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Depressive & Bipolar Disorders

Psychopharmacology 101

For Non-prescribing

Mental Health Professionals -

A Training Resource

By Jim Messina, Ph.D., CCMHC, NCC, DCMHS-T

Depressive Disorders

Resource for Mental Health Professionals:


Hypotheses Concerning Depressive Disorders

Biogenic Amine Hypothesis

Catecholamine Hypothesis of Depression 1965

 

Cortisol Hypothesis

Cortisol & Depression Linked

Cortisol & Stress Response

 

Down-Regulation Hypothesis

Auto-receptors down-regulate suggests depression lifting

 

Neurotrophic Hypothesis (This Holds Promise)

Monoamine Hypothesis + Brain Derived Neurotrophic Growth Factor (BDNF) (nourishment of Nerves)

 

Neurogenic Theory of Depression

New: Neurogenic Theory of Depression

Result of two new discoveries:

1. Existing neurons able to repair/remodel

2. Neurogenesis

  • Involves 2nd messengers
  • Protect neurons from damage
  • Promote health/stability of newly formed neurons
  • Brain Derived Neurotrophic Growth Factor (BDNF)

 

Neurochemistry of Depression

Diagnosing Depression

Medical Rule Outs

  • B12; Folate
  • Urinary Tract Infection (UTI)
  • Hypothyroid
  • Testosterone

Drug Interactions

Chronic Pain vs.Depression

Delirium/Mild Cognitive Disorder

Conflict

Childhood Depression (hard to find it without trauma related)

 

Brain Abnormalities Associated with Depression

Pre-frontal Cortex

Hippocampus memory

Amygdala – Decreased Volume – attaches emotional valence to things

Basal Ganglia

Cingulate System – Cognitive flexibility, smaller in individuals who experience unipolar depression; as a result, perseverating on negative thoughts

 

Psychological Symptoms Often Mask Medical Disorders

General Rules to Remember

Thirty percent of the time bizarre psychological behavior will be the result of the medication Example: Cipro® & Singulair®

If patient is age 50, has no history of psychological problems, rule out organic cause.

If female patient is less than age 40, exhibiting manic behavior with no other history of psychological problems, screen for MS


Causes of Biological Depression

Bad Diet – low diet with protein

Leaky Gut – Symptoms include bloating, gas, cramps, food sensitivities, aches & pains. Medical mystery.

Sleep Disorders

Decreased Vitamin D

Decreased Vitamin B12 = Guilt

Hypothyroidism Doctors Need to do a Full Thyroid Panel to Rule Out Hypothyroidism including:  TSH; Free T4; Free T3

Reverse T3

Thyroid Antibodies

Additional Causes of Biological Depression

Addison’s Disease

Alzheimer’s

Anemia

Asthma

Brain Tumor

Cancer

Cardiovascular

Chronic Fatigue

Chronic Infections

Chronic Pain

Colitis

Huntington’s

Hyperthyroidism

Hypothyroidism

Influenza

Lupus

Congestive Heart Failures

Cushing’s Disease

Diabetes

Fibromyalgia

Hepatitis

HIV/AIDS

Malnutrition

Menopause

Mononucleosis

Myocardial Infarct

Pancreatitis

Porphyria

Postpartum

Pre-menstrual

Rheumatoid Arthritis

Stroke

Syphilis

Tuberculosis

Uremia


Drugs that Cause Biological Depression

Narcotics

Anti-hypertensives

ETOH (alcohol)

Steroids

Sedatives

H2 Blockers

Anti-Psychotics

BZDs

Anti-neoplastics

Thiazides


Drugs that Cause Mania

INH

Indomethacin (NSAID)

Anticholinergics

Captopril (ACE Inhibitor)

BZDs

Baclofen


Biological Causes of Bipolar Disorders

Brain Tumors

CNS Trauma

Influenza

Metastatic Caner

Pellagra (Dermatitis, Dementia, Diarrhea, Death)

Carcinoid Syndrome

Delirium

Hyperthyroidism

Multiple Sclerosis

Postpartum

Encephalitis (herpes & other viruses)

Metabolic (electrolyte abnormalities)

Parkinson’s

Addison’s & Cushing’s


Anti-Depressants

Tricyclic Antidepressants

MAOIs

SSRIs

SNRIs

Atypical Antidepressants

TCA’s (Tricyclic Antidepressants)

  1. Trimipramine (Surmontil®)
  2. Amitryiptyline (Elavil®)
  3. Clomipramine (Anafranil®)
  4. Desipramine (Norpramine®)
  5. Doxepin (Sinequan ®) [Silenor®]
  6. Imipramine (Tofranil®)
  7. Nortriptyline (Pamelor®) (used with elderly)
  8. Protriptyline (Vivactil®)

Been around for awhile and not costly due to generics

Three Ring Chemical Structure

If released today, would be called “SNRIs”

Narrow Therapeutic Index – Lethal

Used for Side Effects

  • Enuresis (imipramine)
  • Sedation (amitriptyline)
  • Pain Management (amitriptyline)

TCA’s Mechanism of Action

1. SRI (Serotonin Reuptake Inhibitor)

2. NRI (Norepinephrine Reuptake Inhibitor)

3. (α1) Alpha-1 Antagonist (Sympathetic Nervous System)

4. (Μ1) Muscarinic-1 Antagonist (Parasympathetic Nervous System)

5. (H1) Histaminergic-1 Antagonist

6. Na+ Channel Blocker

7. 5-HT2A & 5-HT2C Antagonist

MAOIs Monoamine Oxidase Inhibitors

  1. Phenelzine (Nardil ®, gold standard)
  2. Tranylcypromine (Parnate ®)
  3. Isocarboxazid (not available generic)
Effects

Blocks breakdown of Monoamines

Co-Valent Binding

More effective than TCAs for Atypical Depression


MAOI's works on Tyramine - Sympathomimetic

Tyramine – amino acids that helps regulate blood pressure

MAO breaks down excess tyramine

MAOIs block this enzyme’s degredation

Too much tyramine = EMERGENCY! such as headache, vomiting, tachycardia, nausea, sweating, dilated pupils, brain hemorrhage (rare)

Examples of foods high in Tyramine

Aged cheeses

Tap (draft beer) & unpasteurized beer

Wines

Cured meats, such as sausage, pepperoni, and salami

Soy Sauce

Yeast-extract spreads, such as Marmite

Sauerkraut

 

Emsam (Selegiline®)

MAO-A vs. MAO-B

Patch Approved for Major Depressive Disorder (MDD)

 

NEW MAOIs Monoamine Oxidase Inhibitors

Transdermal selegiline (Emsam®)

6 mg, 9 mg, 12 mg patches

No dietary restrictions at 6 mg patch

5 mg oral dose available

IMPORTANT: Can turn up in tox screens as AMPHETAMINES

 

MAOIs Common Averse Drug Reactions (ADRs)

Myoclonus

Asexual

Anti-cholinergic: Dry Mouth; Urinary Retention; Constipation; Tachycardia; & Sedation

Orthostatic Hypotension

Intracranial Hemorrhage


SSRI’s

  1. Fluoxetine (Prozac®)
  2. Citalopram (Celexa®)
  3. Es-citalopram (Lexapro®)
  4. Fluvoxamine (Luvox®)
  5. Paroxetine (Paxil®)
  6. Sertraline (Zoloft®)
  7. Vilazodone (Viibryd®)
  8. Vortioxetine (Brintellix®/Trintellix®)

1. Fluoxetine (Prozac®)

FDA approved for: Major depressive disorder (ages 8+ & higher), OCD (ages 7 & higher,  Premenstrual dysphoric disorder; Bulimia nervosa; Panic disorder; Bipolar depression, combo with olanzapine (Symbyax) and Treatment resistent depression, combo with olanzapine (Symbyax®)

10 mg – 80 mg dosing

Weekly doss available (Serafem®)

Metabolites, 7 day half life

No withdrawal syndrome


2. Citalopram (Celexa®)

FDA approved for Depression

Dose 10mg – 40 mg

IMPORTANT: 8/24/2011, “Should no longer be used at doses greater that 40 mg per day because it can cause abnormal changes in the electrical activity of the heart"

Most selective ; Not over 20 mg for those 60 years and older; Fewer side effects when used with elderly; Some antihistamine properties (sedating)

36 hour half life


3. Escitalopram (Lexapro®)

FDA approved for Major depressive disorder (ages 12 and older) & Generalized Anxiety Disorder

Doses 10 mg – 20 mg (lower doses more effective)

Best tolerated

27-32 hour half life


4. Fluovoxamine (Luvox®)

FDA approved for OCD & Social anxiety disorder

Dose, 100 mg – 300 mg

2 to 4 weeks to generate effect

17 hour half life


5. Paroxetine (Paxil®)

FDA approved for: Major Depressive Disorder; Obsessive-Compulsive Disorder; Panic Disorder; Social Anxiety Disorder; Post Traumatic Stress Disorder; Generalized Anxiety disorder and Premenstrual Dysphoric Disorder

Dosing 20 mg to 50 mg

Dosing 25 mg to 75 mg CR

Calming, sedating early in treatment

Problem with excessive weight gain

Withdrawal Difficult

21 hour half life

Paroxetine (Brisdelle®)

Treat hot flashes (vasomotor symptoms) associated with menopause

Dose lower than Paxil®

 

6. Sertraline (Zoloft®)

FDA approved for: Major Depressive Disorder; Premenstrual Dysphoric Disorder; Panic Disorder; Post Traumatic Stress Disorder; Social Anxiety Disorder and Obsessive-Compulsive Disorder

Dosing 50 mg to 200 mg

Mild antipsychotic effects


7. Vilazodone (Viibryd®) - SPARI

FDA approved for:  Major depression

Mechanism of Action: SPARI: Serotonin partial agonist reuptake inhibitor; Why “double ‘i’” spelling? (i) SRI + (ii) 5HT1A partial agonist: increases Dopamine and decreases Glutamate

Antidepressant + anti-anxiety in one pill

Claim: Fewer sexual side effects & weight gain but does bring on Diarrea!

8. Vortioxetine (Trintellix®)

NOT A SSRI But FDA approved for: Major depression

Mechanism of Action: SSRI with claim of: “Having New Action”

5, 10, 15, 20 mg tablets

Causes more nausea than SSRIs

Why Name Change?

Trintellix® less confusing than Brintellix® and Brintellix® easily confused with Brilinta® (ticagrelor), an anti-platelet medication. .

Mechanism of Action: NOT AN SSRI

5-HT1A agonist

5-HT1B partial agonist

5-HT1D antagonist

5-HT3 antagonist

5-HT7 antagonist

SSRIs Common Adverse Drug Reactions

Insomnia

Sexual

Restlessness/Rx Interactions

Gastro-Intestinal

Suicide


SSRI Withdrawal Problems

RARE

Prozac®

UNUSUAL

Zoloft®

Celexa®

Lexapro®

EXPECTED

Paxil®

Luvox®

 

5-HT Discontinuation Syndrome

Dizziness; Anxiety; Muscle Aches/Myoclonus; Nervousness; Insomnia & Tachycardia

Also: Fever; Hypertension & Nausea

Mental Status: Confusion; Agitation; Hypomania; Anxiety; Mental Restlessness &Headache

GI System: Nausea; Diarrhea; Vomiting

Cardio-Vascular: Sinus Tachycardia & Hyper/Hypotension

Motor Abnormalities: Tremor; Rigidity; Restlessness; Ataxia & Nystagmus

Other: Diaphoresis & Hyperpyrexia

Top 4: Decreased Appetite; Nausea & Vomiting; Diarrhea and Sweating NOTE: Can take up to 8 weeks to completely resolve

Clues: Uncontrolled Crying; Anti-depressant Discontinuation Syndrome or Sudden Cold?

Ask: Did you stop your antidepressants?

 

Symptoms of 5-HT Syndrome

Acute Crisis – Over Stimulation 5-HT2a & 1a

1. Agitation

2. Hyper-reflexia

3. Diaphoresis (excessive sweating)

4. Tremor

5. Mental Status Changes

6. Shivering

7. Myoclonus (involuntary muscle contractions)

8. Diarrhea

9. Poor Coordination

10.Fever

 

Amotivational or Apathy Syndrome with SSRI's

“I don’t feel anything”

Increased 5-HT Decreased DA

Reduce dose or switch

 

SSRI Concerns

1. Amotivational Syndrome

2. SIADH – Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH is brought about by an excess of water rather than a deficit of sodium)

3. Fractures

4. Serotonin Induced Angina (5-HT2B)

5. Jaw Pain/Biting Cheek

6. Contraindicated for Restless Leg Syndrome (RLS) & Periodic Limb Movement (PLM)

SNRIs

 

Venlafaxine (Effexor®)

Nicknames: “Side-Effexor” & “No-Effexor”

FDA approved for: Depression; Generalized Anxiety Disorder; Social Phobia & Panic Disorder

Dose: 150 – 300 mg

Half-life up to 13 hours

Initiation and withdrawal problems - Blood Pressure & Heart Issues

 

Desvenlafaxine (Pristiq®)

FDA Approved for: Major depressive Disorder

Metabolite of venlafaxine

Dose 50 mg – 100 mg, up to 400 mg

Fewer side effects

Withdrawal Issues

 

Duloxetine (Cymbalta®)

FDA Approved for: Major depressive disorder; Diabetic peripheral neuropathic pain (DPNP); Fibromyalgia; Generalized anxiety disorder, acute and maintenance & Chronic musculoskeletal pain

Generic in 2013 & FYI: This drug was originally, a bladder stabilizer

Dose 40 mg – 60 mg, up to 120

Half-life, 12 hours

For pain relief:

1 out of every 5-8 patients get 30% pain reduction

1 out of 8 to 12 patients stop due to side effects

Increase serum transaminase. Do not use with hepatic impairment

Important: increase in ALT (alanine transaminase); blood test “suggests” they may have been imbibing alcohol

 

Levomilnacipran (Fetzima®)

More active isomer of the SNRI, milnacipran (Savella®)

Note: milnacipran approved only for fibromyalgia

Fetzima® approved for depression

Stronger inhibitor of Norepinephrine than other SNRIs

NO PROOF Fetzima® is more effective than other SNRIs

 

SNRIs “Dual Action”

“Two and one/half Action”

Venlafaxine (Effexor®) & Duloxetine (Cymbalta®)

Two and one/half action:

SRI – Increases 5-HT throughout Brain

NRI – Increases NE throughout Brain

Increases DA in prefrontal Cortex

How?

Few DA transporters in prefrontal cortex

DA uses NE reuptake transporters

If NE reuptake transporters blocked. . .

DA can wander off. . .diffusion radius is wider

DA diffuses until it runs into degrading enzyme (COMT) and finds a transport back home

 

Other Antidepressants

Atypical Antidepressants

“The Outliers”

 

Mirtazapine (Remeron®)

NaSSA Noradrenergic antagonist and Specific Serotonin Antagonist (NASSA)

FDA Approved for: Major depression

Dose 15 mg to 45 mg

Nickname: “Big Benadryl®”

Sedation & Weight gain

 

Bupropion (Wellbutrin®)

(NDRI or CRI) Norepinephrine and Dopamine Reuptake Inhibitor

FDA Approved for: Major depressive disorder; Seasonal affective disorder & Nicotine cessation

Dose: 150 mg – 450 mg

Activating, stimulating

Less sexual side effects

 

Trazodone (Desyrel®, Oleptro®) (SARI)

Serotonin Antagonist Reuptake Inhibitor - 2A antagonist

FDA Approval: Major Depression (used more for insomnia, sedation side effect)

Oleptro® – trazodone extended release, spread dose over 24 hours may increase therapeutic dose for depression

No sexual dysfunction or weight gain

 

Other Medical Treatments for Depression

Transcranial Magnetic Stimulation

Deep Brain Stimulation: Invasive & Plants electrodes in ventral striatum but is its MOA is Unknown

Electroconvulsive Therapy: Medication-resistant depressed patients; 50% Relapse Rate& Performed > 100,000 yearly in US

 

Non-Medical Treatments for Depression

Psychotherapy: CBT

Vitamin D

Over-the-Counter Drugs (e.g., St. John’s Wort)

Yoga

Exercise

Journal Writing

Healthy Lifestyle Choices

Light Therapy: Suprachiasmatic nucleus, releases Glutamate, has been shown to work as well as SSRIs

 

EMERGING ISSUE: Tardive Dysphoria (TDp)

Antidepressant-Induced Chronic Depression “The New Normal” = Tardive Dysphoria (TDp)

Do antidepressants worsen the long-term course of depression?

Question first surfaced in 1960s and 1970s – 1994 Italian psychiatrist, Giovanni Fava, editor of Psychotherapy & Psychosomatics: Hypothesized that psychiatric drugs disturb neurotransmitter pathways and the brain attempts to restore “homeostatic equilibrium” compensates to maintain normal function

 

Proposed Criteria Tardive Dysphoria (TDp)

Prolonged (at least 1 year) exposure to a therapeutic dose of 5-HT depressants

Chronic or continuous dysphoric state while receiving a therapeutic dose

After discontinuation of medication and resolution of withdrawal symptoms (4-6 weeks) the individual returns to the baseline depressive state experienced prior to discontinuation

Delayed (several months) and gradual improvement in depressive symptoms (*not

necessarily full remission) after discontinuation

The individual experiences at least 7 depressive symptoms

  • Depressed or dysphoric mood
  • Reduced motivation
  • Reduced interest
  • Reduced energy
  • Reduced pleasure
  • Sleep disturbance
  • Mood or affect lability
  • Irritability
  • No or minimal disturbance in appetite
  • No or minimal disturbance in self care

Bipolar Disorders

Medications Used with Bipolar Disorders
There are two types of medications used with patients with Bipolar Disorders:
Mood Stabilizers
Neuromodulators

Not FDA Approved for Bipolar

Alprazolam, amoxapine, aripiprazole, asenapine, bupropion, carbamazepine, chlorpromazine, clonazepam (adjunct), cyamemazine, doxepin, fluoxetine, flupenthixol,

fluphenazine, gabapentin, haloperidol, iloperidone, lamotrigine, levetiracetam, lithium, lorazepam, loxapine (adjunct), lurasidone, molindone, olanzapine, olanzapinefluoxetine

combo, oxcarbazepine, paliperidone, perphenazine, pipothiazine, quetiapine, risperidone, sertindole, thiothixene, topiramate (adjunct), trifluoperazine, valproate (divalproex), ziprasidone, zonisamide, zotepine, zuclopenthixol

 

Bipolar Medications

FDA Approved

Bipolar Depression

  • Olanzapine-fluoxetine combo
  • Quetiapine
  • Latuda

Bipolar maintenance

  • Aripiprazole
  • Lamotrigine
  • Lithium
  • Olanzapine
  • Quetiapine
  • Risperidone (injectable)
  • Ziprasidone

 

Mood Stabilizers MOA

Voltage Sensitive Sodium Channels

  • Valproate
  • Carbamazepine
  • Oxcarbazepine
  • Lamotrigine
  • Topiramate

Voltage Sensitive Calcium Channels

  • Gabapentin
  • Topiramate

Increases GABA (calms you down)

  • Valproate
  • Clonazepam
  • Topiramate

Decreases Glutamate (incites impulsive behavior but breaks down into GABA)

  • Lamitrogine
  • Topiramate

 

Lithium Carbonate

FDA approved for: Acute manic episodes & Maintenance

Not effective for mixed mania, substance induced mania, or rapid cycling

Mechanism of Action: Unknown

Dose: 300 mg 2-3 times daily, adjust upward based on plasma level (0.6 ≤ x ≤ 1.2 mEq/L)  Narrow Therapeutic Index dose that works almost kills you first thing see is diarrhea

Suicide and self-harm preventative

Lithium Carbonate’s Rx History

Dr. John Frederick Cade (1912 – 1980) – Australian

Standard treatments for manic-depression at time was ECT and lobotomy

1948 - Lithium first effective medication-available to treat mental illness

Cade first gave Lithium to guinea pigs

Guinea pigs grew lethargic

“Intuitive Leap”

But it had side effects. . . . .

Lithium Side Effects “Battery”

Bradycardia

Ataxia & Acne

Tremor & hypoThyroid

Teratogenic

Edema

Rash & Renal Toxicity

LeukocYtosis (WBC above normal)

Lithium Toxicity

Diarrhea

Vomiting

Ataxia

Muscle Weakness & Fasciculations (small, local, muscle contraction & relaxation which may be visible under the skin)

Coarse Tremor (involves large groups of muscle fibers contracting slowly)

 

Valproic Acid (Depakote ®)

• FDA approved for: Acute mania, mixed episodes, seizures, & migraines

• Mechanism of Action:

– Inhibit voltage sensitive Na+ channels

– Boosts GABA

• Monitor Plasma Levels

• Side effects: Hair loss, ↑ weight, sedation

 

Carbamazepine (Tegretol®)

FDA approved for: Partial seizures with complex symptomatology; Generalized tonic-clonic seizures (grand mal); Mixed seizure patterns; Pain associated with true trigeminal neuralgia (Cranial Nerve V) & Acute mania/mixed mania (Equetro®)

Black Box:  5 “A’s”: Affect (flat); Anhedonia no pleasure; inAttention: Alogia & Avolition

CYP 450 auto-inducer - Enzyme in liver functionalization breaks down drugs

Reduces efficacy of hormonal birth control

 

Lamotrigine (Lamictal®)

FDA approved for: Maintenance for Bipolar Disorder & Many off-label uses

MOA: Inhibits voltage gated sodium channels, may reduce glutamate

Warning: Stephens-Johnson Syndrome (SJS) Rash like a burn-smells bad-pain

NOTE: Children on this med more susceptible to SJS.

 

Topiramate (Topamax®)

FDA approved for: Anticonvulsant; Migraines & Off label: Numerous

Side effects: Weight loss & Cognitive dulling

FYI: Qsymia® – phentermine (Atapex for weight loss) & Topamax®

 

Gabapentin (Neurontin®)

FDA approved for: Seizures; Neuralgia & Off-label for anxiety and bipolar disorder

Mechanism of Action: Leucine analogue (muscle growth) (abused to get a body buzz); No action at GABA; Inhibits voltage sensitive calcium channels

 

Neuromodulators FYI (known as mood stabilizers)

Valproate - Sedative

Gabapentin – Anxiolytic reduces anxiety

Carbamazepine - Anti-irritability & Anti-impulsive

Lamotrigine - Well Being