranges from resistance to instructions (negativism); to maintain a rigid, inappropriate or bizarre posture; to a complete lack of verbal and motor responses (mutism and stupor)
- Can also include purposeless and excessive motor activity without obvious cause (catatonic excitement)
- Other features are repeated stereotyped movements, staring, grimacing, mutism, and the echoing of speech
What is dysfunction of communication (alogia)?
Poverty of speech; e.g., talks little, uses few words
What is dysfunction of affect (affective blunting)?
Reduced range of emotions (perception, experience and expression); e.g., feels numb or empty inside, recalls few emotional experiences, good or bad
What is dysfunction of socialization (asociality)?
Reduced social drive and interaction; e.g., little sexual interest, few friends, little interest in spending time with (or little time spent with) friends
What is dysfunction of capacity for pleasure (anhedonia)?
Reduced ability to experience pleasure; e.g., finds previous hobbies or interests unpleasurable
What is dysfunction of motivation (avolition)?
Reduced desire, motivation, persistence; e.g., reduced ability to undertake and complete everyday tasks; may have poor personal hygiene
What are 3 associated clinical features of schizophrenia?
- Substance use
- Smoking (big craving for cigarette)
- Suicidality (leading cause of premature death in pts with schizo)
The initial clinical assessment when diagnosing schizophrenia consists of many components, such as? (5)
- Clinical psychiatric history
- Mental status exam
- Family/social history
- Medical history
- Physical exam
Although there are no labs that can definitively tell us if a person has schizophrenia, what are some things that might be checked when assessing a patient? (6)
- CBC, serum electrolytes, glucose, BUN, SCr, Ca, Mg, P, LFTs, TSH
- Screen for syphilis, Hep C, HIV (high risk pts)
- ECG
- Urinalysis and urine toxicology screen
- Blood levels of medications
- If appropriate:
- CXR
- CT scan/MRI of head
- Lumbar puncture
- Sleep deprived EEG
What are some causes of drug-induced psychosis? (8)
- Amphetamine & cocaine use & withdrawal
- Bupropion
- Caffeine
- Cannabis
- Chloroquine
- Efavirenz
- Ketamine
- Steroids
What is the rating scale used in schizo?
PANSS (Positive and Negative Syndrome Scale)
What are the goals of treatment for schizophrenia? (8)
- Prevent harm to pt and to others (esp in acutely agitated state)
- Improve pt functioning
- Decrease the intensity and duration of active psychotic symptoms
- Optimize medications/treatments to obtain clinical response
- Minimize adverse effects to therapy
- Prevention of relapse
- Promote adherence
- Patient/family education
What are some non-pharm treatment options for schizo? (6)
- Exercise, healthy diet, adequate sleep
- Decrease substance use
- Decrease caffeine/nicotine/alcohol
- Support service interventions to increase medication adherence, individualize based on pts’ needs
- Establish trusting therapeutic relationship; include patients in treatment decisions (shared decision making) when possible
- Community-case management (multidisciplinary team), vocational and occupational rehab techniques, CBT
What are THE major receptor targets of antipsychotics? (5)
- D2
- 5HT2A
- Muscarinic
- 𝜶1
- H1
What receptors do FGAs target? (2)
- D2 receptor antagonism
- “Dirty pharmacology” - mixed receptor affinity at alpha, muscarinic, histamine receptors
What receptors do SGAs target? (3)
- D2 receptor antagonism
- 5HT2A/2C antagonism
- “Dirty pharmacology” - mixed receptor affinity at alpha, muscarinic, histamine receptors
What receptors do TGAs target? (3)
- D2 receptor partial agonism
- 5HT2A antagonism
- 5HT1A&2C partial agonism
What is the big class of adverse effects associated with FGAs?
Movement adverse effects
What is the big class of adverse effects associated with SGAs?
Metabolic adverse effects
What is the adverse effect associated with TGAs?
Akathisia
What are the therapeutic effects of D2 antagonism? (2)
- Antipsychotic effect
- Improve positive symptoms
What are the ADEs of D2 antagonism? (8 - know the 4 important ones)
- EPS*
- Parkinsonism*
- Akathisia
- Dystonic reactions
- Tardive dyskinesia
- Elevated prolactin: gyno, amenorrhea, impotence, osteoporosis*
- Sexual dysfunction
- Worsening of negative symptoms*
What is the therapeutic effect of 5HT2A/2C antagonism?
Antipsychotic effect
- Theoretically improve negative symptoms through increased dopamine release in mesocortical pathway
What is the therapeutic effect of 5HT1A agonism?
Anxiolytic
What are the ADEs of 5HT2A/2C and 1A drugs? (3)
- Hypotension
- Sedation
- Sexual dysfunction
D2 blockade affects mostly which dopamine tract in the brain?
Mesolimbic
5HT2A/2C antagonism affects mostly which dopamine tract in the brain?
Mesocortical
The therapeutic effect of 𝜶1 and 𝜶2 antagonism is nil in schizo. But, what are the ADEs of 𝜶1 antagonism? (6)
- Postural hypotension
- Dizziness
- Reflex tachycardia
- Sedation*
- Incontinence
- Drooling
The therapeutic effect of 𝜶1 and 𝜶2 antagonism is nil in schizo. But, what are the ADEs of 𝜶2 antagonism? (1)
Sexual dysfunction
The therapeutic effect of muscarinic antagonism is nil in schizo. But, what are the ADEs? (5)
- Dry mouth
- Blurred vision
- Constipation
- Urinary retention
- Confusion/memory disturbances
The therapeutic effect of H1 antagonism is nil in schizo. But, what are the ADEs? (4)
- Sedation
- Drowsiness
- Postural hypotension
- Weight gain
What generation of antipsychotic is chlorpromazine?
1st
What generation of antipsychotic is asenapine?
2nd
What generation of antipsychotic is aripiprazole?
3rd
What generation of antipsychotic is flupent(h)ixol?
1st
What generation of antipsychotic is clozapine?
2nd
What generation of antipsychotic is brexpiprazole?
3rd
What generation of antipsychotic is fluphenazine?
1st
What generation of antipsychotic is lurasidone?
2nd
What generation of antipsychotic is cariprazine?
3rd
What generation of antipsychotic is haloperidol?
1st
What generation of antipsychotic is olanzapine?
2nd
What generation of antipsychotic is loxapine?
1st
What generation of antipsychotic is paliperidone?
2nd
What generation of antipsychotic is methotrimeprazine?
1st
What generation of antipsychotic is quetiapine?
2nd
What generation of antipsychotic is perphenazine?
1st
What generation of antipsychotic is risperidone?
2nd
What generation of antipsychotic is pimozide?
1st
What generation of antipsychotic is ziprasidone?
2nd
What generation of antipsychotic is trifluoperazine?
1st
What generation of antipsychotic is zuclopenthixol?
1st
What are the pros and cons of high potency FGAs? (1 each)
Pro:
- Weaker anticholinergic effects
Con:
- Higher risk of movement disorders
Name 4 high potency FGAs
- Haloperidol
- Fluphenazine
- Perphenazine
- Flupenthixol
What are the pros and cons of low potency FGAs? (1 pro, 2 cons)
Pro:
- Lower risk of movement disorders
Cons:
- Stronger anticholinergic effects
- Highly sedating
Name 2 low potency FGAs
- Chlorpromazine
- Methotrimeprazine
What makes an SGA an SGA? (2)
- Developed based on different receptor activity (esp. 5HT2A/2C) in addition to D2 blockade
- Decreased risk of movement disorders but increased metabolic ADEs
What receptors does risperidone have high affinity for? Low affinity? No affinity?
- High affinity for D2, 5HT2, and alpha-adrenergic receptors
- Lower affinity to alpha-2 and H1 receptors
- NO affinity for muscarinic receptors (no anticholinergic side effects)
Risperidone doses >_mg/day have an increased risk of EPS
8
What are the adverse effects of risperidone? (9)
- Headache
- Sedation
- Weight gain (although risk vs. other SGAs)
- Orthostatic hypotension
- Rhinitis
- Anxiety
- Increased prolactin/sexual dysfunction (more vs. other SGAs)**
- EPS (more vs. SGAs; less vs. haloperidol)**
- Possible risk of QT prolongation
Paliperidone is the primary active metabolite of ___________
risperidone
What are the adverse effects of paliperidone? (9)
- Headache
- Orthostatic hypotension (less vs. risperidone)
- EPS
- Insomnia (more vs. risperidone) or somnolence
- Weight gain (less vs. risperidone)
- Increased prolactin/sexual dysfunction (similar to risperidone)**
- Anxiety
- Rhinitis
- Possible risk of QT prolongation
For olanzapine, _________ ____ limit initial use
metabolic ADEs
What are the adverse effects of olanzapine? (9)
- WEIGHT GAIN (>10lbs or ≥7% of baseline weight)**
- Dizziness
- Sedation
- Anticholinergic effects
- Increased liver enzymes
- Orthostatic hypotension
- Increased risk of T2DM, dyslipidemia (more vs. others)
- EPS (especially akathisia); dose-dependent
- Possible risk of QT prolongation
What are the DIs of olanzapine? (2)
- Smoking! (CYP1A2)
- Pharmacodynamic interactions with drugs of similar actions, 1A2 inhibitors/inducers
Lower doses of quetiapine is used for what conditions? (4)
- Insomnia (histamine blocking med, causes sedation)
- Bipolar
- Depression
- Anxiety
What are the adverse effects of quetiapine? (8)
- Headache, dizziness
- Sedation/somnolence
- Orthostatic hypotension
- Conditional risk of QT prolongation
- Weight gain
- Increased liver enzymes
- Increased risk of T2DM and dyslipidemia**
- May reduce thyroid hormone levels
What is the unique dosing requirement for ziprasidone?
Meals with ≥500kcal to maximize absorption and therapeutic effect (a good amount of food needed when taking this med)
What are the adverse effects of ziprasidone? (8)
- Considered to be weight neutral**
- Less hyperglycemia/hyperlipidemia vs. other SGA
- EPS
- Dizziness
- Sedation or insomnia
- Dyspepsia, nausea, constipation
- Orthostatic hypotension
- Conditional risk of QT prolongation**
What are the contraindications of ziprasidone? (4)
Contraindicated in patients with:
1. QT prolongation
2. Recent MI
3. Uncompensated HF
4. Concurrent QT prolonging drugs
What are the adverse effects of asenapine? (10)
- Headache, dizziness
- Drowsiness or insomnia
- EPS
- Akathisia (restless, agitation)
- Suicidal ideation
- Mouth numbness x 1 hr post dose (oral hypoesthesia)**
- Orthostatic hypotension
- Minimal effect on weight, glucose, lipids
- Increased prolactin
- Possible risk for QT prolongation
What are 3 SGAs that are not really used much in practice?
- Lurasidone
- Asenapine
- Ziprasidone
TGAs have a decreased risk of which ADEs? (2)
But a high rate of which other ADE?
- Metabolic and movement ADEs
- High rates of akathisia (aripiprazole > brexpiprazole)
What is the MOA of aripiprazole and brexpiprazole? (2)
- Acts as a partial agonist at the 5HT1A and D2 and antagonist at 5HT2A (+ additional receptor effects)
- Referred to as a “dopamine system stabilizer”
- “Goldilocks Principle”
- In high levels of dopamine production (positive symptoms) it acts as an antagonist
- In low levels of dopamine production (negative symptoms) it acts as an agonist
True or False? The half-life of aripiprazole is short
False - it is long (75h), thus do not increase dose faster than q2weeks
What are the adverse effects of aripiprazole and brexpiprazole? (10)
- Headache
- GI complaints (e.g., nausea)
- Insomnia or sedation (more often activating vs. sedating)
- Akathisia (less so with brexpiprazole)***
- Some anxiety
- Minimal weight gain
- EPS
- Orthostatic hypotension
- Suicidal behaviour
- Possible risk of QT prolongation
Describe the receptor action of cariprazine (5)
- High affinity partial agonist at D3 + D2 receptors
- At low doses –> higher affinity for D3 than D2
- Lower affinity for D2 than aripiprazole and brexpiprazole
- High affinity partial agonist at 5HT1A
- Antagonist at 5HT2A, 5HT2B
What are cariprazine’s unique D3 receptor actions? (3)
- D3 antagonist –> block activity of somatodendritic D3 receptors
- D3 partial agonist –> antagonist at high levels of DA, agonist at low levels of DA
- Prefrontal cortex –> theoretically may improve negative symptoms and cognitive impairment
What are D3 receptors associated with? (4)
- Mood
- Cognition
- Addictive behaviours
- Reward behaviours (in animal models)
Partial agonism of D3 receptors is thought to have….
implications in improving negative symptoms of schizo
Cariprazine is __-__% protein bound
It is extensively metabolized by CYP___
91-97
3A4
Summarize the evidence for using cariprazine in schizo (3)
- May be effective for the treatment of acute exacerbations and prevention of relapse after acute exacerbations
- More direct comparative evidence needed - May have implications for negative symptoms of schizo due to D3 partial agonism
- Safety?
- Limited by short duration of trials
- Long-term withdrawal design trial included enriched population
Why should antipsychotics not be considered a unique pharmacological class?
Each AP has many complex pharmacologic actions, only some of which are shared with other APs
What are some key points to consider when selecting an AP for schizo? (6)
- FGA appear to have comparable efficacy to SGA - except for clozapine
- Individual studies have shown higher discontinuation rates due to both adverse effects and lack of treatment effect with FGA
- Major issue with FGA is significant EPS - particularly in younger pts
- Pts with early psychosis have been shown to be more at risk for EPS and develop it at lower doses than those with a long history of psychosis/AP treatment
- Conflicting evidence for whether risk of relapse is higher with FGA compared to SGA
- Due to the significant increased risk of EPS with FGA, SGA are the preferred agents for the treatment of pts with early psychosis**
The bottom line when picking an AP is to individualize. What are factors to consider? (5)
Tailor the AP most appropriate to the pt based on symptomatology, ADEs, DIs, cost, and convenience
For first-episode psychosis, psychiatrists should behave like cardiologists. Meaning? (3)
- First episode psychosis destroys 10-12cc of brain tissue
- Each subsequent psychotic episode will destroy more brain tissue –> clinical deterioration, treatment resistance, functional disability
- Think of the approach to treatment of schizophrenia after the first episode of psychosis as just as critical as secondary prevention after a myocardial infarction
When might we switch from oral to long-acting injectable antipsychotics (LAIAs)? (2)
- If oral medications are effective and tolerated, may continue with oral therapy or switch to long-acting injectable depot to improve adherence (given q2-4 weeks)
- May be considered if a patient relapses due to non-adherence or if patient prefers injection
What are the benefits of LAIAs? (5)
- Decrease risk of relapse
- Decrease hospitalization
- Decrease patient/caregiver burden
- Increase interactions with healthcare team/rapport
- Increase adherence
What are the 2 most common LAIAs?
- Aripiprazole
- Paliperidone
The 2017 Canadian Schizo Guidelines stress the importance of: (3)
- Earlier treatment of symptoms
- Need for greater attention to the physical care of people with schizophrenia due to the reduced lifespan
- Greater emphasis on recovery and the need to provide personalized care rather than focusing primarily on symptomatic management
In First Episode Psychosis (FEP) why is early treatment critical? (2)
- Early detection & treatment can decrease depression, increase mood/cognitive scores, and increase overall function at 10 years
- First 2-5 years of illness are critical to offset future disability and improve outcomes; longer duration of untreated psychosis results in decreased response to treatment
What treatment/considerations are used for FEP? (4)
- No particular AP or class found to be clinically superior in 1st episode population
- Usually SGA (compared to FGA: decreased AE, decreased discontinuation, & equal efficacy)
- Choose agent based on AE profile & use lowest effective dose
- Using a long-acting antipsychotic injection may decrease relapse vs oral therapy
In FEP, what is the treatment duration? (2 points)
- Controversial; minimum 18 months
- Indefinite therapy reasonable
Once a specific AP is selected it should be initiated and further
titrated based on efficacy and tolerability with a target dose on
the lower end of dose range. How long is an adequate trial?
4-6 weeks @ optimally tolerated dose
What are the first 2 things that are done when a patient has an acute exacerbation of psychosis?
- First, screen for nonadherence, substance use, drug interactions,
- Neither constitute AP treatment failure - Second, increase or change AP, trial x 6-8 weeks to determine effect
Discuss maintenance and relapse prevention in psychosis (4)
- Symptoms fluctuate over lifetime; target therapy to symptoms
- Non-psychotic symptoms such as mood changes may also be present and necessitate treatment with non-AP medications
- Maintenance treatment contributes to relapse prevention and decrease hospitalization rates but does not eliminate risk of relapse
- Risk of re-hospitalization or death increased when the duration of AP treatment prior to discontinuation gets longer; may relate to AP-induced neurologic changes
2017 Can. Schizo Guidelines suggest maintenance AP therapy for _ years
2
True or False? We need to screen all psychosis pts for SUD
True
What is indicative of psychosis in SUD? (5)
- Psychosis persists with abstinence
- Symptoms do not align with type/amount of substance used
- Family hx of psychosis;
- Typical positive symptoms of schizophrenia
- e.g. auditory hallucinations - Presence of negative/cognitive symptoms
What is the treatment for psychosis in SUD?
No evidence of benefit for one AP over another for psychosis and SUD
Clozapine preferred limited data
What are some clinical pearls when caring for pts with psychosis and SUD? (6)
- Stigma is common
- Patients often conceal one or both conditions
- Patients often fear being imprisoned, being forced to take psychiatric meds, or having children taken away
- Create a confidential and private setting for discussions;
- Preserve continuity of care
- Provide user-friendly resources
What is treatment-resistant schizophrenia (TRS)/schizoprenia defined as?
≥2 positive symptoms of moderate severity or 1 positive symptom of severe severity, after ≥2 adequate AP trials
What is defined as an adequate AP trial? (2)
- Orally for minimum 6 wks at ≥ midpoint of licensed dose range
- Long-acting injection: at least 6 weeks at steady state
What must initially be done when TRS is suspected? (4)
- Confirm adherence
- Screen for substance use
- Review for drug interactions
- Assess dose
What is first-line therapy in TRS?
- Clozapine; response rate of 30-60% but often underprescribed due to fear of ADE, lack of familiarity
- Delaying clozapine initiation may decrease response
What is the proposed mechanism of clozapine action? (4)
- Noradrenergic
- Serotonergic
- Mesolimbic subtypes
- Dopamine subtypes (D1, D2, D4)
Clozapine’s most distinctive activity is on which receptors? (4)
- D4
- 5HT2A
- 𝜶1
- M1
The MOST effective AP for TRS is?
Clozapine
What are some other uses for clozapine? (4)
- Tardive dyskinesia (mixed evidence)
- BD
- Schizoaffective disorder
- Psychosis in pts with Parkinsons disease
What are some common side effects of clozapine? (7)
- Constipation
- Blurred vision
- Dizziness
- Drooling**
- Weight gain
- Increased cholesterol and/or blood sugar
- Tachycardia and orthostatic hypotension
What are some of the serious side effects of clozapine? (6)
- Agranulocytosis*
- Myocarditis*
- Cardiomyopathy
- Constipation*
- Seizures
- Neuroleptic Malignant Syndrome
Why does Health Canada require clozapine patients to register for a monitoring program?
Clozapine-induced agranulocytosis
- To detect potentially reversible agranulocytosis
- Requires monitoring of CBC with differential
Clozapine-induced agranulocytosis is most likely to occur within first _ months of treatment
6
Clozapine-induced myocarditis is most likely to occur in first x-y weeks of treatment
4-8
Clozapine-induced cardiomyopathy is most likely to occur after ______ to _____ of treatment
months to years
The clinical presentation of myocarditis and cardiomyopathy are very similar at the start. We are monitoring for: (7)
- Orthostatic blood pressure changes
- Fatigue and decreased exercise tolerance
- Chest pain/discomfort/pressure
- Palpitations with increased heart rate
- Shortness of breath
- Peripheral edema
- Fever
What are two other markers of myocarditis and cardiomyopathy? (2)
- High sensitivity troponin T
- CRP
Clozapine can ONLY be used if what requirement is met?
If hematological monitoring (CBC with diff - neutrophils) can be guaranteed AND patient is actively registered with a clozapine registry (has a clozapine pin #)
Name the 3 clozapine registries in Canada
- AA-Clozapine (SHA pref)
- GEN-Clozapine
- CLOZARIL
Clozapine registries ensure: (3)
- Registration (of pt, physician, testing lab, pharmacy)
- Maintenance (of national database that monitors blood work)
- Identification (of status of all approved suppliers of clozapine)
Go through the process of monitoring clozapine. (4 items)
- Weekly blood tests for the first 6 months
- High risk period - Change to once every 2 weeks if “green light” has been maintained during the first 6 months of therapy and patient is clinically stable
- Change to once every 4 weeks if “green light” for another 6 months
- Monitoring MUST continue for as long as the pt is on clozapine and even for 4 weeks after stopping
What happens if clozapine doses are missed? (2)
- Monitoring freq does not have to be modified if therapy is interrupted for 3 days or less but dosing needs to be re-titrated if miss >48 hours
- Hematological testing should be resumed weekly for an additional 6 weeks if therapy is disrupted for more than 3 days
(Important to assess adherence)
What is the green zone for ANC levels in clozapine users?
≥2.0 x 10^9/L
What is the yellow zone for ANC levels in clozapine users?
1.5 x 10^9/L < ANC < 2.0 x 10^9/L
What are the 2 red zones for ANC levels in clozapine users?
First red zone –> ANC < 1.5 x 10^9/L
Consider protective isolation when: ANC < 0.5 x 10^9/L
What does non-rechallengeable mean (clozapine)? (3)
- Must stop and cannot ever restart therapy if total WBC <2.0 x 10^9 or ANC <1.5 x 10^9 from clozapine therapy
- Must be communicated with clozapine registry
- Will require weekly CBC x 4 weeks when stopped
- Likely would be done more frequently than weekly when pt is neutropenic (pt would be hospitalized)
True or False? It is legal to dispense more clozapine than what aligns with the patient’s scheduled blood work
False - quantity of clozapine dispensed must be limited to the frequency of clozapine blood work
Why is clozapine dosing typically BID?
Because once daily dosing is very sedating
Clozapine is dosed via _________
titration
True or False? You cannot switch between brand and generic clozapine
True
How does smoking affect clozapine levels?
Smoking (chemicals from the tar specifically) induces CYP1A2 which reduces clozapine levels up to 40%, reducing its effects
Clozapine and suicide. How does it affect suicidality?
Reduces the risk of suicide in pts with schizophrenia or schizoaffective disorder
As of right now, what does evidence say about clozapine-resistant (ultra-resistant) schizophrenia treatment?
No consistent evidence to support use of high dose AP, switching APs, or AP polypharmacy
What is the anatomy of extrapyramidal symptoms?
Hypothesized pathways among basal ganglia and other structures of the CNS
What is the timeframe of the following EPS symptoms following initiation of treatment:
1. Dystonic reactions
2. Akathisia
3. Bradykinesia/Rigidity
4. Tremors/Rabbit syndrome/Pisa syndrome
5. Tardive syndromes
- Occur very suddenly (potentially after 1st dose)
- Tends to be early, but can extend out to any time
- Most likely in 3-6 weeks then heavy drop off
- Mostly 6 weeks onward
- Starts 3 months later for the most part
Acute extrapyramidal effects occur within how long?
How about tardive syndromes?
- Within 30 days
- After months or years of treatment, esp if develops after drug dose is decreased or discontinued
How are acute extrapyramidal effects treated?
Respond to antiparkinsonian drugs (except akathisia which may be mediated by alternate mechanism and thus responds to other treatments)
How are tardive syndromes treated? (2, but really 1)
- Valbenzaine and deutetrabenazine are FDA only
- No other meds or strats have proven efficacy in clinical trials - PREVENTION IS KEY
What are the physical symptoms of acute dystonias? (3)
- Torsions and spasms of muscle groups
- Mostly affects muscles of the head and neck
- Examples: oculogyric crisis, trismus, laryngospasm, torti/retro/antero-collis, tortiplevis, blepharospasm
What are the psychological symptoms of acute dystonias? (5)
- Anxiety
- Fear
- Panic
- Dysphoria
- Repetitive meaningless thoughts
What is the onset of acute dystonias? (2)
- Acute (usually within 24-48 hours of the first dose)
- 90% occur within 1st week of treatment
What are the proposed risk factors for acute dystonias? (6)
- Young males, antipsychotic naive, high potency FGA
- Rapid dose increase
- Prior dystonic reaction
- Hypocalcemia, hyperthyroidism
- Dehydration
- Recent cocaine use
What is the clinical course of acute dystonias? (3)
- Acute, painful, spasmodic
- Oculogyria may be recurrent
- Acute laryngeal/pharyngeal dystonia may be life-threatening
What are the treatment options for acute dystonias? (3)
- 1st line = IM benzotropine
- IM diphenhydramine
- Sublingual lorazepam
What monitoring is done for acute dystonias? (2)
- EPS Rating Scale (ESRS)
- Simpson Angus EPS Scale (SAS)
What IS akathisia?
Ants in the pants type of restlessness
What are the physical symptoms of akathisia? (10)
- Motor restlessness
- Fidgeting
- Pacing
- Rocking
- Swinging of legs,
- Trunk rocking forward and backward
- Crossing and uncrossing legs
- Inability to lie still
- Shifting from foot to foot
- Respiratory: dyspnea or breathing discomfort
What are the psychological symptoms of akathisia? (8)
- Restlessness
- Intense urge to move
- Irritability
- Agitation
- Violent outbursts
- Dysphoria
- Feeling “wound up” or “antsy”
- Sensation of skin crawling
What is the onset of akathisia? (2)
- Acute to insidious (hours - days)
- 90% occur within first 6 weeks of treatment
What are the proposed risk factors of akathisia? (9)
- Elderly female, young adults
- High caffeine intake
- High potency FGAs
- Lower risk with SGAs
- Genetic predisposition
- Anxiety
- Mood disorder
- Microcytic anemia, low ferritin
- Concurrent SSRI use
What is the clincal course of akathisia? (3)
- May continue throughout entire treatment
- Increases risk of tardive dyskinesia
- May contribute to suicide and violence
What are the treatment options for akathisia? (4)
- Reduce dose or change antipsychotic
- Benzodiazepines
- Beta-blockers (propranolol 10-20mg BID)
- Mirtazapine 7.5- 15mg qHS
How to monitor for akathisia?
Barnes Akathisia Rating Scale (BARS)
What are the physical symptoms of acute pseudoparkinsonism? (3)
- Tremor: “pill-rolling” type
- Cogwheel rigidity
- Bradykinesia: mask-like facial expression, diminished/absent arm swing, shuffling gait, stooped posture, slowness of movement
What are the psychological symptoms of acute pseudoparkinsonism? (4)
- Slowed thinking
- Fatigue
- Cognitive impairment
- Drowsiness
What is the onset of acute pseudoparkinsonism? (2)
- Acute to insidious
- 90% occur within first 6 weeks of treatment
What are the proposed risk factors for acute pseudoparkinsonism? (8)
- Elderly females
- High potency FGA (low risk with SGA and TGA)
- Increased dose of antipsychotic
- Multiple antipsychotics concurrently
- Discontinuation of anticholinergics
- Concurrent neurological disorder
- HIV infection
- Family history of Parkinson’s disease
What are the treatment options for acute pseudoparkinsonism? (2)
- Reduce dose or change antipsychotic
- Antiparkinsonian drug (benztropine, diphenhydramine, procyclidine, trihexyphenidyl)
How is acute pseudoparkinsonism monitored? (2)
ESRS or SAS (same rating scale as acute dystonia)
What are the physical symptoms of Pisa syndrome and Rabbit syndrome?
Pisa = leaning to one side
Rabbit = fine tremor of lower lip
What is the onset of Pisa and Rabbit syndrome?
Pisa = can be acute or tardive
Rabbit = after months of therapy
What are the proposed risk factors for Pisa and Rabbit syndrome? (3 and 1)
Pisa = elderly pts, compromised brain function, dementia
Rabbit = elderly patients
What are the treatment options for Pisa and Rabbit syndrome? (3)
Same for both:
Antiparkinsonian drugs (benztropine, procyclidine, trihexyphenidyl)
What are the physical symptoms of tardive dyskinesia?
Involuntary abnormal movements of body
- Can co-exist with Parkinsonism and akathisia
What are the psychological symptoms of tardive dyskinesia? (3)
- Cognitive impairment
- Distress (talking, swallowing, eating)
- Embarrassment
What is the onset of tardive dyskinesia? (2)
- After 3 or more months of therapy in adults (earlier in elderly)
- Common early sign is rapid flicking movement of tongue (fly catcher tongue)
What are the proposed risk factors for tardive dyskinesia? (9)
- Over 40 years old
- Female
- History of severe EPS early in treatment
- Chronic use of antipsychotics (FGAs more than SGA/TGAs), metoclopramide
- Chronic use of high doses of dopamine agonists in treatment of Parkinson’s disease
- Presence of mood component
- Diabetes
- Cognitive impairment
- Alcohol and drug abuse
What is the clinical course of tardive dyskinesia? (3)
- Persistent**
- Discontinuation of antipsychotic early increases chance of remission
- Spontaneous remission in 14-24% after 5 years
What are the treatment options for tardive dyskinesia? (3)
- Valbenazine and deutetrabenazine (not available in Canada)
- Switch to SGA or TGA (? Clozapine or quetiapine)
- ? Pyridoxine, clonazepam, tetrabenazine, vitamin E, levetiracetam
What is the monitoring for tardive dyskinesia?
AIMS (Abnormal Involuntary Movement Scale)
What are the physical symptoms of tardive dystonia?
- Sustained muscle contraction of face, jaw, tongue, eyes, neck, limbs, back or trunk (e.g. blepharospasm, laryngeal dystonia)
What are the physical symptoms of tardive akathisia?
Persistent symptoms of akathisia following dose decrease or withdrawal of antipsychotic
What is the onset of tardive dystonia/akathisia?
Months or years of therapy
(Tardive akathisia can be after med withdrawal)
What are the propsed risk factors for tardive dystonia/akathisia? (5)
- Young male
- Genetic predisposition
- Neurologic disorder
- Coexisting tardive dyskinesia
- Akathisia
What is the clinical course of tardive dystonia/akathisia? (2)
- Persistent
- Discontinuation of AP early increases chance of remission
What are the treatment options for tardive dystonia? (3)
- Switch to SGA or TGA (? Clozapine)
Possible treatments: - High dose tetrabenazine or trihexyphenidyl
- Botox
What are the treatment options for tardive akathisia? (4)
- Switch to SGA or TGA
- Anticholinergics
- Benzodiazepines
- Beta-blockers (propranolol)
What is neuroleptic malignant syndrome? (4)
- Acute, life-threatening EPS that can occur with any AP
- Rare, idiosyncratic reaction
- Severe muscle rigidity, fever (>39C), altered mental status, autonomic instability, elevated WBC and creatine kinase
- Mortality 10%
What is the time frame of neuroleptic malignant syndrome? (2)
- Anytime
- Often early in treatment
What is the treatment of neuroleptic malignant syndrome? (4)
- STOP antipsychotic immediately!!!
- Supportive care
- Consider bromocriptine
- Dantrolene sometimes used for malignant hyperthermia
What is the pharmacist’s role in schizophrenia treatment? (5)
- Pharmacists are uniquely positioned to assess patients with schizophrenia for medication-related issues and provide clinical care and support.
- Pharmacists can ensure that patients and their families receive important information about medications including how best to take them to optimize the benefits.
- Pharmacists can identify possible contraindications, drug interactions, and ADEs to optimize tx
- Pharmacists can play a vital role by providing psychoeducation, simplifying dosing regimens, using adherence aids such as blister packs, using automated-refill features, and promoting the use of LAIAs.
- Smoking is the single largest preventable cause of lowered life expectancy in the mental health population. Pharmacists have a role in engaging patients in successfully reducing/quitting smoking.
What schizo drugs have interactions with 1A2 (substrate)? (2)
- Clozapine
- Olanzapine
What schizo drugs have interactions with 2D6 (substrate)? (6)
- Haloperidol
- Risperidone
- Zuclopenthixol
- Aripiprazole
- Chlorpromazine
- Clozapine
What schizo drugs have interactions with 2D6 (inhibitor)? (2)
- Chlorpromazine
- Haloperidol
What schizo drugs have interactions with 3A4 (substrate)? (5)
- Haloperidol
- Quetiapine
- Risperidone
- Ziprasidone
- Clozapine
