Unit 3 Depression

What are the criteria to be diagnosed with depression?

1. Five or more of the following symptoms must be present during the same 2 week period and it must represent a change in functioning: either (1) depressed mood or (2) loss of interest or pleasure (anhedonia)

2. One of the five symptoms has to be depressed mood or loss of interest or pleasure

What are the symptoms of depression?

1. Depressed mood

2. Decreased interest or pleasure

3. Weight loss or weight gain

4. Insomnia or hypersomnia

5. Psychomotor agitation or retardation

6. Fatigue/loss of energy

7. Worthlessness or guilt

8. Decreased concentration

9. Suicidal ideation or attempt

How do the symptoms affect you?

• impairment in functioning

• not attributable to a substance or other medical condition (hypothyroidism)

• no manic (mood is elevated) or hypomanic episodes

What are the signs and symptoms of depression?

SIG E CAPS

1. Sleep (insomnia or hypersomnia)

2. Interest (decrease in interest in things that one used to enjoy)

3. Guilt (guilt in things that you have no control over)

4. Energy (decreased)

5. Concentration/constipation (ability to concentrate is decreased; constipation)

6. Appetite (decreased or increased)

7. Psychomotor agitation or depression (agitated or slowed down)

8. Suicide/Sex (increased thinking about suicide/decreased interest in sex)

What are physical symptoms associated with depression?

1. Sleep problems

2. Fatigue/exhaustion

3. Chest pain

4. Aching muscles and joints

5. Digestive problems

6. Headaches

7. Back pain

8. Changes in weight/appetite

9. Sexual dysfunction

Appetite is decreased and insomnia - what type of depression? 

typical depression

Hypersomnia (sleeping too much) and eating too much - What type of depression?

atypical depression

What can depression result from?

1. Life stressors can often lead to depression

2. Medical conditions

3. Being postpartum

4. Medications side effects

5. Chronic mental disorders

6. Intoxication/withdrawal from drugs/alcohol

7. Premenstrual hormone changes

8. Lack of bright light

9. Care-giving

What medical conditions are associated with depression?

1. Hypothyroidism

2. Diabetes (84%)

3. Chronic pain (15-100%)

4. Heart disease (40-65%)

5. Cancer (one in four)

6. Multiple sclerosis (40%)

7. Parkinson's disease (40%)

8. Coronary artery disease - no heart attack (18-20%)

9. Stroke (10-27%)

What medications are associated with depression?

• anticonvulsants (benzodiazepines)

• antihypertensives (beta blockers)

• hormones (contraceptives and steroids)

• others (alcohol, isotretinoin, varenicline)

What are the risk factors associated with depression?

1. Unemployment

2. Low income

3. Comorbid disorders

4. Physical disability

5. Widowed, separated, divorced

6. Middle aged (45-65 years)

7. Inheriting depression

8. Life stressors

9. Females

10. Native Americans

What are the risk factors for suicide?

What are the warning signs for suicide?

1. Threatening to hurt or kill himself or herself

2. Looking for ways to kill himself/herself, seeking access to pills, weapons, or other means

3. Talking/writing about death, dying, or suicide

4. Expressing hopelessness

5. Feeling rage or anger, seeking revenge

6. Acting recklessly or engaging in risky activities, seemingly without thinking

7. Feeling trapped

8. Increase alcohol or drug use

9. Experiencing anxiety or agitation

10. Undergoing dramatic changes in mood

11. Feeling no reason for living; no sense of purpose in life 

What are the treatment phases of depression? 

1. Acute phase 6-12 weeks

2. Continuation phase 4-9 months

3. Maintenance phase >/= 1 year

What is response?

1. Decline in depression symptoms by at least 50%

What is remission?

1. Resolution of current symptoms

What is relapse? 

1. Return of symptoms prior to 12 months

What is recovery?

• You can say someone is recovered when they have resolution of symptoms at >/= 1 year

What is recurrence?

Return of symptoms after 12 months

What is the median time between the onset of symptoms and recovery (no symptoms) with adequate treatment (antidepressant)?

• 20 weeks

How long can untreated episodes of depression last without treatment?

• 6 months or longer

Are all antidepressants equally effective? What is the efficacy of antidepressants?

• yes; choose an antidepressant for an individual based on the ADRs

How long does it take for antidepressants work?

• 4-6 weeks sometimes 8 weeks

How many patients don’t achieve remission with their first antidepressant?

• two-thirds

What is treatment resistance?

A depressive episode that has failed to respond to two separate trials of different antidepressants of adequate dose and duration

What percentage of patients do not experience sufficient antidepressant response?

46%

How to determine an initial choice of antidepressant during the acute phase (first 6-12 weeks)?

1. Patient preference

2. Prior treatment response

3. Safety

4. Tolerability and adverse effects

5. Comorbid disorder

6. Potential drug-drug interactions

7. Pharmacokinetic parameters

8. Cost

• Treatment moves from the acute phase to continuation phase with clinically significant improvement in symptoms, preferably complete remission of symptoms

What is the continuation phase during months 4-9?

• Antidepressant treatment should continue at the same dosage as required int the acute phase for an additional 4-9 months

• Risk of relapse ranges from 20-85% without continuation of treatment

• Should depressive symptoms recur, potential causes of relapse should be addressed (poor treatment adherence, substance use, and psychosocial stressors)

What is the maintenance phase (treatment after 1 year, indefinite length)?

1. Maintenance antidepressant treatment is recommended for patients with chronic depressive symptoms or with a history of 3 or more depressive episodes

2. Duration of therapy is indefinite and may be lifelong

3. Other factors to consider for maintenance treatment

   1. Presence of residual depressive symptoms

   2. Psychosocial stressors

   3. Family history

   4. Severity of depressive episodes

   5. Early age at onset

   6. Elderly

When a patient has 3 or more depressive episodes, what length of therapy?

continue on indefinite therapy and may be lifelong (maintenance treatment)

What is goal of treatment? 

remission or the absence of depressive symptoms 

What are the drugs class of antidepressants?

• selective serotonin reuptake inhibitors (SSRIs)

• serotonin norepinephrine reuptake inhibitors (SNRIs)

• tricyclic antidepressants (TCAs)

• monoamine oxidase inhibitors (MAOIs)

• norepinephrine and dopamine reuptake inhibitor (NDRI)

• serotonin and alpha 2-adrenergic antagonist (NaSSAs)

• serotonin antagonists and reuptake inhibitors (SARIs)

• serotonin modulators

• 5HT1A agonists

• neuroactive steroids

• NMDA receptor antagonists

Which class of antidepressants causes hypertriglyceridemia?

• NaSSAs (serotonin and alpha 2-adrenergic antagonist)

Which antidepressant class is the most dangerous when it comes to overdose?

• TCA overdose

  • toxicity 2 to 6 hours

  • CNS depression

  • hypotension

  • seizures

  • anticholinergic toxicity

  • orthostatic hypotension

  • QT prolongation

How do you monitor for the efficacy of antidepressants?

• Patient's response to treatment 

  • functional status/quality of life

  • degree of danger to self or others

  • Signs of "switch" to mania

  • Other mental disorders

  • General medical conditions

  • Side effects of treatment

  • Adherence to treatment plan

• rating scale (PHQ9)

• monitoring should be conducted weekly or biweekly for the first 8 weeks 

  • adherence

  • tolerability/side effects

  • depressive symptoms

What are the guidelines for depression?

1. Mild to moderate depression: doesn't always need therapy

   1. St. John's Wort (first line) treats depression or psychotherapy

2. Moderate to severe depression

   1. Use an antidepressant with or without psychotherapy

3. Severe depression

   1. Drug plus psychotherapy

   2. ECT (about 80% effective)

What are first line medications for depression?

• SSRI's are considered first line, but most guidelines recommend if someone can't take an SSRI or if they fail two SSRIs they can use an SNRI, an NDRI, or an NaSSA first line

  1. The reason these are considered first line is because of overall low side effects and safety

What ADRs do all antidepressants have?

• Suicide thinking

• Mania

• Discontinuation syndrome (feel flu-like)

What are additional adverse effects to know?

1. Hypertension: SNRIs and NDRIs can potentially cause elevated BP due to their noradrenergic activity

2. Discontinuation syndrome: SSRIs and SNRIs and potentially shorter acting antidepressants cause discontinuation syndrome which makes individuals feel like they have the flu. They may also feel dizzy, off-balance, and some complain of feeling electrical "zaps" in their brain

3. Serotonergic drugs (SSRIs, SNRIs, and serotonin modulators) have the potential to cause bleeding.

4. The above along with TCAs can cause low sodium levels (hyponatremia), which can lead to seizures

What are drug-food interactions?

• Aged cheeses

• Cured meats

• Pickled or fermented food

• Yeast extract

• Alcoholic beverages

MOA for Selective Serotonin Reuptake Inhibitors (SSRIs)

MOA: Selectively inhibit presynaptic serotonin transporters, increasing synaptic levels of serotonin

side effects of SSRIs

anxiety/nervousness*, insomnia*, nausea*, headache*, serotonin syndrome, sexual dysfunction

Labeled and off-label indication for SSRIs?

depression, generalized anxiety disorder (GAD), social phobia, obsessive compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), hot flashes, premature ejaculation

MOA for serotonin norepinephrine reuptake inhibitors (SNRIs)

Selectively inhibit presynaptic serotonin and norepinephrine transporters, increasing synaptic levels of serotonin and norepinephrine

side effects of SNRIs?

anxiety/nervousness*, insomnia*, nausea*, headache*, hypertension, serotonin syndrome, sexual dysfunction

Labeled and off-label indication for SNRIs?

depression, generalized anxiety disorder (GAD), social phobia, panic disorder, diabetic neuropathy, fibromyalgia, hot flashes, urinary incontinence

MOA for Tricyclic Antidepressants (TCAs)

Inhibit presynaptic serotonin and norepinephrine transporters, increasing synaptic levels of serotonin and norepinephrine

• not first line because of so many side effects

• used for insomnia because side effect is sedation  

labeled and off label indications for TCAs?

depression, anxiety, social phobia, panic disorder, diabetic neuropathy, fibromyalgia, obsessive compulsive disorder (OCD), insomnia

ADRs for TCAs?

sedation*, seizures, anticholinergic effects*, orthostatic hypotension, weight gain, sexual dysfunction

Off target antagonism for TCAs?

Off-target Antagonism	Effect
Histamine ex: Benadryl	sedation, weight gain (appetite regulation)
Muscarinic parasympathetic NS	blurred vision (can’t see), xerostomia (can’t spit), urinary retention (can’t pee*), constipation (can’t poop)
α1-adrenergic constriction of blood vessels  when activated	orthostatic hypotension, dizziness
Na+ and K+ channels# TCAs like class I and II antiarrhythmic drugs	arrythmias, death

• off label use for urinary incontinence

MOA for monoamine oxidase inhibitors (MAOIs)?

Irreversibly# (binds irreversibly which gets rid of the enzyme entirely) inhibit monoamine oxidase MAO enzymes responsible for breaking down monoamines, increasing neuronal levels of serotonin, norepinephrine, and dopamine

• After NE or 5-HT is taken back into the presynapse, it can either be degraded by MAO or repackaged into vesicles. By blocking degradation with an MAO inhibitor, more is repackaged and released into the synapse upon an action potential. 

labeled and off-label indications for MAOIs)?

depression, Parkinson disease

*rasagiline only indicated for PD

ADRs for MAOIs?

orthostatic hypotension*, anticholinergic effects*, hypertensive crisis, serotonin syndrome, sexual dysfunction, weight gain, sleep disturbances (sedation/insomnia)*

MAO-A vs MAO-B?

• Two subtypes, A and B,

  A breaks down 5HT, NE, DA and Tyramine

  B breaks down DA and Tyramine

  A is found in the gut while B is not

MOA for Norepinephrine Dopamine Reuptake Inhibitor (NDRI)?

• Inhibits presynaptic norepinephrine and dopamine reuptake, increasing synaptic levels of norepinephrine and dopamine

• example: bupropion (Wellbutrin)

Labeled and off-label indications for NDRI?

depression, seasonal affective disorder (SAD), tobacco cessation, ADHD

ADRs for NDRI?

weight loss*, seizure activity, insomnia*

• do not give drug in patient with seizures

When switching to an MAOI how long would you need to wait?

• 5 half-lives

• fluoxetine has a half-life of 1-4 days so might take 2 weeks before starting the MAO

How long would you have to wait to switch from an MAOI?

• wait 14 days to synthesize more MAO

• enzymes are inhibited irreversibly so we have to make more enzymes to return to normal function

• too much serotonin can cause hypertensive crisis or serotonin syndrome

MOA for noradrenergic and specific serotonergic antidepressant (NaSSA)?

Inhibits presynaptic α₂ autoreceptors as well as postsynaptic 5HT₂ and 5HT₃, increasing release of norepinephrine and serotonin into the synapse

labeled and off-label indications for NaSSA)?

depression, chronic tension headache prophylaxis, panic disorder

ADRs for NaSSA?

weight gain*, sedation*, hypertriglyceridemia

• don’t see a lot of sexual dysfunction and nausea because of the blockage of 5HT2 and 5HT3

• sedation can be beneficial in patients with insomnia (histamine related)

• weight gain is histamine related

MOA for serotonin antagonist and reuptake inhibitors (SARIs)?

Inhibits reuptake of serotonin presynaptically and acts as an antagonist at postsynaptic 5HT₂ receptors

• Trazodone often used for insomnia

• orthostatic hypotension is due to anti-alpha 1

labeled and off-label indication for SARIs?

depression, insomnia, alcohol dependence, generalized anxiety disorder (GAD), panic disorder

ADRs for SARIs?

sedation*, liver toxicity, orthostatic hypotension*, priapism, serotonin syndrome

MOA for serotonin modulators?

Selectively inhibits presynaptic reuptake of serotonin and acts as a partial agonist/antagonist at presynaptic 5HT_1A autoreceptors

labeled indication of serotonin modulators?

depression

ADRs for serotonin modulators? 

anxiety/nervousness*, insomnia*, nausea*, headache*, serotonin syndrome

• lots of nausea because the 5HT  binds postsynaptic 5-HT3

• more risk of serotonin syndrome 

MOA for NMDAR antagonist?

Inhibits extrasynaptic NMDA receptors, leading to preferential glutamate signaling at the synapse and enhanced action of brain-derived neurotrophic factor (BDNF)

• ketamine (controlled substance with high abuse potential; administered under clinical supervision

• improvement is immediate

labeled indication for NMDAR antagonist?

depression*, major depressive disorder with suicidality*, agitation, analgesia, general anesthesia, procedural sedation, rapid sequence intubation (RSI), status epilepticus

*esketamine only indicated for treatment resistant depression and MDD with suicidality

ADRs for NMDAR antagonist? 

sedation*, nausea/vomiting*, dissociation*, hypertension, cognitive and motor impairment

MOA for neuroactive steroids?

positive allosteric modulation (PAM) of GABA_A receptors; reduces activity in hypothalamic-pituitary-adrenal (HPA) axis

• brexanolone

labeled indication for neuroactive steroids?

postpartum depression

ADRs for neuroactive steroids?

• sedation*, hypoxia, abuse/dependence

• allosteric - means it binds somewhere other than the natural ligand

Briefly describe how inhibition of auto receptors and inhibition of reuptake transporters produce similar outcomes….

Inhibition of an auto receptor increase NT _______ from the pre synapse while inhibition of a reuptake transporter decreases _____ of NT from the synapse.

• inhibition of an auto receptor increases NT release from the presynapse 

• inhibition of a reuptake transporter decreases the reabsorption of that neurotransmitter from the synapse

What are the NT associated with depression?

• serotonin (5-HT)

• norepinephrine (NE)

• Dopamine (DA)

• Glutamate

• GABA (gamma-aminobutyric acid)

What does serotonin do?

• low levels of serotonin are associated with depression

• plays a role in regulating mood, sleep, and appetite

What does norepinephrine do?

• deficits in NE are also linked to depression

• involved in attention, focus, and arousal

What does dopamine do?

• reduced dopamine levels may contribute to depression 

• associated with pleasure, motivation, and reward

Glutamate and depression?

excessive glutamate activity can lead to neuronal damage and inflammation, which may contribute to depression

GABA and depression?

• low levels of GABA can increase anxiety and depression

Identify presynaptic mechanisms in which a drug alters neurotransmission at the synapse

Presynaptic mechanisms

• drugs block presynaptic reuptake transporters (more NT in synapse)

• drugs block auto receptors (disinhibition of NT release so more release)

• MAO enzyme inhibitor - so more NT

Agonists vs antagonists?

• Agonists: These drugs bind to and activate postsynaptic receptors, just like a neurotransmitter would. This can increase the signal or effect of the neurotransmitter.

• Antagonists: These drugs bind to postsynaptic receptors but do not activate them. Instead, they block the receptors, preventing the natural neurotransmitter from binding and reducing its effect. 

Identify postsynaptic mechanisms in which a drug alters neurotransmission at the synapse

Postsynaptic mechanisms: increase NT availability, block reuptake, increase receptor stimulation

• GPCR (5-HT2)

  • GPCR are cell receptors that respond to NT

  • drugs (mirtaxapine) act directly on GPCRs like serotonin (5-HT) receptors to modulate mood and behavior

  • SSRIs work indirectly by increasing NT levels which then activates GPCRs

  • MAOIs block the enzymes that break down monoamine NT, which also results in more NT available to activate GPCRs

• glutamate receptor (extra synaptic)

  • can reduce function of NMDA receptors

  • interfere with glutamate release (ketamine works directly by modulating glutamate receptors)

• serotonin (5-HT3)

  • drugs affect the amount available in the brain

  • drugs block the reuptake of serotonin into nerve cells leaving more in the synapse

Types of agonists?

• agonist: activates a receptor and causes a response

• antagonist: binds to a receptor and blocks the action of an agonist but has no effect on its own

• partial agonist: type of agonist that activates a receptor but produces a sub maximal response compared to a full agonist

  • partial agonist is also a partial antagonist

• inverse agonist: binds to a receptor and produces a response opposite to that of an agonist

• can only exist at a receptor that exhibits constitutive (basal) activity in the absence of natural ligand binding

• it would not be beneficial to use an inverse agonist if there’s no basal activity

typical vs atypical depression?

• typical: appetite is decreased and insomnia

• atypical: appetite is increased and hypersomnia