Bipolar & Depressive Disorders

Our “mood”

Our mood is our ‘emotional tone’, such as being happy or sad.

From your textbook, “mood is a pervasive and sustained emotion that may have a profound influence on a person’s perception of the world.”

Think about people you know- some seem to be happy (or in a “good mood”) all the time, others seem to be sad, or negative (“bad mood”), most of the time.

Mood

an individual’s sustained emotional tone, which significantly influences behavior, personality and perception.

• cheerful, depressed, romantic, gloomy, anxious

• Elevated →Mania (manic)

• Lowered → Depression

Affect

the outward expression of mood (facial)

• the emotional reaction associated with an experience.

Risk Factors for mood

Gender- increased in females 2:1

Age

Social Class- not well defined

Marital Status- not well defined

Family History- more common among first-degree biological relatives

Seasonality- increased in fall and winter

• SAD

Life Events & Social Supports

Genetics- suggested but not yet known

Biochemical- neurotransmitters

Genetics + Biochemical = most credible theory at this time

Biochemical Aspects

Neurotransmitters- decreased or increased can affect mood; imbalance between ACh and monoamines

Monoamines (Biogenic Amines)-

• Serotonin- linked to depression

• Norepinephrine- linked to mania

• Dopamine- low= depression; high= mania

Amino Acids- GABA~ Glutamate

Electrical Threshold

Starts with the attachment of the neurotransmitter to the dendrite.

Takes many neurons being activated at the same time to set up enough electrical activity to pass the electricity down the axon.

Electrical impulses are all or nothing.

Threshold has to be reached or electricity won’t pass and neurotransmitters are NOT released

Neurotransmitter Regulation

Enzymes

Reuptake

Change in receptor response

Modify the “sending” neuron

Depression~ definition

An alteration in mood expressed by feelings of sadness, despair, and pessimism. There is a loss of interest in usual activities and somatic symptoms may be evident. Changes in appetite, sleep patterns, and cognition are common.

Depression~ Symptoms

• Previous manic episodes

• mood: dysphoric, depressive, despairing

• ↓ interest in pleasure

• negative views

• fatigue

• ↓ appetite

• constipation

• insomnia

• ↓ libido

• suicidal preoccupation

• may be agitated or some movement retardation

Grief

A subjective state of emotional, physical and social responses to the loss of a valued entity. Normal grief is adaptive; lasts about 4-6 weeks.

Can last weeks to years

denial → anger → bargaining → depression → acceptance

Maladaptive Grief

Abnormal grief – can’t progress through stages:

Delayed grief- fixed in denial stage

Prolonged grief

• intense preoccupation with loss for many years

• can develop into pathological depression

Distorted (Exaggerated) grief- fixed in anger stage

Levels of Depression

Transient depression:

• Typical human emotion- sadness

Mild depression:

• Sx. are similar to regular grieving

Moderate depression:

• Persistent Depressive Disorder (Dysthymia)

Severe depression:

• Major Depressive Disorder

Mild Depression

Still able to function

Denial of feelings

Preoccupied with loss

Self blame and blaming of others

Anorexic or overeating

Insomnia or hypersomnia

Aches and pains

Dysthymia~ symptoms

Sx. for at least 2 years

Difficulty experiencing pleasure

Difficulty with concentration & memory

Slumped posture

Slowed physical movements

Limited verbalizations

Increased focus on the self

Increased use of substances

Low Energy Level

Difficulty with concentration

Anorexia to Overeating

Insomnia to Hypersomnia

Decreased libido

May exhibit self destructive behavior

Dysthymia~ DSM5 criteria

Depressed mood for most of the day, for most days, for at least 2 years (children and adolescents 1 year).

Presence, while depressed, of 2 or more:

1. Poor appetite or overeating.

2. Insomnia or hypersomnia

3. Low energy or fatigue

4. Low self-esteem

5. Poor concentration or difficulty making decisions

6. Feelings of hopelessness.

During the 2-year period the individual has never been without S/Sx of criteria A. or B. for more than 2 months at a time.

Criteria for Major Depressive disorder may be continuously present for 2 years.

Never been a manic or hypomanic episode and not cyclothymic

The disturbance is not better explained by other psychotic disorder.

Not due to drugs or medical condition

S/Sx cause clinically significant distress or impairment in functioning

Dysthymia~ specifiers

“With melancholic features”

“With anxious distress”

“With mixed features”

“With atypical features”

“Late onset” (after age 21)

Major Depressive Disorder~ DSM-5 criteria

a 2 week period of time with 5 or more of the following, and must include #1 or #2:

1. Depressed mood, most of the day, nearly every day.

2. Markedly diminished pleasure in activities, most of the day, nearly every day.

3. Significant weight loss (not dieting) or weight gain or change in appetite nearly every day.

4. Insomnia, or hypersomnia, nearly every day.

5. Psychomotor agitation, or retardation, nearly every day.

6. Fatigue or loss of energy nearly every day.

7. Feelings of worthlessness, or excessive or inappropriate guilt nearly every day.

8. Diminished ability to think or concentrate nearly every day; indecisiveness.

9. Recurrent thoughts of death, suicidal ideation (no plan), suicide attempt or plan.

Symptoms cause clinically significant distress or impairment in functioning.

The episode not related to a substance or medical condition.

The episode is not better explained by psychotic disorders.

Never had a manic or hypomanic episode.

Major Depressive Disorder~ What pt. “looks like”

Feeling of total despair

Flat unchanging affect

Slumped posture

Lays in fetal position

Non-existent communication

Poor ADL’s

Socially isolated

May have delusions of persecution or somatic delusions

Confused, indecisive, inability to concentrate

At risk for death from dehydration or malnutrition

Thoughts of suicide

Major Depressive Disorder~ Specifiers

“With anxious distress”

“With mixed features”

“With catatonia”

“With atypical Features”

“With mood-congruent psychotic features”

“With mood-incongruent psychotic features”

Depressed Client: Nursing Issues

Risk for Suicide

Low Self Esteem

Dysfunctional Grieving

Powerlessness

Imbalanced Nutrition

Social Isolation

Sleep Disturbance

Depressed Client: Nursing Assessment

Mental Status- focused or confused?

Suicide Risk

• thought content- plan? Giving away personal belongings?

Physical Status - hydration and nutrition

• Inactivity and Dehydration lead to? constipation

Increase or decrease in symptoms?

Effects of medications?

Sleep patterns?

Activity Level?

ADLs?

Depressed Client: Nursing Interventions

Medicate as ordered

Contact pt. at regular intervals

Provide opportunities for them to express their feelings

1:1 for expressed suicidal ideation

Provide for safety - shakedown room

Assist with their ADL’s

Provide positive feedback

Encourage/ Engage in diversional activities

Offer foods and fluids

• ** State in “matter of fact” way- “Time to drink some water”; “Let’s go outside for fresh air”

Encourage focusing on their strengths

Maximize opportunities to make choices

Restore hope

Construct a written/verbal behavioral contract

Depressed Client: Evaluation Criteria

Has not expressed any desire to harm self

Discusses feelings with others

Able to stay out of bed and participate in activities willingly

Hygiene and grooming are adequate

Eats well balanced meals routinely

Sleeps 6-8 hours per night

Is able to concentrate, reason, solve problems

Presents with a more cheerful affect

Tolerates medication well, takes meds willingly, no harmful side effects.

Is not afraid to try new activities

Sets realistic goals

Mania~ definition

An alteration in mood that may be expressed by feelings of elation, inflated self-esteem, grandiosity, hyperactivity, agitation, racing thoughts, and accelerated speech.

(person’s mood is elevated and person has lots of energy)

Can be due to psych. disorder, bipolar disorder, medical condition, response to substances.

Manic Episode

when a person’s mood is elevated with more-than-normal Energy for a period of time (days).

Manic Episode~ DSM-5 criteria

Abnormally and persistently elevated, expansive, or irritable mood, and goal directed activity or energy, lasting at least 1 week and present most of the day, nearly every day (or if hospitalized).

During A. , 3 (or more) of the following (4 if mood is irritable) are present to a significant degree, and represent a noticeable change from usual Bx:

1. Grandiose inflated self esteem

2. Decreased need for sleep

3. Talkative or pressure to keep talking

4. Flight of ideas or racing thoughts.

5. Distractibility

6. Increase in activity, goal directed or not; psychomotor agitation

7. Excessive involvement in activities that have a high potential for painful consequences.

The mood disturbance IS sufficiently severe to cause marked impairment in social or occupational functioning, or needing hospitalization to prevent harm, or there are psychotic features.

The episode is not due to a substance (drug abuse or meds), or another medical condition

Manic Episode~ Specifiers

Mild, Moderate, Severe

Mixed Features

With Anxious Distress

Rapid Cycling

With Psychotic Features

Seasonal Pattern

In partial or full remission

Hypomania~ Stages of Mania

mild mania and excitement, with a moderate change in behavior

Acute Mania~ Stages of Mania

a mental disorder characterized by excessive excitement, elation, delusions of grandeur, distractibility, impulsivity, irritability, restlessness, speech, and/or poor judgement

Delirious Mania~ Stages of Mania

most severe; characterized by the rapid onset of delirium and mania; life threatening

Hypomania~ symptoms

Same S/Sx. as manic; somewhat mild.

Cheerful expansive mood

Volatile and fluctuating; labile

Self perception is that of great ability- grandiose

Intrusive, talks a lot

Increase in activity and libido- “spending sprees”

Decrease in appetite

Does not cause severe impairment in functioning

Does not require hospitalization

Hypomania~ DSM-5 criteria

A distinct period of abnormally & persistently elevated, expansive, or irritable mood, and abnormally and persistently increased goal directed activity or energy, lasting at least 4 consecutive days and present most of the day, nearly every day (or any duration if hospitalization is necessary).

During A. , 3 (or more) of the following (4 if mood is irritable) are present to a significant degree, and represent a noticeable change from usual Bx:

1. Inflated self-esteem or grandiosity

2. Decreased need for sleep

3. More talkative than usual, or pressure to keep talking

4. Flight of ideas or subjective experience that thoughts are racing.

5. Distractibility, as reported or observed.

6. Increase in goal directed activity or psychomotor agitation.

7. Excessive involvement in activities that have potential for painful consequences (spending, sex, business investments).

The episode is associated with an unequivocal change in functioning that is uncharacteristic of the individual when not symptomatic.

The disturbance in mood and change in functioning are observable by others.

The episode is not severe enough to cause marked impairment in social or occupational functioning; no hospitalization (if psychotic features present the episode is manic)

The episode is not attributable to a substance (drug abuse or meds).

Acute Mania~ symptoms

Marked impairment in functioning

Mood is euphoric, elated; irritable

Inability to sleep

Rapid thinking; flight of ideas

Accelerated, pressured speech

May be psychotic

Excessive psychomotor activity

Poor impulse control, increased libido

Most people require hospitalization

Delirious Mania~ symptoms

Grave form of mania

Severe clouding of consciousness

Mood is extremely labile- despair quickly changes to unrestrained merriment

Confused, disoriented, stupor

Hallucinations and incoherent speech

Psychomotor activity is frenzied

Pt. safety at risk

Also at risk for exhaustion and death

Rare because we have medications to help

Nursing Issues R/T Mania

Risk for Injury

Risk for Violence

Nutrition Imbalance

Disturbed Thought Process

Impaired Social Interactions

Disturbed Sleep Pattern

Nursing Assessment - Mania

Mental status

Physical status

Nutritional and fluid status

Safety to self and others

Activities of Daily Living

Social Interactions

Sleep Patterns

Activity level

Nursing Interventions - Mania

Provide for safety to self and others

Medicate as ordered

Monitor Lithium levels, BUN, Creatinine

Provide a quiet environment. Keep outside stimuli to a minimum

Maintain adequate nutrition, hydration

Monitor Weight

Assist with ADL’s

Assist the client to achieve adequate rest.

Monitor social interactions with peers.

Set limits on behavior.

Offer diversional activities - sports, walks.

Provide an opportunity to remove themselves from the milieu.

Protect from ridicule.

Evaluation Criteria - Manic Client

No evidence of physical injury

Has not harmed self or others

No signs of physical agitation

Activity level is appropriate

Eats well balanced meals

Weight is stable

Is able to fall asleep within 30 minutes

Interacts appropriately with others

Does not manipulate others

Tolerates the medication well and takes it willingly

Verbalizes hallucinations have subsided

Verbalizes an accurate interpretation of the environment.

Bipolar

disorder characterized by mood swings from profound depression to extreme euphoria (mania), with intervening periods of normalcy (cycle). Delusions or hallucinations may or may not be part of the clinical picture, and onset of symptoms may reflect a seasonal pattern.

Bipolar I

Has had at least one full manic episode

May have also experienced episodes of depression

Rapid Cyclers usually Bipolar I

Patient is mostly manic

Bipolar II

Recurrent bouts of major depression with at least 1 episode of hypomania.

Never has full blown manic episode.

Patient is mostly depressed.

Cyclothymia~ symptoms

Mild form of Bipolar Disorder.

Cycles from Simple Depression to Hypomania.

Chronic mood disturbance of at least 2 years’ duration.

Never without S/Sx for more than 2 months.

Never had Major Depressive, Manic, or Hypomanic episode.

Cyclothymia~ DSM-5 criteria

For at least 2 years there have been numerous periods with hypomanic sx that do not meet criteria for hypomanic episode and numerous periods with depressive sx that do not meet the criteria for a major depressive episode.

The above episodes were present for 50% of the time and pt. not without S/Sx. for more than a 2- month period.

Criteria for major depressive, manic, or hypomanic episode never met.

Criterion A. not better explained by schizoaffective d/o, schizophrenia, schizophreniform d/o, delusional d/o, or other schiz. or psych. Disorder.

S/Sx. not due to drug abuse or meds.

The Sx. cause clinically significant distress or impairment in social, occupational, or other important areas or functioning.

Mixed Episode

Characterized by mood swings from profound depression to extreme euphoria (exaggerated feeling of well-being or elation).

Criteria are met for both a manic and a major depressive episode.

Mood disturbance is severe enough to cause marked impairment of functioning.

Treatment of Mood Disorders

Individual Therapy

Group Therapy

Cognitive Therapy

• change thinking errors

ECT- Electroconvulsive Therapy

Induction of a grand mal (generalized) seizure by application of electrical current to the brain.

Most effective for treatment resistant depression

Light~ Treatment of Mood Disorders

helps with Seasonal and treatment resistant depression- reduces melatonin and increases serotonin.

Medications~ Treatment of Mood Disorders

Antidepressants

• critical to watch for suicidal thoughts/activity in first 2 months of starting medication.

Mood stabilizers (“anti-manics”)

Anxiolytics

Antipsychotics

Most antidepressants and mood stabilizers take days or weeks to reach therapeutic level.

Classifications of Antidepressants

MAOI – Monoamine Oxidase Inhibitor

TCA – Tri-cyclic Antidepressants

SSRI – Selective Serotonin Reuptake Inhibitor

Others – SNRI, NDRI

Serotonin Syndrome~ cause

The goal of most antidepressants is to increase serotonin.

Serotonin Syndrome results from excessive Serotonin in the body

Potentially Fatal

Serotonin Syndrome- S/Sx

Starts with Nausea and Vomiting

Progresses to Restlessness & Irritability

Muscle Twitching, Incoordination

Agitation, Confusion, Psychosis

Seizures, Status Epilepticus

Autonomic Instability

Cardiovascular Collapse and Death

Discontinuation Syndrome

Stopping a medication suddenly and serotonin is out of balance:

• Starts 2 – 4 Days after last dose.

• Risk is higher if SSRI is taken for more than one month.

• Symptoms improve if med. restarted .

• Tapering off preferred.

• Symptoms will self-limit within 14 days.

• Depressed mood, crying spells

• Anxiety, Agitation, Irritability

• Sleep Disturbance – Insomnia

• Nausea, Vomiting, Flu Like Sx

• Dizziness, Lightheadedness

Anti-Manics” / Mood Stabilizers

Lithium (Li+)

Valproic Acid – VPA

• Double gloves when administering

Carbamazepine

Lamotrigine

Anti psychotics

Nursing Considerations - Lithium

Therapeutic Blood Level

Narrow Therapeutic Window

Toxicity

Water/Salt Balance

Thyroid and Kidney Function

Side Effect Management

Lithium - Side Effects

• Dry Mouth

• Fine hand tremor

• Slight decrease in muscle coordination

• Weight Gain

• Drowsiness

Some of these side effects tend to disappear over time.

• Vomiting

• Diarrhea

• Slurred Speech

• Drowsiness

• Muscle weakness

• Muscle twitching

• Decreased coordination

• Confusion

• Blurred Vision

• Tinnitus

• Weight loss (N/V)

Mood Disorders by the numbers…

The 12-month prevalence of Major Depressive Disorder in the United States is 7%

It is roughly twice as common in women than to men

~5-20% of those diagnosed with Major Depressive Disorder will have psychotic features

~30% of those with Major Depressive Disorder will be treatment resistant

Major Depressive Disorder (must have 5 for at least a 2-week period):

Depressed Mood*

Anhedonia: Loss of interest in pleasurable activities*

Weight loss

Objective psychomotor agitation or retardation

Insomnia or hypersomnia

Fatigue/loss of energy

Feelings of worthlessness / inappropriate guilt

Inability to concentrate

Suicidality

• Not attributable to an underlying medical condition or substance

• Must cause clinically significant distress or impairment in functioning

The Mood Disorders: Bipolar Illness

Mania = elevated, expansive or irritable mood

Hallmark Symptoms of Disease (must have 3 or 4):

• Grandiosity / inflated self-esteem

• Decreased need for sleep

• Intensified speech

• Racing thoughts

• Distractibility

• Psychomotor agitation

• Risk-taking behaviors, pleasure seeking

Psychiatric Symptomatic Overlap

Anhedonia

Sleep disruption

Fatigue

Poor self-esteem

Suicidality

Poor concentration

Weight loss

Agitation

Irritatability

Suicide in the United States

Firearms are the most commonly used method (54.6%), followed by suffocation (25.8%), poisoning (11.6%), other (8%)

Suicide rate increased 37% between 2000-2018 and decreased 5% between 2018-2020. However, rates nearly returned to their peak in 2021

Individual Risk Factors~ Suicide Risk Factors

These personal factors contribute to risk:

Previous suicide attempt

History of depression and other mental illnesses

Serious illness such as chronic pain

Criminal/legal problems

Job/financial problems or loss

Impulsive or aggressive tendencies

Substance use

Current or prior history of adverse childhood experiences

Sense of hopelessness

Violence victimization and/or perpetration

Relationship Risk Factors~ Suicide Risk Factors

These harmful or hurtful experiences within relationships contribute to risk:

Bullying

Family/loved one's history of suicide

Loss of relationships

High conflict or violent relationships

Social isolation

Community Risk Factors~ Suicide Risk Factors

These challenging issues within a person's community contribute to risk:

Lack of access to healthcare

Suicide cluster in the community

Stress of acculturation

Community violence

Historical trauma

Discrimination

Societal Risk Factors~ Suicide Risk Factors

These cultural and environmental factors within the larger society contribute to risk:

Stigma associated with help-seeking and mental illness

Easy access to lethal means of suicide among people at risk

Unsafe media portrayals of suicide

Suicide and ASH

Since 2006, >70 attempts, with at least 5 patients completing suicide

>70% of those have been 2684s and MDOs

Most common method used was hanging/asphyxiation

• Bed sheets/clothing/phone cords in conjunction

with furniture or doors

Others: chemical cleaner ingestion, medication hording with intent of overdose

Neuronal Communication

Neurons talk to each other via Neurotransmitter exchange at the synapse

How can we modify this Process to treat illnesses?

Block NT Breakdown

Block Receptors

Block NT Reuptake

Modify sending neuron

Serotonin~ Neurotransmitters & Mood Disorders

Too Low = Depression, Too High = Anxiety

Regulates: mood, sleep, libido, perception of pain, appetite, etc, etc

Norepinephrine~ Neurotransmitters & Mood Disorders

Too Low = Depression, Too High = Mania

Regulates: mood, cognition, perception, locomotion, sleep cycles, etc, etc

Dopamine~ Neurotransmitters & Mood Disorders

Too Low = Depression, Too High = Psychosis, Mania

Regulates: emotions, judgment, movement

GABA~ Neurotransmitters & Mood Disorders

Inhibitory NT capable of slowing down bodily activities

Drugs which increase GABA’s activity may work to reduce Mania, Anxiety and Seizures

Glutamate

Excitatory NT capable of speeding up bodily activities

Overstimulation of glutamatergic neurons is implicated in Anxiety/Panic, Seizures, Mania and Psychosis

Pharmacologic Treatment of Mood Disorders

Antidepressants (ADs)

• Selective Serotonin Reuptake Inhibitors (SSRI’s)

• Selective Serotonin & Norepinephrine Reuptake Inhibitors (SNRI’s)

• Distinct Mechanism of Action AD’s (i.e. bupropion, etc)

• Older AD’s (i.e. TCA’s, MAOI’s)

Mood Stabilizers (MSs)

• Lithium

• Antiepileptic Medications (i.e. Depakote, etc)

Anxiolytics

• Benzodiazepines (i.e. Lorazepam, Clonazepam, etc)

Antipsychotics

Tricyclic Antidepressants (TCA’s)~ max

amitriptyline (Elavil)~ 300mg

Nortriptyline (Pamelor)~ 150mg

doxepin (Sinequan)~ 300mg

clomipramine (Anafranil)~ 250mg

desipramine (Norpramin)~ 300mg

Developed as sedatives in the late 1940s, found effective as antidepressants in the 1950s

Antidepressant effects are due to blockade of serotonin and norepinepherine reuptake

Tricyclic Antidepressants (TCA) Summary

The Good:

Effective, target multiple, neurotransmitters

Useful for co-morbidities

• Neuropathic pain syndromes

• Migraine prophylaxis

The Bad:

Adverse effects

• Sedation, weight gain

• Orthostasis

• Urinary retention, constipation

Many drug interactions

The Ugly:

Cardiotoxic in overdose

TCA Case Study at ASH Background

Patient MW, a 49 y/o BM admitted to ASH pursuant to PC 1370 on 11/15/2011

Admissions meds included:

• amitriptyline 50mg daily (migraine prophylaxis)

• fluoxetine 20mg daily (antidepressant)

• perphenazine 8mg twice

• daily (antipsychotic)

Upon admission, amitriptyline was increased from 50mg to 100mg secondary to increased complaint of migraine frequency

Over next several months, patient begins to experience persistent dizziness, hypotension and several syncopal episodes

In Feburary, after a severe syncopal episode that resulted in fall with injury, the patient was sent to the UCR

Attending psychiatrist orders lab work, ECG and requests pharmacists to review medication history

• ECG = QRS interval, widening, tachycardia

Therapeutic levels for amitriptyline:

• Total: 80-220ng/mL

• Toxic: ≥500ng/mL

Patient’s amitriptyline levels:

• amitriptyline 364ng/mL

• nortriptyline 492ng/mL

• COMBINED: 856ng/mL!

Problem: both perphenazine and fluoxetine are inhibitors of amitriptyline metabolism!

Medication changes:

• amitriptyline was discontinued in favor of topiramate for migraine

• fluoxetine was changed to sertraline  (less potential for drug interactions than fluoxetine)

ECG = QRS interval widening, tachycardia normalized over subsequent couple of weeks

Patient suffered no lasting cardiac damage

MW was discharged back to county to stand trial

Moral of the story

• In polypharmacy, seemingly small changes can have dramatic effects on medication levels if there are medications that have potential drug-drug interactions

It was decided that TCA would be made non- formulary at ASH

Monoamine Oxidase Inhibitors (MAOi)~ MOA

Developed in 1950s from antibiotics used to treat tuberculosis

Increase 5HT,NE and DA by blocking the enzyme which breaks down these neurotransmitters

Older Medications:

• phenelzine (Nardil)

• tranylcypromine (Parnate)

• isocarboxazid (Marplan)

Transdermal Patch: Selegeline (Emsam)

• Non-Formulary at ASH

Monoamine Oxidase Inhibitors (MAOI)~ drug and food interactions

Hypertensive Crisis can occur due to drug interactions AND food interactions

Patients on MAOI’s must avoid foods rich in tyramine:

Aged Meats, Aged Cheeses, Yogurt, Liver, Sauerkraut, Caviar, herring, Corned Beef, Wines, Beer, Bananas, Raisins. Avocados, Fava Beans, Chinese pea pods, Caffeinated beverages

Monoamine Oxidase Inhibitors Summary

The Good…

• May be effective in refractory depression

The Bad…

• Dietary Restrictions and Drug Interactions

• Poorly tolerated with Complicated Dosing

The Ugly…

• Risk of lethal overdose and hypertensive crisis

Selective Serotonin Reuptake Inhibitors (SSRI)~ MOA

Work by selectively blocking the reuptake of serotonin

Prototype to market in US was fluoxetine (Prozac)

• Developed from the antihistamine diphenhydramine in the 1970s, came to market in the late 1980s

• 1st psychotropic medication to result from rational drug design; breakthrough in safety and tolerability from TCA

Many other SSRIs soon followed

• fluvoxamine (Luvox)

• paroxetine (Paxil)

• sertraline (Zoloft)

Immediately became widely prescribed

• Aggressive advertising

• Entered popular culture

SSRI’s indications

SSRIs could still be used off label for major depressive disorder, general anxiety disorder, post traumatic stress disorder, and obsessive compulsive disorder

SSRI’s summary

The Good…

• Safer than the older medications (TCA’s and MAOI’s)

• Once Daily (QD) dosing

• Better tolerated than older medications

The Bad…

• Insomnia, GI upset (nausea/vomiting, diarrhea), sexual side effects, Anorexia, Anxiety/”Jitteriness”

• Drug-drug Interactions (p450 enzyme interactions with some)

• Discontinuation syndrome

The Ugly…

• Serotonin Syndrome

• Black Box Warning! Increased suicidal ideation in children, adolescents, young adults

Serotonin (5-HT) Syndrome

Rare but Potentially fatal reaction (coma, CV shock, death) due to high levels of 5-HT which may result from combinations of serotonergic medications

Serotonin (5-HT) Syndrome~ Signs & Symptoms:

Dilated pupils

Irritability & Restlessness

Muscle twitching, tremor

Agitation & Confusion

Delirium

Tachycardia and HTN

Fever, Sweating, flushed skin

Seizures

Myoclonus

hyperreflexia

Serotonin (5-HT) Syndrome~ Serotonergic Med’s:

AD’s: SSRI’s, SNRI’s, MAOI’s, TCA’s, etc

Lithium

Buspirone (Buspar), Tramadol (Ultram), Meperidine (Demerol)

Triptans (i.e. Imitrex, etc)

Amphetamines

Herbals (St. John’s Wort)

5-HT Syndrome: Treatment

After DC of Serotonergic agents, Patients should remain under close observation.

Treatment may include:

• Benzodiazepines such as diazepam (Valium) or lorazepam (Ativan) to decrease agitation, seizure-like movements, and muscle stiffness

• Cyproheptadine (Periactin), a drug that blocks serotonin activity

• IV Fluids

• Cooling measures

In life-threatening cases, medicines that keep your muscles still (paralyze them) and a temporary breathing tube and breathing machine will be needed to prevent further muscle damage.

SSRI Discontinuation Syndrome

Common in patients who have taken an SSRI for a long time who abruptly stop, more common with shorter half-life medications

Symptoms generally begin within 2-4 days of DC and last up to 14 days:

- Most common: Fatigue, Dizziness, Headache, Nausea

• Others: Agitation, anxiety, chills, sweating, dysphoria, electric shock-like sensations, insomnia, irritability, muscle aches, paresthesias, rhinorrhea, tremor, vivid dreams

Which of the following medications would be unlikely to contribute to a case of serotonin syndrome?

likely: Lithium, Citalopram (Celexa), Sumatriptan (Imitrex), Venlafaxine (Effexor)

unlikely: Oxcarbazepine (Trileptal)

SNRI’s example

Venlafaxine (Effexor)

ASH Max Dosage

• 375mg for IR (tablets)

• 225mg for XR (capsules)

FDA Indications: MDD, GAD, Social Anxiety d/o, Panic d/o

Duloxetine (Cymbalta)

• ASH Max Dosage = 120mg

• FDA Indications: MDD, GAD, Diabetic Neuropathy, Fibromyalgia

SNRI’s~ summary

The Good…

• Dual Mechanism of Action

• May be helpful in patients with co-morbid pain

The Bad…

• Nausea, dry mouth, constipation

• Akathisia, insomnia, irritability

• Cardiac instability (hypertension, orthostasis)

• Possibly reater risk of switch to mania in bipolar patients

The Ugly…

• Serotonin Syndrome

• Black Box Warning! Increased suicidal ideation in children, adolescents, young adults

NDRI: Bupropion (Wellbutrin)

Unique mechanism

• Inhibits norepinephrine and dopamine reuptake

Also FDA approved for smoking cessation (Zyban)

ASH Max = 450mg

• IR, SR and XL

High abuse potential

• Must be crushed to avoid potential for diversion

• non-formulary at ASH

Bupropion (Wellbutrin)~ summary

The Good…

• Dual mechanism of action which may be complementary to SSRI’s

• Weight neutral (weight loss possible)

• Low rate of sexual side effects

• Good choice for co-morbid ADHD

The Bad…

• Dry mouth, anxiety, insomnia, agitation

• Tinnitus (ringing in ears), sweating

The Ugly…

• Lowers seizure threshold and can cause seizures

• Induction of mania/aggravation of psychosis

• Black Box Warning! Increased suicidal ideation in children, adolescents, young adults

Mirtazapine (Remeron)~ summary

The Good…

• Unique mechanism (alpha-2 antagonist) which leads to higher levels of NE and 5-HT

• Works well in depression with insomnia/anorexia

• Often used to treat akathisia and/or insomnia

• Low propensity for GI adverse events

The Bad…

• Weight gain, Sedation (antihistamine effects)

• Dry mouth, constipation

The Ugly…

• Postural Hypotension may occur (rare)

• Black Box Warning! Increased suicidal ideation in children, adolescents, young adults

Trazodone (Deseryl)~ summary

Serotonin antagonist and reuptake inhibitor

Most often used to treat insomnia at lower doses

Orthostasis

Priapism can occur~ unwanted erection

ASH Max = 600mg/day

Black Box Warning! Increased suicidal ideation in children, adolescents, young adults

New Class of Antidepressant~ vilazodone HCl (Viibyrid)

Unrelated to TCA and tetracyclic compounds

• Novel pharmacologic profile: has SSRI and partial agonist activity at 5-HT1A receptors

• Approved 1/21/2011 for MDD

Available in 10, 20 and 40mg tablets

• Titrate dose weekly to recommended dose (usually 40mg)

Same black box warning, side effect profile and drug interactions as other SSRI medications

Non-Formulary at ASH

Some antidepressants can be activating, two exceptions are:

• Bupropion (Welbutrin) and sertraline (Zoloft)

• Venlafaxine (Effexor) and citalopram (Celexa)

• Mirtazapine(Remeron) and Trazodone(Desyrel)

• Both A and B

• A, B and C

Treatment Resistant Depression

Pharmacologic Augmentation strategies

• Antidepressant combinations

• Lithium, lamotrigine

• Thyroid hormone

• Atypical Antipsychotics

• Stimulants (e.g. Ritalin, others)

  • Not available at ASH

Procedures

• Electroconvulsive Therapy (ECT)

• Vagus Nerve Stimulation (VNS)

• Transcranial Magnetic Stimulation (TMS)

Pharmacotherapy of Bipolar Disorder

Mood Stabilizers

• Lithium

• Antiepileptic Medications (i.e.Depakote, etc)

• Antipsychotics (i.e. Quetiapine, etc) *

Anxiolytics

• Benzodiazepines (i.e. Lorazepam, Clonazepam, etc) *

• Hydroxyzine (Vistaril) *

Antidepressants

• Risk of switching from depressed to manic episode

• In some patients may be used safely in combination with a mood stabilizer

Lithium History

Discovered in 1817

First use in gout and as sedative and anticonvulsant

• Too toxic

Patent medicines

Fountain drinks

Salt substitute

• Too toxic

Psychosis research

Lithium Overview

The Prototype – used to treat Mania for 50+ years

Mechanism of Action: Unknown

Effective in treating and preventing mania, less effective in treating bipolar depression

Reduces suicide in patients with Bipolar d/o

Acute Treatment Response Time: 3-5 days with improvement ongoing for several weeks

Narrow Therapeutic Window!

• Black Box Warning for risk of Lithium Toxicity