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PHAR 358 > Bipolar Disorder > Flashcards

Bipolar Disorder Flashcards

1
Q

Define Mood

A

A pervasive and sustained emotion or feeling tone that influences a person’s behavior and colors his or her perception of the world

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2
Q

How may mood be described by a patient in a counsel?

A

Depressed, sad, empty, melancholic, distressed, irritable, disconsolate, elated, euphoric, manic, gleeful,

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3
Q

Describe mood. Is it stationary? What can it lead to?

A

Mood can be labile, fluctuating, or alternating rapidly between extremes

Laughing loudly at one moment, tearful the next

Can also lead to drastic changes in activity level, cognitive abilities, vegetative functions

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4
Q

Describe the mood spectrum

A
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5
Q

When does mood become not “normal”?

A

Fluctuations in mood are normal

Persistent episodes in extreme ends of the spectrum, or rapid fluctuations that impair functioning are not normal

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6
Q

Regarding mood, a pharmacist should consider __________ regarding pateints. How can this be used to distinguish between two disorders?

A

There are differences in how people can present –> AT the end of mania –> Can lead to psychosis

Hallucinations and psychotic sx in the end of spectrum, but goes back to stable (difference between schizophrenia and bipolar)

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7
Q

What are some mood disorders (affective disorders)?

A

Bipolar disorder

Cyclothymia

Dysthymia

Major depressive disorder (unipolar depression)

Other and unspecified bipolar disorder and related

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8
Q

Define Dysthymia

A

persistent depressive disorder

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9
Q

Define cyclothymia

A

mood swings between short periods of mild depression and hypomania that do not meet the full criteria for bipolar or major depressive disorder

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10
Q

Define (overarching) the definition of Bipolar Disorder

A

A chronic mood disorder subcategorized into:

Bipolar I Disorder (BDI)
A distinct period of at least one week of full manic episode: abnormally & persistently elevated mood and increased energy

Bipolar II Disorder (BDII)
A current or past hypomanic episode and a current or past major depressive episode

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11
Q

S.C. is a 40 year old male with a week long history of elevated mood. S.C. is talking way more than usual, engaging in unsafe sexual practices (not normal), and has mentioned he would like to “pursue a career to cure cancer.” It has been mentioned that he has not been sleeping and such elevations in mood have impacted his ability to show up to work and therefore his family brought him to the hospital to prevent more harm. His family informs you that he has never had an episode of decreased mood (depression). It is determined that his elevated mood is not caused by any medication or substance. Is a diagnosis of bipolar appropriate? If so, which bipolar disorder? Explain?

A

A diagnosis of bipolar 1 is reasonable

Bipolar 1 Disorder: a lifetime history of atleast one clear cut manic episode, with or WITHOUT episodes of hypo-mania or depression

A manic episode is defined as:

Mood: Abnormally and persistently elevated, expansive or irritable; must have cocncomitant increases in activity or energy; psychotic sx may occur

Duration: atleast 1 week, causing significant distress/disability or requiring hospital admission

PLUS:

If mood is elevated or expansive, 3 or more of the following features must be present. If mood is predominately irritable, 4 or more are required:

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 (activity or energy increase)

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12
Q

As soon as a patient is labelled with mania, a diagnosis of bipolar (I or II) is apppropriate.

A

Bipolar I

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13
Q

Descirbe lifetime prevaence of bipolar

A

Subthreshold - 1.4
Bipolar 1 –> 0.6
Bipolar 2 –> 0.4

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14
Q

Describe the difference between bipolar disorder in men and women?

A

Men = Women
Men have more manic episodes, women more depressive or mixed

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15
Q

Briefly describe the course of bipolar disorder? (Hint: What type of condition is it regarding its length?) What is an achievable goal? Why is it achievable?

A

Lifelong illness with variable course
Full recovery/maintenance is possible
A “cure” is not

Medications available to get people back to recovery and maintenance of remission is an achievable goal (can return to normal as defined within society)

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16
Q

Describe the etiology of Bipolar Disorder

A

Original and underlying causes of bipolar is multifactorial and many interrelated risk factors

Developmental
Genetic
Neurologic
Psychologic

Environmental stressors, emotional trauma, individual psychological makeup, genetic predisposition, anatomical abnormalities, and neurobiological makeup are all at interplay with each other and have all been postulated in some way to be contributing factors to bipolar disorder

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17
Q

Briefly describe the pathophysiology of bipolar disorder?

A

The exact cause of bipolar disorder is unknown.

Several theories involving neurotransmitters and signal transduction have been proposed.

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18
Q

Describe the risk factors for bipolar disorder?

A

1) Having a first degree relative
2) Period of high stress
3) Drugs or alcohol misuse
4) Major life changes, such as the death of a loved one or other traumatic experiences
5) Medical conditions

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19
Q

What medical conditions are risk factors for bipolar depression?

A

Hyperthyroidism
Hormonal Changes
CNS Disorders
Endocrine Dysregulation
CVD

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20
Q

How can drugs be a risk factor for bipolar disorder? Examples?

A

Drugs can unmask bipolar through de-regulation of neurotransmitters

Drugs: Corticosteroids, Antidepressants, Stimulants

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21
Q

Which medications or drugs can induce mania?

A

Alcohol Intoxication

Drug withdrawal states (alcohol,a2 adrenergic agonists (clonidine), antideppressants, barbituates, benzodiazepines, opiates)

Antidepressants –> MAOIs, TCAs, 5-HT and/or NE and/or DA reuptake inhibutors, 5-HT antagonists

DA Augmenting Agents (CNS stimulants: amphetamines, cocaine, sympathominemetics; DA agonists, releasers, and reuptake inhibitors

Hallucinogens (LSD, PCP)

Marijuana Intoxication (precipitates psychosis, paranoid thoughts, anxiety and restlessness)

NE Augmenting agents (a2 adrenergic agonits, Beta-agonists, NE reuptake inhibitors)

Steroids –> Anabolic, adrenocorticotropic hormone, corticosteroids) - especially high cancer doses

Thyroid preparations –> Levothyroxine

Stimulants –> Caffeine, decongestants

ADHD assumes many normal students take stimulants

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22
Q

Controversy of Anti-depressants in Bipolar. Evaluation by pharmacist?

A

Often an early diagnosis of depression –> depression is not well managed –> suddenly becomes manic

Antidepressnats can push someone into mania

Presentation with mania or hypomania, should evaluate anti-depressant usage

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23
Q

Should anti-depressants be suddenly stopped? Issue?

A

When pt presents with mania or hypomania, anti-depressants should be discontinued

Run the risk of FINISH

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24
Q

What are some medical conditions that can induce mania?

A

CNS Disorders (brain tumor, head injuries, subdural hematoma, multiple slcerosis, systemic lupus, temporal lobe seizures, Huntington’s dx)

Infections –> Encephalitis, sepsis, HIV

Electrolyte or Metabolic Abnormalities (calcium or sodium fluctuations, hyperglycemia or hypoglycemia)

Endocrine or hormonal dysregulation (Addison Dx, Cushing Dx, Hyperthyroidism, or hypothyroidism, menstrual-related or perimenopausal mood disorders)

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25
Q

What are some somatic therapies that can induce mania?

A

Bright light therapy

Deep brain stimulation

Sleep Deprivation

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26
Q

Describe the onset of bipolar (all types)? Most common age? Problems with diagnosis?

A

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

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27
Q

How long does it commonly take to recieve a diagnosis for bipolar? Do many recieve treatment? Why or why not?

A

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.

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28
Q

What is an issue with the diagnosis of bipolar in the first year of sx presentation? Why?

A

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

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29
Q

What is the prognosis of bipolar disorder/Describe the disease course?

A

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)

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30
Q

Is euthymia a complete return to normal? How common is it?

A

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.

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31
Q

Bipolar disorder has a profound rate of __________ and ___________. Some effects include:

A

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

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32
Q

What is the best predictor of the level of functioning in bipolar disorder? What is the reason for medication usage?

A

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

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33
Q

What is the comparison of life expectancy for patients with bipolar compared to those without?

A

Life expectancy is 10 years less

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34
Q

What are some conditions that worsen existing Bipolar Disorder? How can this effect treatment?

A

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

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35
Q

What is one of the leading causes of death in bipolar disorder? Prevalence?

A

SUICIDE

One of the leading causes of death in BD

6-7% of identified patients with bipolar die by suicide

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36
Q

How much higher is sucidie in Bipolar than general population?

A

Death by suicide up to 20x higher than general population

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37
Q

Who us at higher risk of death of suicide between the geneders?

A

Men are at higher risk of death by suicide than women

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38
Q

How many individuals with Bipolar attempt sucidie?

A

20-50% attempt suicide at least once

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39
Q

What are some factors that are associated with suicide attempts?

A

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

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40
Q

What should occur at every patient encounter for bipolar disorder?

A

Comprehensive assessment for suicide risk should occur during all patient interactions

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41
Q

Describe the criteria of MANIA in the DSM-5

A

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

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42
Q

Describe some of the sx in Mania and when they occur? What occurs first?

A

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

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43
Q

How is a hypomanic episode defined according to the DSM-5?

A

Mood: Same sx as for mania, but milder and not disabling; no psychotic sx

Duration: 4 days or longer

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44
Q

How is a major depressive episode defined according to the DSM-5 (CPS)?

A

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
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45
Q

For a manic episode to be considered a manic episode, what should be ruled out? Exception?

A

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.

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46
Q

What is a pneumonic to help remember the symptoms of mania?

A

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

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47
Q

For a diagnosis of Bipolar 1, what is the DSM-5 criteria regarding depressive episodes and mania?

A

Manic episode required for diagnosis.

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

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48
Q

Define a hypomanic episode according to the DSM-5?

A

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.

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49
Q

Define hypomanic episode according to CPS/DSM-5

A

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

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50
Q

Can a diagnosis of hypomania be made if the individual is on anti-depressants? What should be noted regarding the diagnosis if applicable?

A

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.

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51
Q

Describe the Bipolar 2 DSM-5 Criteria?

A

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
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52
Q

Describe the differences in diagnosis of bipolar 1 and 2 in a table.

A
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53
Q

Define the diagnostic criteria of a major depressive episode according to the DSM-5?

A

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

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54
Q

Describe the standardized rating scales for Bipolar1 and 2? Purpose and INterpretation?

A
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55
Q

What are some challenges in Bipolar diagnosis and treatment?

A

Delay to diagnosis

Misdiagnosis

Limited Clinical Trials

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56
Q

Describe the delay to diagnosis in Bipolar

A

Average delay 8-12 years

Often patients do not recall hypomanic symptoms

More likely to seek help for depression vs. mania

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57
Q

Describe the misdiagnosis of BIpolar Disorder

A

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)

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58
Q

Describe the effect of limited clinical trials in the diagnosis of bipolar disorder?

A

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

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59
Q

Define a manic or hypomanic episode with mixed features

A

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

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60
Q

Define a depressive episode with mixed features

A

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

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61
Q

Can an individual be diagnosed with one type of bipolar but switch to another? Why or why not?

A

May see bipolar 2 become bipolar 1 if have a clear-cut manic episode

Bipolar 1 cannot become Bipolar 2

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62
Q

CPS: Describe the comparison of the bipolar disorder to other disorders regarding the difficulties with diagnosis

A

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

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63
Q

Describe the goals of therapy of Bipolar Disorder

A
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64
Q

For a diagnosis of bipolar disorder, what are two useful diagnostic tools?

A

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

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65
Q

Describe the timeline for medication improvement in Mania.

A

Response 1-2 weeks

Full clinical benefit 3-4 weeks

Responds faster to pharmacotherapy than depression

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66
Q

Describe the timeline for medication improvement in depression for bipolar? Comparison to Unipolar?

A

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.

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67
Q

What are some non-pharamcological strategies for bipolar disorder?

A

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!

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68
Q

What is a relapse prevention plan?

A

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 theNational Suicide Prevention Hotline (1-800-273-8255)

What their triggers are

And a post-crisis plan

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69
Q

Describe the pharmacotherapy options for bipolar disorder?

A

First generation “typical” antipsychotics are rarely used for bipolar

RATS AFFECT ANYONES QOL

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70
Q

Describe the available mood stabilizers and how common they are for use?

A
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71
Q

What are the brand names for lithium?

A

Carbolith, Lithmax

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72
Q

What are the indications for lithium?

A

Bipolar disorder
Acute mania treatment
Prophylaxis/maintenance

Schizoaffective disorder

Unipolar depression
Antidepressant augmentation

Low dose after TBI can be neuroprotective

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73
Q

Describe the pharmacology of lithium

A

Exact mechanism of action is not fully understood

Multiple effects on cellular function details

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74
Q

Describe the bioavailability (F) of Lithium

A

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

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75
Q

Describe the absorption of Lithium

A

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

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76
Q

Describe the time to peak concentrations.for lithium

A

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

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77
Q

What are some issues with peak effect? Management?

A

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

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78
Q

When counselling a patient on lithium and its dosing, a good way for a pharmacist to communicate dosing with a patient is to…..

A

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

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79
Q

Does lithium exhibit protein binding?

A

Not bound to plasma proteins

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80
Q

Describe the volume of distribution of lithium

A

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

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81
Q

Describe the t1/2 of lithium?

A

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

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82
Q

Describe the elimination of lithium

A

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

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83
Q

Describe the clearence of lithium

A

ClLi= 10-40 ml/min (25% of GFR) [ClLi= 0.25 x ClCr]

Follows linear, dose-proportional pharmacokinetics

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84
Q

When would someone expect a decrease in clearance of lithium?

A

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

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85
Q

Is the renal clearance of lithium the same throughput the day?

A

Varies with circadian rhythm like GFR (chronokinetics)

Nocturnal ClLi is 78% of daytime value (20.7 vs. 26.4 ml/min)

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86
Q

Describe the t1/2 of lithium in different tissues?

A

Brain half life 28 hours vs 16 hours in serum

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87
Q

Regarding fluid status, what are some important counselling points to inform a patient of?

A

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.)

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88
Q

What are some potential common drug interactions that may lead to lithium toxicity?

A

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

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89
Q

Where in the kidney is lithium reabsorped? Is this the same for everyone?

A

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

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90
Q

What is a big counselling part regarding diet/fluid intake for a patient on lithium?

A

COUNSEL: CONSISTENTCY OF NA+ INTAKE

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91
Q

Describe the lithium therapeutic range (EXAM) Issue?

A

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

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92
Q

Describe the therapeutic range and the effects of such lithium levels

A

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

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93
Q

What are the differences in therapeutic range for acute mania and maintenance therapy? Why?

A

Mania we aim for higher levels

Maintennace phase move downwards

MOVE DOWN TO HELP REDUCE THE RISK OF A/E

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94
Q

Describe the time of sampling for lithium

A

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

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95
Q

If someone may be experiencing toxicity, a pharmacists main action should be too….

A

Get emergency medical help

Get a level stat

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96
Q

What are two scenarios where an individual should get a lithium level drawn STAT?

A

Toxicity

Non-adherence

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97
Q

How frequent should sampling of lithium occur?

A

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

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98
Q

What are some patient conditions that would necessitate sampling of lithium?

A

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

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99
Q

Lithium Dosing Target in Acute Mania (EXAM)

A

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

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100
Q

Describe how lithium can be dosed in acute mania? S/e? Mangement?

A

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

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101
Q

Dosing of lithium in acute mania in elderly patients

A

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

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102
Q

Why are lower doses of lithium used in elderly patients in acute mania?

A

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

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103
Q

A major consideration in dosing of lithium for in patients…..

A

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

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104
Q

What is the lithium maintenance dosing target plasma concentration? (EXAM)

A

Target plasma level 0.6-1 mmol/L

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105
Q

Maintenance therapy of lithium dosing

A

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

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106
Q

When someone becomes stabilized on lithium, what are some strategies a pharmacist can employ and why are these important?

A

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

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107
Q

What is the effect of once daily evening dosing of lithium (proposed theory)?

A

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

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108
Q

Is there any change in lithium plasma concentrations when switching from multiple daily doses to single dose?

A

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

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109
Q

Describe the dosing of lithium in renal impairment

A

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

110
Q

What should a pharmacist do when a toxic level of lithium is noticed?

A

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

111
Q

Describe the available formulations of lithium

A
112
Q

Describe the available dosage forms and coversion for lithium

A

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

113
Q

Which salt form of lithium is commonly used? Why?

A

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.

114
Q

Is there IV formulations of lithium avilable?

A

No

115
Q

What can be done if an individual experiences peak associated nauseau and tremors? What else can necessitate this decision?

A

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

116
Q

Describe the factors that can decrease lithium levels

A
117
Q

How can pregnancy affect lithium levels?

A

Plasma volume and GFR increase- lithium clearance increase 50-100% by 3rd trimester

Returns to normal after delivery

Decrease lithium levels

118
Q

How can manage lithium in pregnancy? Is it contraindicated?

A

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

119
Q

How does caffeine affect lithium levels?

A

May decrease the serum concentration of Lithium.

120
Q

How can a sodium supplement (or increased salt intake) affect lithium?

A

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

121
Q

What are some factors that can increase lithium levels?

A
122
Q

How does dehydration affect lithium?

A

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

123
Q

How does cirhhosis effect lithium levels?

A

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

124
Q

What are some other factors that can influence influence lithium levels?

A

Increased risk neurotoxicity when used with antipsychotics or carbamazepine

Loop diuretics and CCBs may increase or decrease levels

125
Q

What are the contraindications to lithium use?

A

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

126
Q

Explain how NSAID’s affect lithium levels

A

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.

127
Q

How do loop diuretics influence lithium concentrations?

A

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

128
Q

Explain the effects of diuretics on lithium

A
129
Q

How do ACEi affect lithium levels?

A

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

130
Q

How does renal impairment affect lithium levels?

A

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.
131
Q

How do anti-psychotics affect lithium?

A

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

132
Q

How do anti-depressants affect lithium?

A

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

133
Q

What are some adverse effects of lithium?

A
134
Q

What are some serious (idiosyncratic) adverse effects of lithium?

A

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.

135
Q

Adverse effects of lithium are thought to be a direct result of what?

A

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)

136
Q

With sustained release lithium, what side effects may be more prominent?

A

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

137
Q

What three things should a patient keep consistent while on lithium?

A

Fluid
Salt
Caffeine

138
Q

Describe lithium toxicity and its associated ranges

A
139
Q

What are some examples of what someone may expect as adverse effects when in certain toxic ranges of lithium?

A
140
Q

What should be monitored for lithium therapy? When should this be monitored?

A

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

141
Q

What are some common side effects of lithium and how can they be managed?

A

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

142
Q

What are some essential counselling points for lithium?

A

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)

143
Q

Is lithium contraindicated in pregnancy

A

Not contraindicated in pregnancy

Lower lithium dose to the lowest effective

PLanning in advance is important; can switch to different mood stabilizer

Consider contraception

144
Q

What should be monitored for lithium?

A

Monitor serum level, renal, lytes, thyroid regularly

145
Q

Valproic Acid available formulations

A

Valproic Acid

Divalproex Sodium (prodrug)

Sodium divalproex is cleaved in the GI tract to valproic acid

146
Q

What are the indications for valproic acid?

A

Seizures:
generalized tonic-clonic (grand mal), partial-onset, absence
Has broad-spectrum anti-epileptic activity

Bipolar disorder
Acute mania treatment
Maintenance (prophylaxis)

147
Q

Describe the mechanism of action of valproic acid?

A

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

148
Q

Describe the bioavailability of valproic acid

A

0.90-1.0

Divalproex Na+ and Valproate Na+ convert to valproic acid in stomach

149
Q

Describe the time to peak serum concentrations for valproic acid

A

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

150
Q

Salt factor of available valproic acid formulations

A

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

151
Q

What is the protein binding of valproic acid? Describe its protein binding properties?

A

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)

152
Q

Dsecribe the absorption of enteric coated VPA and its effect on extent of absorption?

A

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.

153
Q

How can one switch between the capsules and syrup formulations of VPA?

A

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.

154
Q

Describe VPA in the plasma

A

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

155
Q

Does the free fraction and total concentration of VPA remain consistent throughout the day?

A

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

156
Q

Describe the volume of distribution of VPA. Where does it distribute?

A

0.15-0.2 L/kg

Enters the brain rapidly after a dose

Distributes to other tissues (liver, kidney, bones and intestines)

157
Q

Describe the elimination of VPA?

A

> 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

158
Q

Describe the clearence of VPA?

A

Low extraction drug

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

159
Q

Describe the t1/2 of VPA?

A

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

160
Q

Describe the effect of liver disease (with hypoalbuminemia) on VPA?

A

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

161
Q

Since VPA is primarily hepatically eliminated, it is common to see __________ in people who use VPA consistently

A

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

162
Q

Describe the therapeutic range of VPA. Is it a set guidleine? Is the range specifically for bipolar?

A

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

163
Q

Describe the sampling of VPA

A

Trough (steady state)

164
Q

When should VPA plasma concentrations be conducted? What scenarios necessitate sampling?

A

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

165
Q

Describe the dosing of valproic acid (not actual numbers)?

A

Loading dose and Maintenance Dosing

166
Q

In maintenance dosing of VPA, titration can occur by….. Dosing frequency?

A

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

167
Q

Patient on NG or PEG tube, what formulation of VPA should be used?

A

Use syrup to administer through NG or PEG tube

168
Q

Can EC VPA be crushed? Why or why not?

A

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

169
Q

Describe the dosing principles of VPA

A
170
Q

Describe the available formulations of VPA

A

Divalproex tablets (EC) most commonly used in Bipolar

Seizures - Not bioequivalent –> Do levels if switching between –. Mainly in seizures

171
Q

Describe the switch in dosing between VPA and DVP PO? Syrup?

A

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

172
Q

Describe the overall principles of VPA drug interactions

A

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)

173
Q

Describe the drug interactions of VPA and how to manage them

A
174
Q

What drug can be increased by VPA?

A

LAMOTRIGINE

Inhibition by VPA increases lamotrigine by 50%

THEREFORE: Decrease lamotrigine dose by 50%

175
Q

What are some dose related adverse effects of VPA?

A

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)

176
Q

What are some idiosyncratic adverse effects of VPA?

A
177
Q

What are some chronic a/e of VPA?

A

Weight gain (up to 60% of patients, mean 8-14 kg)

Menstrual disturbances, polycystic ovaries

Alopecia

178
Q

Describe the management of hepatotoxicity with VPA

A

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

179
Q

Describe the use of VPA in pregnancy

A

VPA/DVP in patients of childbearing potential = use contraception

Can lead to neural tube defects –> C.I.

180
Q

Describe relavant monitoring parameters for VPA

A
181
Q

Regarding the rash A/E of VPA, a pharmacist should counsel to….

A

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

182
Q

What are some ways to manage common VPA A/E?

A

Common side effect management

GI upset: take with food, use DVP, use H2RAs

Sedation: take higher dose at HS

183
Q

What are some critical counselling points for VPA?

A

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

184
Q

Describe the indications for lamotrigine

A

Seizures:
Partial seizures (adjunctive), absence seizures (monotherapy), generalized tonic-clonic (monotherapy)

Bipolar disorder
Acute bipolar depression
Maintenance in BDI or II

185
Q

LAMOTRIGINE’s ROLE in BIPOLAR

A

Not recommended in acute mania

Role: Depressive side of bipolar; does not help much with mania

186
Q

Describe the MOA of Lamotrigine

A

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

187
Q

Describe the pharmacokinetics of Lamotrigineb (t1/2, peak time, eliminaion)

A

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

188
Q

Describe the therapeutic range of lamotrigine

A

Not done clinically; not helpful for levels

Only helpful for saying whether the pt is taking the medication

189
Q

Describe the relevant drug interactions of lamotrigine

A
190
Q

Lamotrigine requires dose adjustments in….

A

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

191
Q

Describe the titration of lamotrigine dosing

A

lamotrigine dosing: SLOW TITRATION IS IMPORTANT

192
Q

Out of the medications used in bipolar, Lamotrigine has the highest risk of…..

A

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

193
Q

Describe lamotrigine and missed doses. How should this be managed?

A

After 5 days, lamotrigine is washed out of the body –> NEED TO RESTART SLOW TITRATION

Counsel on this to ensure adherence

194
Q

What are some common a/e of lamotrigine?

A

Usually well tolerated

195
Q

What are some less common a/e of lamotrigine?

A
196
Q

What are some rare/serious a/e of lamotrigine?

A
197
Q

Describe the monitoring for Lamotrigine

A

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

198
Q

Describe the clinically relevant drug interactions of lamotrigine and its effect on lamotrigine.

A

OCP –> Related to estrogen levels

Other drugs that induce metabolism (decrease lamotrigine levels)
Olanzapine
chronic use of acetaminophen 4g/d
some antiretrovirals
rifampin

199
Q

If someone is on an OCP and lamotrigine, what dosing of OCP is more safe? What contraception should be recommended?

A

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

200
Q

What are some counselling points for lamotrigine?

A

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

201
Q

What is a critical counselling point for any anti-seizure med (lomotrigine, VPA)? Is it common for everyone?

A

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

202
Q

Carbamazepine is structurally related to…… Therefore its s/e are…..

A

Tricyclic Anti-depressants

Anticholinergic properties

203
Q

What are the indications for Carbamazepine?

A

Seizures:
generalized tonic-clonic (grand mal), partial-onset

Bipolar disorder
Acute mania treatment
Maintenance

Neuropathic pain (off-label)

Trigeminal neuralgia

204
Q

Describe the pharmacology of carbmazepine

A

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

205
Q

What is a mechanism of CBZ that is not related to mood but important to know?

A

Stimulates the release of ADH and potentiates its action in promoting reabsorption of water

SIADH A/E

206
Q

What is SIADH?

A

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.

207
Q

Sx of SIADH

A

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

208
Q

How can SIADH be managed?

A

inpatient care, discontinue offending agent, water restrictions

209
Q

Describe the elimination of CBZ –> Enzymes

A

> 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)

210
Q

Describe the autoinduction of CBZ

A

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

211
Q

Describe the Clearence of CBZ

A

Variable due to autoinduction

0.4 ± 0.1 ml/min/kg (single dosing)
1.3 ± 0.5 ml/min/kg (multiple dosing)

212
Q

When is CL of CNZ increased ajd decreased?

A
213
Q

Describe the t1/2 of CBZ

A
214
Q

CBZ and Renal Disease Dosing

A

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

215
Q

Therapeutuc range of CBZ. What is actually measured?

A
216
Q

Time of sampling CBZ

A
217
Q

When should CBZ levels be taken regarding timing?

A

Until stabilized at target dose

During auto-induction (every 1-2 weeks until on stable regimen)

Steady state trough (after 5 weeks)

218
Q

What scenarios would necessitate CBZ sampling?

A

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

219
Q

What are some dosing principles for CBZ?

A

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

220
Q

Describe the dosing frequency of avilable CBZ formulations

A

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

221
Q

Describe factors influencing dosing of CBZ

A
222
Q

CBZ Formulations

A
223
Q

Describe the D.I. of CBZ (overall picture)

A
224
Q

Describe specific drug interactions of CBZ

A

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

225
Q

CBZ Dose-related A/e

A
226
Q

CBZ idiosyncratic A/E

A
227
Q

CBZ Chronic A/E

A

Osteomalacia
Vitamin D deficiency

228
Q

C.I. CBZ

A

History of hepatic disease, CVD, blood dyscrasias, bone-marrow depression

And concurrent use with clozapine (both drop WBC’s)

229
Q

Monitoring of CBZ

A

Baseline pregnancy or allele testing if applicable

TDM per previous slide – usually just as clinically indicated

230
Q

Counselling Tips CBZ

A

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)

231
Q

Antipsychotics primary mode of action

A

Primary mode of action: Dopamine blockade

232
Q

Describe the difference between typical and atypical anti-psychotics

A

Typical vs atypical:

Atypicals (or SGAs) generally have lower risk of EPS and hyperprolactinemia

Typical antipsychotics are very rarely used for bipolar

233
Q

Antipsychotics Use in Bipolar compared to other conditions

A

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

234
Q

Antipsychotics A/e

A

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

235
Q

Monitoring of antipsychotics

A

QT prolongation: (especially Chlorpromazine, ziprasidone

236
Q

Anti-depressants in Bipolar?

A

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

237
Q

STEP-BD Trial Findings

A
238
Q

Consensus on anti-depressant use in Bipolar they be avoided?

A

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

239
Q

Antidepressants in Bipolar: Which ones?

A

Avoid TCAs&raquo_space; 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

240
Q

Length of ANti-depressant USe Bipolar

A

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

241
Q

Can an anti-depressnat be used alone in Bipolar?

A

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

242
Q

recommended ANtidepressantrs in Bip[olar

A
243
Q

Not recommended anti-depressants Bipolar

A
244
Q

Describe the approach to tx

A
245
Q

Acute MAnia 1st Line Mon-Tx? When should improvement be seen?

A

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

246
Q

Mania First Line COmbo Tx

A

Lithium or divalproex + quetiapine (L1), risperidone (L1), or asenapine (L2)

Greater efficacy than monotherapy with lithium or divalproex alone, especially in more severe illness

247
Q

When is combo tx recommended in BD?

A

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.

248
Q

Acute Mania TX’s CANMat

A

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

249
Q

When is lithium preferred for acute mania?

A

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.

250
Q

When is DVP recommended for acute mania?

A

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

251
Q

When is CBZ preferred?

A

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)

252
Q

Mixed Features Bipolar

A

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

253
Q

When would we add on or switch in acute mania? What agents?

A

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.

254
Q

A full trial of agents for acute mania is how long?

A

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

255
Q

Which agents are not recommended for acute mania?

A

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

256
Q

1st Line TX Bipolar 1 Depression

A
257
Q

CANMAt Bipolar Depression 1st Line agents

A
258
Q

STudy FIndings for CAute Dperession and Lithium

A

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

259
Q

Bipolar 1 Depression Add on or Switch Recommendation

A
260
Q

Which agents are not recommended for acute Bipolar 1 depression?

A

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)

261
Q

Bipolar 1 Maintennace Therapy

A

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

262
Q

WHy is ear;y maintenance tx important?

A

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

263
Q

Risk factors for recurrence

A

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

264
Q

What else must be inc;luded in maintenace tx?

A
265
Q

Maintenance TX CANMAT

A
266
Q

Maintenace TX Add on or Switch

A
267
Q

Balance 2010 Resukts

A

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

268
Q

Mixed EPisodes MGMT

A

Recommended pharmacotherapy:

Discontinue antidepressants

Monotherapy:
Atypical antipsychotic

Combination therapy:
Lithium OR divalproex + atypical antipsychotic

269
Q

Preganancy MGMT

A
270
Q

Suicide Prevention - WHich agent?

A

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

271
Q

Overall recommendation of pharmacotx in Bipolar

A

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

PHAR 358 (4 decks)

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