Neuro Exam 3

Define bipolar disorder

Mood disorder characterized by recurrent fluctuations in energy, mood, and behavior
Characterized by at least one manic, hypomanic, or mixed episode during the course of illness

What are the different types of bipolar disorders

Bipolar Disorder Type I
Bipolar Disorder Type II
Cyclothymic Disorder
Bipolar Disorder NOS

Define bipolar 1 disorder

Characterized by one or more manic or mixed episodes, usually accompanied by major depressive episode

define bipolar 2 disorder

characterized by one or more major depressive episodes accompanied by at least one hypomanic episode (at least 4 consecutive days)

Describe a manic episode

A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week

During the period of mood disturbance, 3 or more of the following are present:
---Inflated self-esteem or grandiosity
---decreased need for sleep (rested after 3 hrs)
---More talkative than usual or pressured speech
---Flight of ideas/thought racing
---Distractibility
---Increase in goal-directed activity/psychomotor agitation
---Excessive involvement in pleasurable activities that have a high potential for painful consequences (overly spending, ect)

Sufficiently severe to cause marked impairment

What is the pneumonic to remember mania/hypomania

DIGFAST (Hint)
D: Distractibility/Poorly Confused
I: Insomnia
G: Grandiosity/Increased self-esteem’=
F: Flight of Ideas/Racing thoughts
A: Activity increased in goal directed activity
S: Speech pressured…more talkative
T: Thoughtlessness: “risky behaviors”

What is the theory behind cause of bipolar disorder

Neurochemical imbalance theories
---Excess in excitatory neurotransmission + decrease in inhibitory neurotransmission
--------Excess catecholamine activity manifests as mania
--------Deficiencies in GABA &  glutamate cause dysregulation of neurotransmitters


Dysregulation in 2nd Messenger Systems
---Abnormal cAMP and phophoinositide 2nd messenger systems
--------Hyperactive G proteins in bipolar patients

What is the 1st line treatment for mania

Monotherapy with lithium, valproate, or an atypical antipsychotic for mania of moderate severity

Combination therapy of [lithium or valproate] + an atypical antipsychotic for patients with severe mania or mania w/psychotic features

What is the first line treatment for Mixed episodes or Rapid Cycling

Use valproate

What are the 1st line monotherapies for mania

Lithium
Divalproex
Quetiapine
Asenapine
Aripiprazole
Paliperidone (> 6 mg)
Risperidone
Cariprazine

Whar are the second line treatements for mania

Olanzapine (Mono or combo w/Li or DVX)
Carbamazepine
Ziprasidone
Haloperidol

Lithium indications

Bipolar Disorder (Maintenance Treatment)

Bipolar Disorder (Manic Episode)

Other usage
---Depressive episodes associated with Bipolar Disorder
---Psychotic features associated with Bipolar Disorder

What are some MOAs of lithium

Inhibit presynaptic exocytoxic release of dopamine
Inhibition of glycogen synthase kinase-3β
Modulation of gene expression
Serotenergic involvement(??)
Inh apoptosis, neuroprotective
MOOD STABILIZER

How do we check lithium labs

12hrs after dose

What are the most common ADEs of lithium

CNS Effects
---Weakness, drowsiness, fatigue, dizziness, ataxia, slurred speech, memory difficulties (dose dependednt)
---tremor (dose dependent)
GI upset
---Nausea (up to 50%)
---Vomiting
---Diarrhea
NEPHROGENIC DIABETS INSIPIDUS (dysregulation of ADH)
Weight gain (Up to 4-10 kg in 30% of patients)
EKG changes (QT prolongation)
Hypercalcemia (quarter of pts)
Hyperparathyroidism
Leukocytosis (Increase 1.5 x baseline neutrophil count)
Dermatological (Acne, Psoriasis activation)

How does Lithium Induce Hypothyroidism

Inhibits thyroid ability to concentrate iodine and synthesize iodinated thyroglobulin
Suppresses 2nd messenger system response of TSH activation
Inhibits conversion of T4 to T3

Most common dose lithium plasma concentration for acute phase

0.8-1.0 mEq/L

Most common dose lithium plasma concentration for Maintenance Phase

0.6-0.8 mEq/L

How long does it take to reach steady state on lithium

5 days

How often do you check lithium levels

Acute phase (inpatient): q 1-2 times weekly
Maintenance phase (outpatient): q 3-6 months

Divalproex Sodium brand

Depakote

Divalproex Sodium (Depakote)MOA

Blockade of voltage-sensitive Na+ channels

increases GABA concentrations
(Stimulation via glutamic acid decarboxylase)

Regulate downstream signal transduction
---Inhibits glycogen synthetase kinase 3 (GSK3)
---Inhibits phosphokinase C
------Inhibiting signals hypothesized to deacreases mania
---Activates neuroprotective factors

Black box warnings for Divalproex Sodium (Depakote)?

hepatic failure
Pancreatitis
teratogenic

Common adverse effects of divalproex/valproic acid derivatives?

Gastro intestinal (give with food and PPI/H2RA/antacid)
(vomiting, diarrhea, constipation)
Thrombocytopenia (esp if on aspirin)
Can increase ammonia levels (encephalopathy)
Increased suicidal risk

Drug-drug Interactions for divalproex?

Drug reactions with eosinophilia and systemic symptoms
Thrombocytopenia w/aspirin

Carbamazepine (Equetro) Mechanism in bipolar disorder

Blockade of voltage-sensitive Na+ channels
Blocks kindling
Modulates or decreases presynaptic aspartate and glutamate release (?)

Carbamazepine brand in bipolar

Equetro

Common adverse effects of carbamazepine?

Gastrointestinal side effects (nausea most common and Constipation least common)
anticholinergic side effects (mostly dry mouth)
dangerous and overdose
hyponatremia
teratogenic

Black box warnings for carbamazepine?

anemia and agranulocytosis
fatal hypersensitivity reactions (DRESS, Steven Johnsons)

Drug-Drug Interactions for carbamazepine

enzyme inducer
increases metabolism of vitamin D
decreases effects of other medications
decreases clozapine

Is an important dosing note for carbamazepine

it is a autoinducer which happens for the first four weeks

Which drug can you get the quickest response in mania

Depakote

What drug is most effective for those who are rapid cycling

VPA/Depakote

What is the primary mechanism of action of atypical anti psychotics in bipolar disorder

Blockade of dopamine (D2) and serotonin (5HT2A) receptors
Reduces glutamate hyperactivity
Blocks DA hyperactivity

What is the role of atypical antipsychotics in bipolar disorder

1st line treatment for manic episodes

Faster onset of action compared to other mood stabilizers
(+) for psychotic features of mania
Long term use is still questioned

All antipsychotics are antimanic

Common adverse effects of atypical antipsychotics?

Metabolic issues
EPS

Lithium pregnancy class and risks

Category D
Avoid in 1st Trimester
Epstein anomaly (4-12% risk

Valproic Acid pregnancy class and risks

Category D
Avoid during pregnancy
Risk of neural tube defects
Fetal valproate syndrome
FOLATE SUPPLEMENTATION

Carbamazepine pregnancy class and risks

Category D
Avoid during pregnancy/1st trimester
Risk of neural tube defects
FOLATE SUPPLEMENTATION

How are Typical antipsychotics used as adjunctive agents for bipolar disorder

Largely replaced by the atypical antipsychotics
Risk of TD increased in patients w/mood disorders
Effective for agitation if no AAP on board

How are Benzodiazepines used as agents for bipolar disorder

May be as needed throughout course of disease
Substance abuse considerations

How are Beta Blockers used as agents for bipolar disorder

Utilized for treatment of tremor associated with lithium or divalproex sodium

What are some discriminating symptoms between your neck doing a polar and bipolar depression

Racing thoughts, irritability, or both
Depression marked by hypersomnolence, anergia, and hyperphagia
Earlier age of onset (bipolar depression in mid 20s and a little younger in females
Sudden or paradoxical responses to traditional antidepressants
Overall less time spent well

First line agents for bipolar depression

Quetiapine
Lurasidone (Mono or combo w/Li + DVX)
Lithium
Lamotrigine

Our second line agents for bipolar depression

Divalproex
Adjunctive bupropion or SSRIs
Cariprazine
Olanzapine/Fluoxetine
ECT

Which atypical anti psychotics are approved for bipolar depression

Quetiapine (Seroquel®)
Lurasidone (Latuda®)
Cariprazine (Vraylar®)
Olanzapine/Fluoxetine [OFC] (Symbyax®)
Lumateperone

What is the starting dose for Lurasidone (Latuda) in bipolar depression

20 milligrams per day

What is a drawback when using quetiapine in bipolar depression

metabolic side effects

when is a dose of quetiapine given for bipolar depression

long acting night time dose

Quetiapine brand

Seroquel

Lurasidone brand

Latuda

Cariprazine brand

Vraylar

Olanzapine/Fluoxetine [OFC] brand

Symbyax

What are some advantages of Cariprazine (Vraylar®)

works for both mania and depression
not as sedating
low metabolic risk
long half-life

What are some advantages of Cariprazine (Vraylar®)

higher risk of akethesia

Olanzapine/Fluoxetine [OFC] indications and disadvantages

unipolar and bipolar depression
metabolic symptoms

What is the recommended dose for Lurasidone (Latuda) four bipolar depression

20 mg to 120 mg per day

What receptors does Lurasidone (Latuda) work at

5-HT2A≥D2>5-HT7/5-HT1A>α2
Very weak α1 & 5-HT2C affinity
No affinity for M1 & H1

Describe the pharmacokinetics of Lurasidone (Latuda)

decreased absorption
Highly protein bound
Metabolism via CYP 3A4
T½ : 18 hours
Two active metabolites

Cariprazine (Vraylar) starting dose for bipolar depression or mania

1.5 milligrams per day

Cariprazine (Vraylar) recommended dose for bipolar depression or mania

3 mg/day to 6 mg/day

What receptors does Cariprazine (Vraylar) work at

D3, D2, 5-HT1A partial agonist
D3>D2>5-HT1A≈α1>5-HT2A>H1

Cariprazine (Vraylar) pharmacokinetics

Highly protein bound
Metabolized by CYP 3A4
Two major active metabolites
---Desmethyl cariprazine (DCAR)
---Didesmethyl cariprazine (DDCAR)
Long t½ for parent drug: 2-4 days
1-3 weeks for DDCAR

How effective is lithium in treating bipolar depression

better than placebo
suicide protective

How does lamotrigine (Lamictal) work in bipolar disorder

1st line treatment for acute bipolar depression
Not FDA approved

Common adverse effects of lamotrigine?

well tolerated
watch out for rash
aseptic meningitis

What is the target dose of lamotrigine (Lamictal) in bipolar disorder

200 mg

Why do we need to titrate lamotrigine slowly

risk of Steven Johnson syndrome

What should we do to lamotrigine doses if pts are taking valproic acid

decrease dose

What should be do to lamotrigine dose if a patient is taking a EIAED

increase dose

What are some important points to remember when using antidepressants in bipolar depression

Induction of mania tends to be higher among antidepressants with noradrenergic activity
Maintenance treatment suggest a possible role in patients with BPAD II disorder and in patients with a robust acute response initially

What antidepressants that should be avoided in bipolar depression

TCAS

Pathophysiology of anxiety disorders

hyperactive amygdala and fear
Increased activity of the LC (locus coeruleus)--> increased release of NE --> causes autonomic symptoms like sweating, tachycardia, and dilated pupils

Comorbid conditions associated with anxiety

Substance Abuse
Tourette's Disorder (OCD)
Hypochondriasis
Major Depressive Disorder
Psychosis (OCD)
Personality Disorders

What other kinds of agents can cause anxiety?

CNS stimulants
Antidepressants (especially fluoxetine)
Anticholinergic toxicity
Cycloserine
Dapsone
Withdraw Effects from alcohol, anxiolytics (benzos and opioids)

What are CNS stimulants that can induce anxiety?

B2 agonists
Amphetamines
Cocaine
Methylphenidate
Caffeine
Ephedrine
Weight loss agents
Decongestants

What is the best way to avoid inducing anxiety with a lot of prescription agents, especially for antidepressants

Start low, go slow

Define phobia vs simple anxiety

Marked or persistent fear in excess cued by the presence or anticipation of a specific object or situation

Characteristics differentiating phobias from anxiety

Exposure= immediate anxiety
Person recognizes fear is in excess
The situation is avoided or endured w/ distress
The avoidance or distress in the feared situation interferes with the person's life

Treatment for specific phobias

non-pharmacologic methods are best/ 1st line
Cognitive behavioral therapy (CBT)
Exposure therapy

Medication use for Phobias?

NOT indicated
Benzodiazepines can interfere with CBT and should not be used together

Social anxiety disorder (SAD)

Marked or persistent fear of one or more social or performance situations
-Fears they will act in a particular way causing humiliation or embarrassment
-Exposure to the fears social situation provokes anxiety
-The person recognizes the fear is excessive
the avoidance or distress in the feared situation interferes with the person's life

What scale is used to evaluate someone's social anxiety (diagnosis and treatment response) and how is it interpreted?

Liebowitz Social Anxiety Scale (LSAS) (clinician rated)
24 item scale; each item is ranked 0-3 with 0 being never and 3 being severe/usually

Scoring
Moderate: 55-60
Marked: 65-80
Severe: 80-95
Very Severe: >95

Response: score=50
Remission: score

Treatment for SAD

NonPharm: CBT; Social skills training; Exposure therapy
Pharm 1st line: SSRIs, Venlafaxine XR
Pharm 2nd line: SSRI or venlafaxine (2nd trial of one not used in 1st trial)
Pharm 3rd line: Mirtazapine, MAOIs

What is the next step if a patient with SAD does not respond to SSRI or SNRI for the first 12 weeks of treatment?

switch to another SSRI or SNRI--> if still inadequate switch to mirtazapine or phenelzine

What is appropriate, but not frequently used for partial response to treatment of SAD

Consider augmenting with buspirone or clonazepam

If the first chosen SSRI or SNRI used to treat SAD is working after the first 12 weeks, what is next?

Continue therapy for 12 months

What are FDA approved Txs for SAD

Paroxetine, Paroxetine CR
Sertraline
Venlafaxine XR
ALL SSRIs are effective

How are beta blockers used for performance anxiety

They decrease percetion anxiety; not an actual treatment
They blunt autonomic overflow from increased release of NE
Decreases symptoms of increased HR, blushing, tremors, and BP changes

What BB are used in for performance anxiety

Propranolol 10-80 mg PO 1 hr prior to event
Atenolol 25-100 mg PO 1 hr prior to event

What are absolute contraindications to using BB for Performance anxiety

Cardiogenic shock
Sinus bradycardia; > than 1st degree heart block
Cardiac Failure
Bronchial asthma
Known hypersensitivity

What are relative contraindications to BB for Performance anxiety

Underlying resp illness
Diabetes/hyoperglycemia
Depression
Peripheral Vascular disease
Cardiac insufficiency
Reyauds's Disease

Common side effects of BB

-fatigue
-bradycardia, hypotension
-depression
-dizziness
-vivid dreams
-impotence
-insomnia

Dosing for Fluvoxamine CR for SAD Tx

Initial: 100 mg/day
Titration: 50 mg/week
Dose range: 150-300 mg/day
MDD: 300 mg/day

Metabolized by 1A2

Dosing for Paroxetine for SAD Tx

Initial: 20 mg/day
Titration: 10 mg/week
Dose range: 10-60 mg/day
MDD: 60 mg/day

Metabolized by 2D6

Dosing for Paroxetine CR for SAD Tx

Initial: 25 mg/day
Titration: 12.5 mg/day
Dose range: 25-75 mg/day
MDD: 75 mg/day

Metabolized by 2D6

Dosing for Venlafaxine XR for SAD Tx

Initial: 37.5 mg/day
Titration: 37.5-75 mg/week
Dose range: 75-225 mg/day
MDD: 225 mg/day

Metabolized by 2D6

Dosing for Sertraline for SAD Tx

Initial: 25-50 mg/day
Titration: 50 mg/week
Dose range: 50-200 mg/day
MDD: 200 mg/day

Metabolized by 2D6, 2C9

Key points for SAD

-Distinguish between SAD, performance anxiety, stage fright and shyness; BB can be used PRN for performance anxiety
-1st line Txs are SSRIs/Venlafaxine XR
-Rule out concurrent substance abuse prior to recommending tx

Generalized Anxiety Disorder (GAD)

Excessive anxiety and worry, occurring more days than not for at least 6 months, about a number of events or activities ( 2 or more)
The person finds it difficult to control worries
Causes significant impairment or distress