Bipolar Disorder Flashcards

Question

What are some somatic therapies that can induce mania?

Answer 1

Bright light therapy Deep brain stimulation Sleep Deprivation

Answer 2

Before 18 --> Most commonly depressive pole --> Often labelled with unipolar depression --> tend to have greater delay to proper tx --> Chalaenges down the road as comorbid substance abuse (self management) Average age --> 20-25 --> Late onset if diagnosed in the 30’s Most common is before the age of 25

Answer 3

Commonly takes up to 10 years to receive diagnosis Estimated that only 50% receive treatment due to delay of treatment onset and challenging for manic patients to have insight to seek help.

Answer 4

Up to 69% who seek tx during first year of onset are misdiagnosed Commonly presents as depression first and mania sx are either not comprehensively assessed or is not yet present

Answer 5

With treatment, illness usually includes periods of remission with risk of full or sub-syndromal relapses Kindling Theory --> Abnormalities lead to more abnormalities Syndromal episodes increase vulnerability to more episodes --> becomes harder to reach and stay stable in euthymic states; chronic subthreshold depression LEADS TO...... Neurodegeneration --> Persistent neurocognitive deficits, increasing impairment, delayed functional recovery --> Getting proper tx and maintaining --> preserve the brain, w/t tx can lead to neurodegeneration (less function, detioration in QOL and function will not be able to return)

Answer 6

Even during periods of euthymia, patients may experience impairments in psychosocial functioning or residual symptoms of depression or mania/hypomania. As many as 60% patients have chronic difficulties in interpersonal/occupational functioning even between acute episodes.

Answer 7

Profound morbidity & mortality 2-2.5x higher mortality rate compared to individuals without bipolar Significant functional impairment Disruptive courses of hospitalization Global burden of disease

Answer 8

Best predictor of level of functioning is medication adherence ~50% of patients discontinue medications due to adverse effects Important for pharmacists to educate patients and intervene! Medications can keep people in a functional state and prevent decline =-> Meds have a/e, so may take some tine to find a medication that works

Answer 9

Life expectancy is 10 years less

Answer 10

Anxiety disorders (50-60%) --> Anti-depressants are main tx;however can lead to mania or hypomania Substance use disorder (60%) --> More than half of patients with bipolar disorder misuse illicit substances, which can complicate the presentation, diagnosis, and treatment of BD. -->Alcohol is most commonly abused substance Attention Deficit Hyperactivity Disorder (20%) --> Stimulants can make mania worse Post-traumatic stress disorder Medical comorbidities --> Diabetes, dyslipidemia, obesity, cardiovascular disease

Answer 11

SUICIDE One of the leading causes of death in BD 6-7% of identified patients with bipolar die by suicide

Answer 12

Death by suicide up to 20x higher than general population

Answer 13

Men are at higher risk of death by suicide than women

Answer 14

20-50% attempt suicide at least once

Answer 15

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

Answer 16

Comprehensive assessment for suicide risk should occur during all patient interactions

Answer 17

3+ Specific Sx AND: 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

Answer 18

Flight of ideas: accelerated speech with a shifting of ideas connected only remotely Usually begins abruptly and escalates over a few days Decreased need for sleep with increased goal directed activity may be first to appear Euphoria, elated, irritable Engagement in multiple new projects may occur & perpetuated by inflated self-esteem/delusional grandiosity Rapid, pressured, loud speech Racing thoughts leading to flight of ideas Increased motor activity, sexuality, physical restlessness, distractibility Psychotic sxs in severe episodes (resolve as mood improves Co-occurring depressive sxs can be present

Answer 19

Mood: Same sx as for mania, but milder and not disabling; no psychotic sx Duration: 4 days or longer

Answer 20

Mood: Depressed most of the day, nearly everyday OR markedly diminished interest or pleasure in all or most activities (anhedonia) Duration: At least 2 weeks with significant change from previous functioning Plus: Five or more of the follwoing: - Insomnia or hypersomnia - Significant wt loss/gain or change in appetite - Fatigiue or loss of energy - Psychomotor retardation or agitation (observable) - Worthlessness or excessive guilt - Impaired thinking, concnetrating or making decisions - Reccurrent thoughts of death, suicidal ideation, or attempt/plan

Answer 21

The episode is not the result of a substance (e.g., drug of abuse, a medication, other treatment) or caused by another medical condition. (Exception: if a full manic episode occurs during antidepressant therapy and persists, it can be considered a manic episode for the diagnosis of bipolar I disorder) The occurrence of the manic and major depressive episode(s) is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified or unspecified schizophrenia spectrum and other psychotic disorder.

Answer 22

DIGFAST D: distractibility I: irritability or indiscretion G: grandiosity F: flight of ideas (racing thoughts) A: activity (or energy) increased S: sleep decreased T: talkativeness

Answer 23

Manic episode required for diagnosis. Hypomanic or major depressive episodes may occur before or after manic episode but are NOT required for diagnosis.

Answer 24

SHORTER TIME PERIOD, LESS Severe 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.

Answer 25

Mood: Same sx as for mania, but milder and not disabling; no psychotic sx Duration: lasting up to 4 days 1) Grandiosity 2) More Talkative 3) Excessive involvement in pleasurable/high risk activities that may have unpleasant consequences 4) Less need for sleep 5) Flight of ideas 6) Distractability 7) More goal-directed activity

Answer 26

A full hypomanic episode that emerges during antidepressant treatment (e.g., medication, electroconvulsive therapy) but persists at a fully syndromal level beyond the physiological effect of that treatment is sufficient evidence for a hypomanic episode diagnosis. However, caution is indicated so that one or two symptoms (particularly increased irritability, edginess, or agitation following antidepressant use) are not taken as sufficient for diagnosis of a hypomanic episode, nor necessarily indicative of a bipolar diathesis.

Answer 27

Hypomanic episode AND major depressive episode (current or past episodes) Occurrence of one hypomanic episode and at least one major depressive episode. There is no history of a manic episode. Depressive symptoms or frequent alteration between depression and hypomania result in significant distress or impairments in functioning. - Need to have both of them

Answer 28

5+ sx must be present nearly everyday during the same 2 week perios and result in change in functioning Must include one or both of: 1) Depressed mood most of the day, nearly everyday 2) Diminished interest or pleasure in all or most activities SIGECAPS Changes in sleep patterns Changes in interest or activity Feeling of guilt or increased worry Changes in energy Changes in concentration Changes in appetite Psychomotor disturbances Suicidal Ideation

Answer 29

Delay to diagnosis Misdiagnosis Limited Clinical Trials

Answer 30

Average delay 8-12 years Often patients do not recall hypomanic symptoms More likely to seek help for depression vs. mania

Answer 31

Most often misdiagnosis: depression Consequences: 55% of those prescribed antidepressants developed hypo/manic episodes, 23% developed rapid cycling (results from an outpatient psychiatric clinic study)

Answer 32

Heterogenous illness Co-morbidities Manic symptoms  impaired judgment  impaired adherence Require longitudinal assessment Hard to quantify/qualify BD into 1 illness where all patients would meet study inclusion criteria thus challenging to develop a robust study. Most trials are only 6-8 weeks  Hard to guage \ May only have one mood episode

Answer 33

Criteria met during the same time period for hypomanic episode or manic episode with 3 or more features of a depressive episode

Answer 34

Criteria met during same time period for a major depressive episode with 3 or more features of manic or hypomanic episode

Answer 35

May see bipolar 2 become bipolar 1 if have a clear-cut manic episode Bipolar 1 cannot become Bipolar 2

Answer 36

Bipolar has the most variable clinical presentation and is associated with: the highest number of episodes Highest degre eof comorbidity Highest mortality of the major psychiatric conditions

Answer 37

Mood Disorder Questionaire Diagnosis is merely not only on clinical presentation but also on reliable collateral history from a friend or family member who can corrobate episodes of elevated mood, inappropriate behaviour, decreased sleep with increased energy or grandiosity

Answer 38

Response 1-2 weeks Full clinical benefit 3-4 weeks Responds faster to pharmacotherapy than depression

Answer 39

Response 2-4 weeks Full clinical benefit 6-12 weeks Depresison is much longer. Bipolar is longer than unipolar depression to respond. Can take up to. 4months to for a patient to see benefit.

Answer 40

Exercise, adequate sleep, healthy diet, decreased/abstinent substance use, decreased caffeine/nicotine/alcohol (TALK TO ALL PATIENTS ABOUT) Bright light More for depression Relapse prevention plan Plan to management stress and interpersonal conflicts Psychoeducation, supportive counselling, biosocial rhythm normalization, psychotherapy (CBT, interpersonal therapy) ECT Collaborative care Case management Medication adherence!

Answer 41

Wellness Recovery Action Plan (WRAP) List their early warning symptoms Tools they can use when the threat of a crisis starts to come on What they have to do to stay well What their responsibilities are How they feel when they are well What they will do and who the will entrust to do things for them – help take care of them – when they are in crisis A list of people they can call when in a crisis such as the National Suicide Prevention Hotline (1-800-273-8255) What their triggers are And a post-crisis plan

Answer 42

First generation “typical” antipsychotics are rarely used for bipolar RATS AFFECT ANYONES QOL

Answer 43

Carbolith, Lithmax

Answer 44

Bipolar disorder Acute mania treatment Prophylaxis/maintenance Schizoaffective disorder Unipolar depression Antidepressant augmentation Low dose after TBI can be neuroprotective

Answer 45

Exact mechanism of action is not fully understood Multiple effects on cellular function details

Answer 46

Liquid: 100% Regular release cap: 95-100% Extended release tab: 60-90%

Answer 47

Completely dissociates to lithium cation Almost completely absorbed from small intestine Absorption rate is greater for regular release than sustained release Small amount actively exchanged for sodium

Answer 48

Liquid: 0.5-1 hour Regular release cap: 1-3 hours Extended release tab: 4-12 hours

Answer 49

Issues with peak effect --> liquid and reg. release has fast effect --> tremors and nauseau with dose --> may switch to XR Body treats it as a salt --> Widely distributed --> toxicity risk

Answer 50

Describe that TDM can be used for monitoring A natural medication that we can tailor the dose based off the amount of drug in the blood

Answer 51

Not bound to plasma proteins

Answer 52

Open, 2-compartment model Initially: distributed in extracellular space Vd = 0.307 L/kg Later: accumulates in varies organs (brain, kidney thyroid, bone) Adults: 0.8L/kg (0.5 to 1.2) Geriatric: 0.7L/kg (0.5 to 0.9)* Distributes evenly in the total body water space *20-30% ↓ Vd in elderly due to ↓ % of body water and lean body mass (results in ↑ lithium concentrations) Distributes relatively TBW --> Older have less TBW

Answer 53

Large inter-individual variation Normal renal function: 12-27 hours (range 5-79) Elderly: 30-36 hours Elderly --> t1/2 can be increased due to decreased renal function

Answer 54

95% renal, 4% perspiration Not metabolized, primarily excreted renally as free cation Not protein bound--> freely filtered by glomerulus like sodium and potassium 80% reabsorbed in the proximal tubules (with sodium) Filtered sodium ↓ = ↑ lithium and sodium reabsorption = lithium toxicity

Answer 55

ClLi= 10-40 ml/min (25% of GFR) [ClLi= 0.25 x ClCr] Follows linear, dose-proportional pharmacokinetics

Answer 56

↓ clearance: hyponatremia, dehydration, renal failure or dysfunction, ↓ renal blood flow*

Answer 57

Varies with circadian rhythm like GFR (chronokinetics) Nocturnal ClLi is 78% of daytime value (20.7 vs. 26.4 ml/min)

Answer 58

Brain half life 28 hours vs 16 hours in serum

Answer 59

Important to counsel patients on the risk of dehydration, danger of negative sodium balance, and need for caution if decreased fluid volume (e.g. periods of illness, excessive heat exposure, etc.)

Answer 60

Potential for lithium toxicity with ACE inhibitors, NSAIDS, thiazides (all can contribute to renal toxicity)

Answer 61

Not absorbed in distal tubule except in severe hyponatremia Clearance: 80% of filtered lithium is reabsorbed in the proximal convoluted tubules; decreased in elderly patients secondary to age-related decreases in renal function

Answer 62

COUNSEL: CONSISTENTCY OF NA+ INTAKE

Answer 63

NARROW THERAPEUTIC RANGE INTER-INDIVIDUAL VARIATION: Some pt;’s at 1.2 will experience toxicity Some pt’s will have nauseaus and tremors at lower levels

Answer 64

Elderly – more susceptible to A/E Some pt;’s at 1.2 will experience toxicity Some pt’s will have nauseaus and tremors at lower levels

Answer 65

Mania we aim for higher levels Maintennace phase move downwards MOVE DOWN TO HELP REDUCE THE RISK OF A/E

Answer 66

12 hour post dose level -12 hour post dose allows for complete absorption and distribution -usually in the morning after the evening dose (due to chronokinetics) (if BID, wait till after drawn before taking dose) Stat if toxicity or non-adherence is suspected

Answer 67

Get emergency medical help Get a level stat

Answer 68

Toxicity Non-adherence

Answer 69

5-7 days after starting therapy or changing dose (steady state), then once weekly until at a stabilized dose x 2 weeks, then monthly for up to 3 months, then at least every 6 months

Answer 70

During times of infection, debilitation, changes in diet, recurrence of symptoms, noncompliance, signs of toxicity – may do levels more frequently

Answer 71

Target 0.8-1.2 mmol/L (some guidelines up to 1.4-1.5, however, monitor closely for toxicity at higher levels)

Answer 72

Initial: 600-900 mg per day (in 1-2 divided doses) Higher initial doses increase likelihood of GI side effects Give with food to minimize and/or divide dose BID Subsequent doses guided by plasma level and clinical response Target 0.8-1.2 mmol/L (some guidelines up to 1.4-1.5, however, monitor closely for toxicity at higher levels) Predictive dosing methods show inconsistent results Usual doses 900-2100 mg/day in two divided doses

Answer 73

Start at lower doses in the elderly Starting dose should not exceed 300 mg/day Usual dose range 300-1200 mg/day

Answer 74

Reduced doses due to: smaller volume of distribution decreased renal blood flow decreased GFR decreased clearance.

Answer 75

The dose required to reach therapeutic serum concentration exhibits wide inter-individual variation

Answer 76

Target plasma level 0.6-1 mmol/L

Answer 77

Maintenance therapy: 900 mg (600-1800 mg/day) in divided doses

Answer 78

Once stabilized can be given once daily: --> Only if able to tolerate --> Usually given at night to improve compliance --> Some trials show a decrease in urine volume and decrease renal toxicity with once daily evening dosing --> Patients sensitive to peak related side effects (e.g. tremor, urinary frequency, nausea) may respond to extended release formulation

Answer 79

Long-term --> Change to OD as can be easier to tolerate from the kidney perspective Body working harder to clear lithium --> Potentially has less long term s/e if kidneys only clearing OD Chronically will lead to some degree of renal dysfunction Monitoring can help prevent decline

Answer 80

When lithium changes from multiple daily dosing to once daily dosing, can expect ~10-25% increase in 12hr Lithium level

Answer 81

CrCl 10-50 mL/min – 50 to 75% of normal dose CrCl below 10mL/min – 25% to 50% of normal dose Contraindicated in acute renal failure Patients undergoing dialysis should have dose after dialysis

Answer 82

Hold dose Repeat plasma level next day (recall t1/2 = ~24 hours) Restart therapy when within target range

Answer 83

Doses only come in multiples of 150 mg (unless using syrup), and that there are dose conversions that need to be done when switching between capsule and syrup

Answer 84

Lithium carbonate is most commonly used salt form as it has longer shelf life stability and contains more lithium on a weight for weight basis than other salt forms.

Answer 85

Those who develop peak associated nausea and tremors (early mornings edation can also necessitate an XR - reaches less of a peak)

Answer 86

Plasma volume and GFR increase- lithium clearance increase 50-100% by 3rd trimester Returns to normal after delivery Decrease lithium levels

Answer 87

Lithium does have a risk of ~2.4% vs 1.2% in general population of a cardiac malformation (Ebstein's anomaly). Highest risk is in the first trimester. Use of lowest effective dose of lithium may reduce fetal harm without increasing risk of mood episodes. For planned pregnancies, use of lithium during the first trimester should be avoided if possible. However, the absolute risk of Ebstein anomaly is small and treatment for bipolar disorder should not be withheld when clinically indicated. Due to pregnancy-induced physiologic changes, women who are pregnant may require dose adjustments of lithium to achieve euthymia and avoid toxicity

Answer 88

May decrease the serum concentration of Lithium.

Answer 89

Lithium behaves like a salt like Sodium Therefore, increased sodium excretion (due to higher levels) can cause increased lithium excretion via the kidneys May increase the excretion of Lithium

Answer 90

Dehydration leads to compensatory Na+ re-absorption in the proximal tubule leading to increased lithium reabsorption Aldosterone increases Na+ reabsorption in the distal tubule leading to lithium reabsoprtion

Answer 91

Cirrohosis can active the RAAS system Leading to Na+ and water retention Aldosterone - Increased Na+ reabsorption Increased Na+, increased LI+

Answer 92

Increased risk neurotoxicity when used with antipsychotics or carbamazepine Loop diuretics and CCBs may increase or decrease levels

Answer 93

Contraindicated in acute renal failure, use cautiously in chronic renal failure

Answer 94

NSAIDs (e.g. Ibuprofen, naproxen, ketorolac): Decrease lithium clearance Increase lithium concentrations Prostaglandins serve to dilate the afferent arteriole; by blocking this prostaglandin-mediated effect, NSAIDs cause unopposed constriction of the afferent arteriole and decrease renal perfusion pressure.

Answer 95

Diuretics (e.g. furosemide) Potentially mixed effects Decreased lithium clearance and increased lithium concentrations or Increased lithium clearance and decreased lithium concentrations The specific mechanism of this possible interaction is not clear, but any increase in lithium concentrations may possibly be related to urinary sodium loss caused by the diuretic with subsequent changes in lithium excretion. Any decrease in lithium concentrations may result from impaired lithium reabsorption

Answer 96

ACE Inhibitors (e.g. ramipril, perindopril) Mechanism not clearly established Angiotensin II and decreased aldosterone levels, result in sodium depletion/lithium retention; average increase in lithium level of ~ 40% Vasodilation results in decreased renal perfusion, decreased lithium clearance, increased lithium level

Answer 97

Up until CrCl reaches about 30 ml/min, lithium clearance will gradually decrease in a relatively proportional manner to the drop in CrCl. This means that as kidney function gets worse, the body holds onto more lithium. If CrCl drops by 50%, lithium clearance will also drop by a similar percentage.

Answer 98

Risk of additive neurotoxicity (altered cognition, motor impairment, etc.) – not C.I.; but watch for

Answer 99

Theoretical risk of serotonin syndrome (usually not clinical relevant; monitor)

Answer 100

NDI: polyuria, polydypsia due to inability to concentrate urine. Can occur at therapeutic concentrations. Volume depletion leads to lithium reabsorption = lithium toxicity. Amiloride (potassium sparing diuretic) is the treatment of choice for lithium induced NDI.

Answer 101

Adverse effects and toxicities are believed to be a direct result of the distribution of lithium to compartments in which lithium concentrates (ie. Kidney, thyroid, brain, bone)

Answer 102

Sustained release: increased exposure of lithium cation to gut wall which can cause increased GI ADEs

Answer 103

Fluid Salt Caffeine

Answer 104

Include baseline checks for: renal, lytes, thyroid, CBC, metabolic assessment (fBG, BMI), and ECG if > 40 or hx CVD

Answer 105

Common side effect management Thirst: drink water, hard candies (should subside) Nausea: take with food; can consider ER formulation if doesn’t subside Sedation: take at bedtime, don’t drive Acne: talk to pharmacist or physician for treatment Tremors: talk to physician if doesn’t subside

Answer 106

May take several weeks to see benefit Maintain adequate hydration and consistent salt/caffeine intake Self-monitor for signs of toxicity Will require regular blood level monitoring Avoid NSAIDs; check with pharmacist when starting any new medications Consider contraception if child-bearing potential If tolerated and stabilized, consider once daily dosing at HS (less AEs and risk of renal injury) Monitor serum level, renal, lytes, thyroid regularly Hold lithium dose the night before ECT (increased risk of delirium)

Answer 107

Not contraindicated in pregnancy Lower lithium dose to the lowest effective PLanning in advance is important; can switch to different mood stabilizer Consider contraception

Answer 108

Monitor serum level, renal, lytes, thyroid regularly

Answer 109

Valproic Acid Divalproex Sodium (prodrug) Sodium divalproex is cleaved in the GI tract to valproic acid

Answer 110

Seizures: generalized tonic-clonic (grand mal), partial-onset, absence Has broad-spectrum anti-epileptic activity Bipolar disorder Acute mania treatment Maintenance (prophylaxis)

Answer 111

Exact mechanism of action unknown Slows down neurological activity Inhibits voltage gated Na channe;s Increases action of GABA Modulates siynal transduction casacdes and gene expresison Affects neuronal excitatiob by NDMA subtype glutamate recpyors Serortonin, doapmine, aspartate, and T-type calcium channels

Answer 112

0.90-1.0 Divalproex Na+ and Valproate Na+ convert to valproic acid in stomach

Answer 113

Time to peak serum concentration varies with product formulation IV <1 hr, liquid 1-2 hrs, capsules 2-3 hrs, enteric coated tabs 4-6 hrs

Answer 114

1.0 Valproic acid (syrup, capsules) 1.0 Valproate sodium (IV) 1.0 Divalproex sodium (EC tabs)

Answer 115

85-90% to serum albumin Saturable protein binding occurs within therapeutic range At 500 umol/L valproic acid is 90% bound to albumin Above 500 umol/L binding saturates and there is ↑ free (unbound) At higher concentrations change in free fraction is disproportional to increases in dose (↑ free)

Answer 116

Enteric coated designed to reduce GI side effects associated with valproic acid by decreasing contact between drug and stomach. Enteric coating does not dissolve in stomach. Coating dissolves in the basic environment of the small intestine and sodium divalproex is cleaved to form valproic acid. Thus, absorption is delayed but extent of absorption is unchanged.

Answer 117

When switching between capsules and syrup, daily dosing is the same, but with the syrup it may need to be divided TID. Change and check levels at steady state.

Answer 118

VPA is highly ionized at physiological pH and is therefore highly bound to plasma proteins. Primarily albumin.

Answer 119

There are greater daily fluctuations in the free fraction than in the total concentration of VPA

Answer 120

0.15-0.2 L/kg Enters the brain rapidly after a dose Distributes to other tissues (liver, kidney, bones and intestines)

Answer 121

>95% hepatic metabolism via glucoronidation, B-oxidation, alpha-hydroxylation Major metabolism via UDPGT-catalyzed glucoronidation and B-oxidation Minor metabolism via CYP (2A6, 2C9, 2C19, 2B6) No active metabolite but 4-ene-valproic acid metabolite can cause liver tox <5% recovered unchanged in urine

Answer 122

Low extraction drug Cl is independent of hepatic blood flow but directly dependant on free fraction

Answer 123

12- 18 hours (closer to 12 if taking enzyme inducing drugs)

Answer 124

Hepatic disease with hypoalbuminemia would result in an increase in free fraction, increasing clearance but with decreased liver function, decreasing clearance.

Answer 125

Not uncommon to see increase in aminotransaminases in patients who use consistently

Answer 126

Total 350-700 umol/L (50-150 mcg/mL) Free valproic acid levels are not routinely available Therapeutic range is a guideline only and must be individualized Target range is often expanded to include higher levels (ie. 875 umol/L) Seizure range is extrapolated to bipolar disorder

Answer 127

Trough (steady state)

Answer 128

Steady steady state trough level 3-4 days after initial therapy Seizure activity: at time of seizure to determine seizure threshold Suspected signs and symptoms of valproic acid toxicity Addition or withdrawal of other enzyme inducing drugs Suspected non-adherence

Answer 129

Loading dose and Maintenance Dosing

Answer 130

Generally 250 mg PO BID for bipolar Increase 5-10mg/kg/day (generally 250-500 mg/day) using dosing multiples of 125 based on response, levels, tolerance Therapeutic doses usually between 1500-2500 mg/day Dosing frequency is usually BID-TID

Answer 131

Use syrup to administer through NG or PEG tube

Answer 132

EC tabs cannot be crushed and capsules should be swallowed whole (may cause local irritation to mouth)

Answer 133

Divalproex tablets (EC) most commonly used in Bipolar Seizures - Not bioequivalent --> Do levels if switching between --. Mainly in seizures

Answer 134

Dosing between VPA and DVP PO (including syrup) is considered 1:1 equivalent, but should check levels at steady state to be sure Not considered bioequivalent

Answer 135

Valproic Acid is an enzyme inhibitor --> Most commonly seen with drugs metabolized by CYP2C9, epoxide hydroxylase, UDPGT Due to high protein binding valproic acid is subject to displacement interactions with other drugs and endogenous substances (e.g. free fatty acids)

Answer 136

LAMOTRIGINE Inhibition by VPA increases lamotrigine by 50% THEREFORE: Decrease lamotrigine dose by 50%

Answer 137

GI: nausea, vomiting, anorexia, diarrhea, constipation (reported to be lower with divalproex vs valproic acid) CNS: tremor, sedation, ataxia, dizziness Thrombocytopenia (can continue if mild to moderate)

Answer 138

Weight gain (up to 60% of patients, mean 8-14 kg) Menstrual disturbances, polycystic ovaries Alopecia

Answer 139

Attributed to the 4-ene-metabolite; adjust therapy if enzymes >3x ULN (transient, minor elevations can be seen)

Answer 140

VPA/DVP in patients of childbearing potential = use contraception Can lead to neural tube defects --> C.I.

Answer 141

Do not start new laundry detergent, soap, etc. so if you get a rash we know it’s the medication

Answer 142

Common side effect management GI upset: take with food, use DVP, use H2RAs Sedation: take higher dose at HS

Answer 143

May take several weeks to see benefit Check with pharmacist or physician before starting any new prescribed or non-prescribed medications Self-monitor for symptoms of liver failure or pancreatitis Use reliable contraception if child-bearing potential; take folic acid supplementation Avoid excessive alcohol due to risk of hepatic injury DI check every time starting or stopping VPA/DVP

Answer 144

Seizures: Partial seizures (adjunctive), absence seizures (monotherapy), generalized tonic-clonic (monotherapy) Bipolar disorder Acute bipolar depression Maintenance in BDI or II

Answer 145

Not recommended in acute mania Role: Depressive side of bipolar; does not help much with mania

Answer 146

Alters signal transduction via: --> binding to the open channel conformation of the voltage-gated sodium 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

Answer 147

Half life 25-33 h (adults, with no interacting drugs) Peak plasma levels at 1-5 h Hepatic and renal metabolism Metabolized by glucuronidation and UGT enzymes

Answer 148

Not done clinically; not helpful for levels Only helpful for saying whether the pt is taking the medication

Answer 149

Requires dose adjustment in either hepatic or renal impairment, and in elderly

Answer 150

lamotrigine dosing: SLOW TITRATION IS IMPORTANT

Answer 151

Highest for inducing a skijn rash – Steven Johnson’s and TENs (lethal- inflammatory state leading to end organ failure) Rare --> super important counselling point --> STICK TO THE REGIMEN

Answer 152

After 5 days, lamotrigine is washed out of the body --> NEED TO RESTART SLOW TITRATION Counsel on this to ensure adherence

Answer 153

Usually well tolerated

Answer 154

Baseline: hepatic and renal function ( then q36 months) Ongoing: rash No serum levels necessary No lab monitoring required other than standard/annual blood work

Answer 155

OCP --> Related to estrogen levels Other drugs that induce metabolism (decrease lamotrigine levels) Olanzapine chronic use of acetaminophen 4g/d some antiretrovirals rifampin

Answer 156

Hormone Free week – increase in lamotrigine during that week --> ideally its recommended if someone on OCP and lamotrigine -->Continous dosing Related to the estrogen levels - Progestin only, copper IUD also good options

Answer 157

May take several weeks to see benefit (especially due to slow titration) Adherence is important; contact physician if missed more than 5 days as you may need to restart titration Common side effect management Usually well tolerated Can take without regards to food or time of day Self-monitoring for rash is very important. If any signs of skin abnormalities, stop taking lamotrigine and seek medical attention (ER if sudden, rapid development) Avoid trying new products or food that can commonly result in skin sensitivities during titration period Watch out for enzyme inhibitors, especially VPA or CBZ

Answer 158

VPA and lamotrigine – even if doesn’t have seizure disorder, if stopped abruptly, taper them down – withdrawal could trigger a seizure do not stop meds without talking to someone Any seizure med if stopped abruptly (even if has not had seizure), could potentiate a seizure less risk in those without a seizure disorder, but can occur

Answer 159

Tricyclic Anti-depressants Anticholinergic properties

Answer 160

Seizures: generalized tonic-clonic (grand mal), partial-onset Bipolar disorder Acute mania treatment Maintenance Neuropathic pain (off-label) Trigeminal neuralgia

Answer 161

Signal transduction modulation (decrease repetitive action potential firing) and anti-kindling properties

Answer 162

Stimulates the release of ADH and potentiates its action in promoting reabsorption of water SIADH A/E

Answer 163

yndrome of inappropriate antidiuretic hormone secretion (SIADH) is a condition in which the body makes too much antidiuretic hormone (ADH). ADH is also called vasopressin. This hormone helps the kidneys control the amount of water your body loses through the urine. SIADH causes your body to retain too much water.

Answer 164

lethargy change in mental status, Na < 135 mEq/l, hyperosmolar urine (>300 mosmol/kg)

Answer 165

inpatient care, discontinue offending agent, water restrictions

Answer 166

>99% hepatic metabolism via CYP enzymes, 2-3% unchanged in urine CYP3A4 (major), CYP2C8 (minor), CYP1A2 (minor) Major metabolite (carbamazepine-10,11-epoxide) is active and has therapeutic and toxic effects Epoxide is hydrolyzed by CYP1A2 to an inactive diol metabolite that is excreted in the urine UDPGT is also involved in metabolism Induces its own metabolism via the epoxide-diol pathway (AUTOINDUCTION)

Answer 167

Induces its own metabolism via the epoxide-diol pathway (AUTOINDUCTION) Onset within 1-5 days Time to completion 1 to 5 weeks Dose related (each increase in dose results in further autoinduction) Results in increased clearance and decraesed t1/2 with continued dosing Css levels are lower than predicted from single dose studies

Answer 168

Variable due to autoinduction 0.4 ± 0.1 ml/min/kg (single dosing) 1.3 ± 0.5 ml/min/kg (multiple dosing)

Answer 169

Not altered by renal disease, dialysis But severe renal impairment may lead to accumulation of the epoxide metabolite; some references suggest dose reduction if CrCl < 30

Answer 170

Until stabilized at target dose During auto-induction (every 1-2 weeks until on stable regimen) Steady state trough (after 5 weeks)

Answer 171

Suspected non-adherence Suspected signs and symptoms of carbamazepine toxicity Potential DIs or altered PK Conversion between carbamazepine dosage forms To establish what concentration resulted in mood stability

Answer 172

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

Answer 173

Controlled release tabs: Q12H Chew tabs and immediate release: Q8H Suspension: Q8H

Answer 174

Increase CBZ Levels Macrolides --> Clarithromycin, erythromycin, telithromycin Use alt antibiotic if possible. Monitor CBZ levels after starting or stopping the antibiotics AZOLEs (anti-fungals) Itraconazole, fluconazole, ketoconazole, voriconazole (C.I.) Monitor CBZ levels after start and stop of antifungal. Monitor for antifungal failure or relapse Cardiovascular CCB --> Diltiazem and, verapamil use alt. agent if possivble Monitor CBZ levels after start, stop, or CCFB doseage change Grapefruit JUice --> AVOID or suggest to not significantly alter ingestion while taking CBZ DRUGS Decreased by CBZ Warfarin --> Monitor INR during CBZ initiation, dose titration, or discontinuation. Recheck INR weekly until stable DOAC's --> USe not recommended Antipsychotics (e.g. aripiprazole, brexpiprazole, quetiapine, olanzapine, risperidone, haloperidol, clozapine, lurasidone) Antidepressants (e.g. citalopram) Antiretrovirals (e.g. NNRTIs) Non-DHP CCBs (amlodipine, nifedipine) Estrogen or progresterone contraceptives Caspofungin, azole antifungals Immunosuppressants (e.g. tacrolimus, cyclosporin) Methadone

Answer 175

Osteomalacia Vitamin D deficiency

Answer 176

History of hepatic disease, CVD, blood dyscrasias, bone-marrow depression And concurrent use with clozapine (both drop WBC’s)

Answer 177

Baseline pregnancy or allele testing if applicable TDM per previous slide – usually just as clinically indicated

Answer 178

Take with food to minimize GI upset Report rash or flu-like symptoms right away Carbamazepine will decrease efficacy of estrogen or progestin based contraception. Recommend alternative methods of birth control (ie. Copper IUD, condoms). Recommend regular folic acid supplementation. All the drug interactions Strong recommendation to test for HLA-B*1502 allele in anyone of Asian ancestry (other allele testing is not routinely recommended) Recommend Ca and Vit D supplementation (potential effect on bones)

Answer 179

Primary mode of action: Dopamine blockade

Answer 180

Typical vs atypical: Atypicals (or SGAs) generally have lower risk of EPS and hyperprolactinemia Typical antipsychotics are very rarely used for bipolar

Answer 181

Bipolar patients are more likely to show EPS when treated with comparable doses of antipsychotics compared to patients with psychosis -->A patient on typical antipsychotic is more likely to switch into depression (compared to Lithium/VPA) Doses are lower for bipolar than they are for psychosis

Answer 182

EPS Hyperprolactinemia, sexual dysfunction Metabolic disturbance (weight gain, dyslipidemia, DM, CVD) Anticholinergic: sedation, constipation, dry mouth, blurred vision, confusion Antihistaminergic: sedation Alpha1 blockade: hypotension, reflex tachy, dizziness, sedation QT prolongation Seizures

Answer 183

QT prolongation: (especially Chlorpromazine, ziprasidone

Answer 184

Conflicting Data Risk of switching patients to mania! But bipolar depression is very difficult to treat The risk of switching to mania may not be as high as once thought, especially for BDII

Answer 185

Avoid AD monotherapy without antimanic agent Use with caution in people with history of AD-induced mania, mixed features, or rapid cycling Discontinue during acute manic episode (taper or abrupt discontinuation if severe mania) Consider tapering off once depression symptoms eliminated for 3-4 mon

Answer 186

Avoid TCAs >> Avoid SNRIs (higher risk of switch) Safest in BDII (don’t need to know BDII for exam) bupropion > sertraline, then fluoxetine or other SSRIs > venlafaxine(?) Paroxetine not recommended due to level 2 negative evidence in BDII

Answer 187

Using short courses (~3-4 months) is prudent May taper off antidepressant once asymptomatic for 6-12wks Prolonged use beyond 1 yr increases risk of mania

Answer 188

NEVER USE ANTI_DEPRESSANT ALONE  Always in combo with mood stabilizer \

Answer 189

Lithium, quetiapine, divalproex, aripiprazole, paliperidone (dose >6 mg), risperidone (L1) Comparable efficacy, small-medium effects 50% will respond to monotherapy with significant improvement in mania in 3-4 weeks Some improvement to mania should be seen in first week, especially with DVP or APs

Answer 190

Lithium or divalproex + quetiapine (L1), risperidone (L1), or asenapine (L2) Greater efficacy than monotherapy with lithium or divalproex alone, especially in more severe illness

Answer 191

Combo therapy is recommended when a response is needed faster (especially in hospital), in patients judged at risk, who have had a previous history of partial acute or prophylactic response to monotherapy or in those with more severe manic episodes.

Answer 192

Lets quit dicking around and Perform Rasputin carefully Quiet as Rasputin Arrives

Answer 193

Lithium is preferred over divalproex 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 those with a family history of BD, especially with a family history of lithium response.

Answer 194

Divalproex is equally effective in those with classical and dysphoric mania (irritable 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.  Anti-seizure effect that lithium does not have

Answer 195

Patients with specific factors such as a history of head trauma, neurologic symptoms, comorbid anxiety and substance abuse, schizoaffective presentations with mood-incongruent delusions, or negative history of bipolar illness in first-degree relatives may respond to carbamazepine. (Atypical Bipolar Picture)

Answer 196

Mixed features: DVP or APs, especially AP + DVP.

Answer 197

Some therapeutic response is expected within 1-2 weeks after starting 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.

Answer 198

4-6 weeks however can consider switch/add on at 2 weeks if no response

Answer 199

Gabapentin (L2 negative) Lamotrigine (L1 negative) Omega 3 fatty acids (L1 negative) Topiramate (L1 negative)

Answer 200

STEP-BD study suggested that mood stabilizers which include lithium are as effective as mood stabilizers plus antidepressants in treating acute bipolar depression. In the only large double blind placebo controlled trial conducted to date, lithium was not more effective than placebo for treating acute bipolar depression (Young et al. 2010) Finnish observational study (n = 18,018) found that lithium was more effective than all others at preventing psychiatric or all cause hospitalization Clearly demonstrated efficacy in preventing any mood episodes in multiple trials/MAs (Yatham et al. 2018

Answer 201

Agents not recommended for acute bipolar depression Antidepressant monotherapy (L2N) Available trials do not support their efficacy Safety concern = mood switching Not monotx (combo with mood stabilizer) Aripiprazole monotherapy (L1N) Ziprasidone mono/adjunctive therapy (L1N) Lamotrigine with folic acid (L2N) Mifepristone adjunctive (L2N)

Answer 202

Almost all individuals with BD require maintenance therapy to prevent subsequent episodes, reduce residual symptoms, and restore functioning Recurrence may be associated with decreased brain matter volumes, worsened cognitive impairment, decreased inter-episodic function, higher rate and severity of relapse, reduced rate of treatment response to pharmacotherapy and psychotherapy

Answer 203

Effective maintenance treatment early in illness, even after first episode: Reverse cognitive impairment Preserve brain plasticity May lead to improved prognosis and minimization of illness progression

Answer 204

Younger age at onset Psychotic features Rapid cycling More previous episodes Comorbid anxiety Comorbid substance use

Answer 205

Primary Outcome: Initiation of new intervention for an emerging mood episode (follow up 2 years) Combo 54% vs. valproic acid 69% vs. lithium 59% Statistical analysis (hazard ratios) significantly favored combo over valproic acid & lithium over valproic acid Lithium superior to valproic acid for maintenance of BDI (NNT= 10/2years to prevent 1 relapse) Secondary Outcome: No significant differences in adverse drug effects

Answer 206

Recommended pharmacotherapy: Discontinue antidepressants Monotherapy: Atypical antipsychotic Combination therapy: Lithium OR divalproex + atypical antipsychotic

Answer 207

Some evidence for anticonvulsants for having a protective effect Antidepressants are controversial Recall differences seen in children/adolescents, etc Antipsychotics Positive evidence for clozapine (InterSePT trial) for prevention of suicide; however, this evidence comes from Schizophrenia literature In general, though, antipsychotics do not appear to have any anti-suicidal effect

Answer 208

Very little difference in efficacy (and not many predictors of response) Can be large differences in tolerability Patient involvement and empowerment may lead to better outcomes