Mood Disorders: Depression and Bipolar Flashcards
Reactive sadness
Transient emotional reaction to a minor event
Grief
Normal response to a major interpresonal loss, can be prolonged
Clinical Depression
Persistent sadness that interferes with normal functioning
* loss of interest
* Low-self esteem
What are the signs and symptoms of depression?
- Persistent sad, anxious, or “empty” feelings
- Feelings of hopelessness or pessimism
- Feelings of guilt, worthlessness, or helplessness
- Irritability, restlessness
- Loss of interest in activities or hobbies once pleasurable
- Fatigue and decreased energy
- Difficulty concentrating, remembering details, and making decision
- Insomnia, early-morning wakefulness, or excessive sleeping
- Overeating, or appetite loss
- Thoughts of suicide, suicide attempts
- Aches or pains, headaches, cramps, or digestive problems that do not ease even with treatment
What are the risk factors for depression?
- Female (particularly in adolescence, post-partum, and in older age)
- Prior depressive episodes
- Medical comorbidity
- Substance use disorder
- Lack of social support
- Stress
What are the DSM-V criteria for depression?
- Must have 5 or more symptoms in same 2 week period
- Must include depressed mood and/or anhedonia
- Must represent change from previous functioning
- Cause social or occupational impairment
- Not be due to an organic disorder or other cause
What is a manic episode?
Consists of a persistent elevated or irritable mood that is extreme, which lasts for at least one week
* And at least three (four if only irritable mood) other features are also involved:
- Inflated self-esteem for sleep
- Decreased need for sleep
- More talkative than usual or compelled to keep talking
- Experiencing racing thoughts or ideas
- Easily distracted
- Increase in goal-oriented activity or excessive movements
- Excessive involvement in potentially risky pleasurable behavior
Monoamine hypothesis
Decreased synaptic concentrations of monoamines results in sustained depression
Dysregulation hypothesis
Dysregulation of neurotransmission release results in changes in pre- and post- synaptic receptors, which ultimately result in sustained depression
Neuroendocrine hypothesis
Dysregulation of thyroid and HPA axis result in sustained depression
What were the findings of depressed patients that support the monoamine deficiency hypothesis?
- Relapse of depression with tyrosine hydroxylase inhibitors or depletion of dietary tryptophan
- Increase mutation in the brain specific form of tryptophan hydroxylase (TPH-2)
- Increase MOA ligand binding
- Subsensitive 5-HT1A receptors
- Malfunction in 5-HT1B receptors
- Polymorphisms of the serotonin-reuptake transporter
- Inadequate response of G proteins to monoaminergic signals
- Decrease levels of cAMP, inositol and CREB in postmortem brains
What are the findings in depressed patients that support the endocrine hypothesis?
- Cortisol level are sometimes increased in severe depression; non-suppression of cortisol by dexamethasone (dexamethasone suppression test. DST), reversed by antidepressants
- Size of anterior pituitary, adrenal cortex is increased
- CRH levels in CSF and CRH expression in the limbic brain regions are increased
- Hippocampal size and numbers of neurons and glia decrease (due to decrease BDNF?)
What are the general mechanism of increasing neurotransmission including increasing the “synpatic residence time”?
- Blocking the reuptake of NE, 5-HT, and DA into nerve terminals (reuptake inhibitors)
- Blocking the metabolism of NE and 5-HT in nerve terminals (monoamine oxidase inhibitors)
What is the onset of therapeutic?
- Week 1 – sleep, appetite, energy, anxiety
- Weeks 1-3 – activity, drive, concentration, memory
- Weeks 4-6 – mood, hopelessness
What is an adequate trial of antidepressant?
Approximately 6-8 weeks
Name the class of antidepressants
- TCAs
- MAOIs
- SSRIs
- SNRI
- NDRI
- 5-HT and/or NE modulators
What are the disvantages of tricyclic antidepressants?
- Toxic in overdose
- Side effects
What are the side effects of tricyclic depressants?
- Orthostatic hypotension
- Tachycardia
- EEG changes
- Anticholinergic effects
- Seizure threshold lowered
- Weight gain
T/F: Tricyclic are not stimulants
T
What are the mechanism of action of tricylic depressants?
- Block reuptake of monoamines (both NE and 5-HT) to varying degrees
- Neurotransmitter levels in the synaptic cleft increase, but clinical effect are delayed around 2-3 weeks
- Also bind to histamine (H1 & H2), alpha 1 & 2, GABA-A, and muscurinic receptors, which accounts for many side effects
What are the pharmacokinetics of tricylic depressants?
- Well absorbed orally and have long half-lives. Highly protein-bound
- Cause sedation–dose at. bedtime
- Drug inactivation by hepatic metabolism
T/F: Tricyclic depressants used to be the first most common cause of overdose fatalities in developed countries
F; second
Why aren’t tricyclic depressant not first line?
Anticholinergic and cardiac side effects
What is the mechanism of MAOIs?
- Increase neurotransmission by increasing NE, 5-HT, and DA levels in nerve terminal
- Inhibition of MAOIs is irreversible
EmSam (selegiline transdermal)
- Approved for treatment of Major Depressive Disorder
- More selective for MAO-B; avoids inhibition of intestinal MAO-A enzyme
What are some safety issues that limit use of MAO inhibitors?
Hepatic and intestinal MAO serve to inactivate biogenic amines present in food (tyramine) as well as biogenic amines administered as drugs (sympathomimetic decongestants in OTC cold remedies)
* must avoid foods high in tyramine (not necessary with EmSam)
What are some side effects of MAOI?
- Orthostatic hypotension
- Insomnia
- Anticholinergic
- Serotonin Syndrome when combined with SSRIs or if overdose
Citalopram (Celexa)
- Most selective of the SSRIs
- Low inhibition of cytochrome P450s
- Combination with MAOIs can be fatal
- Escitalopram: active S-enantiomer of citalopram
What are the side effects of SSRIs?
- GI disturbances
- CNS excitation
- Anorexia and weight loss during early treatment; possible weight gain with long-term use
- Decreased libido and significant sexual dysfunction
What are the symptoms of SSRI Discontinuation Syndrome?
- Flu-like symptoms
- GI effects
- Dizziness
- Paresthesia
- Mood, appetite, and sleep changes
Bupropion (Wellbutrin)
- Norepinephrine/dopamine reuptake inhibitor (NDRI)
- Weak blocker of DA uptake, even weaker blocker of NE uptake and affinity no effect 5-HT uptake
- Used for ADHD (Aplenzin) and for smoking cessation
What are the side effects of Bupropion (Wellbutrin)?
- Generally well tolerated due to little or no muscurinic, alpha-adrenergic, and histamine receptor effects
- Nausea, restlessness, insomnia, anxiety
- Low incidence of sedation, hypotension, weight gain, sexual side effects
- High risk of seizure activity at doses of 450 mg/day
- May precipitate psychotic episodes
Venlafaxine (Effexor)
- SSRI at low doses but inhibits NE uptake at higher doses
- Little affinity for muscurinic, cholinergic, H1-histaminic, or alpha-adrenergic receptors
Duloxetine (Cymbalta)
- Used in patients with neuropathic pain
- Unproven claims that it works faster (1-2 weeks)
What are some Serotonin Antagonist and Reuptake Inhibitors (SARIs)?
- Trazodone (Oleptro)
- Nefazodone (Serzone)
Trazodone (Oleptro)
- Acts as 5-HT2 antagonist and 5-HT reuptake blocker
- Very sedating (not effective as an antidepressant)
Nefazodone (Serzone)
- Analogue of trazodone withe less sedating and postural hypotension)
- Acts much like trazodone
Mirtazapine (Remeron)
- Noradrenergic and specific serotoninergic antidepressant (NSSA)
What are the mechanism of action of Mirtazapine (Remeron)
Serotonin and norepinephrine modulator
* Blocks alpha 2 autoreceptors resulting in increased NA release
* Antagonize 5-HT2 receptors
* Enhances activity at 5-HT1 receptors
* Blocks H1 and muscarinic receptors
What are the side effects of Mirtazapine (Remeron)?
- Sedation due to blockade of histamine receptors
- Increased appetite
- Significant weight gain
What are the non-pharmacologic therapies of depression?
- Electroconvulsive Therapy (ECT)
- Light therapy
- Psychotherapy
- Transcranial Magnetic Stimulation (TMS)
- Vagus Nerve Stimulation (VNS)
- Deep Brain Stimulation (DBS)
- Exercise
What are some augmentation strategies of depression?
- Lithium
- Thyroid supplementation
- Stimulants
- Atypical antipsychotics
- Anticonvulsants
- Esketamine
Thyroid Supplementation
- T3 (liothyronine): 20-25 mcg/day
- May accelerate response or result in improvement of residual symptoms
- May work best in patients with sub-clinical hypothyroidism
Ketamine
- Dissociative anesthetic
- Non-competitive NMDA receptor antagonist
- Most commonly used anesthetic in the world
- Plays an essential role in surgeries in low-resource countries and in emergencies
Esketamine (Spravato)
- The S (+) enantiomer of ketamine
- Received Breakthrough Therapy Designation from FDA for treatment-resistant depression
- Also acts as a partial DA reuptake inhibitor
What are the only two atypicals with FDA approval as adjunctive treatment for MDD in combination with current antidepressant therapy?
Ariprazole (Abilify) and Quetiapine (Seroquel XR)
