Depressive Disorders and Antidepressants Flashcards

1
Q

What are the risk factors for suicide?

A

Male sex, Age <19 or >45, Depression, Previous attempts, Ethanol use or other substances, Rational Thinking Loss, Single, Organised Plan, No social support, Sickness or other comorbidities.
(SADPERSONS)

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2
Q

Discuss the psychopharmacology of Mirtazapine and its uses

A

MOA - NaSSA - Noradrenergic and Specific Serotonergic Antidepressant.
- No monoamine reuptake inhibition
- antagonist at alpha2, H1, 5HT2A, 5HT2C, 5HT3

  • blocks alpha2 autoreceptors in noradrenergic neurons. Activation of these receptors in the pre-synaptic neuron causes inhibition of NE release and therefore blocking this receptor causes loss of inhibition which in turn causes an increase in NE release
  • blocks alpha2 heteroreceptors in serotonergic neurons. Serotonergic neurons are also inhibited by alpha2 receptors and therefore blocking them causes loss of inhibition and therefore more serotonin
  • blocks 5HT3 receptors in the chemoreceptor trigger zone (which is linked to vomiting) and this is why mirtazapine is useful in chemotherapy patients to treat nausea and vomiting
  • the blockade of 5HT2A and 5HT2C receptors has been linked to the antidepressant effects

H1 antagonist (therefore can cause sedation and weight gain)

Commonly used in elderly population

No significant drug drug interactions which makes it a popular choice for augmentation. Venlafaxine and Mirtazapine combination has been called “California Rocket Fuel”

DOSAGE: 15-45mg/day
Half-life of 20-40hrs
No active metabolites
Not a significant inhibitor of cytochrome P450 enzymes.
Metabolized in the liver by 3 different cytochrome P450 enzymes - CYP1A2, CYP2D6, CYP3A4.
No significant DDI

USES: depression, PD, GAD, SAD, add-on to SCZ for negative symptoms, emesis, insomnia

SIDE EFFECTS
Most side effects are related to the blockade of H1 receptors. Sedation, increased appetite and weight gain, dry mouth

BENEFITS OVER OTHER ADS:
- less sexual dysfunction, GI upset and insomnia

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3
Q

Discuss Trazodone MOA and use

A

MOA - weak inhibitor of serotonin reuptake. Blocks the post-synaptic 5HT2 receptors.
Also has potent H1 blocking activity and is therefore sedating.

Labeled use for MDD. Off-label use for alcohol dependence, anxiety, panic disorder, insomnia.

DOSAGE: Initial dose is 150mg/day in divided doses. Increase by 50mg/day every 3-4 days.
Maximum dose for inpatients 600mg/day in divided doses.
Outpatient 400mg/day in divided doses.

CONTRAINDICATION: Initial recovery phase following an MI. Hypersensitivity. ECT therapy.
Use with caution in cardiac disease and those with risk of suicide.

COMMON SIDE EFFECTS: dry mouth, dizziness, drowsiness, fatigue, anxiety, nausea, weight gain, increased appetite
SERIOUS SIDE EFFECTS: hypotension, orthostatic hypotension, arrythmias, priapism, leukopenia

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4
Q

What is the monoamine hypothesis?

A

Depression results from a deficiency in one of the three key monoamines (serotonin, norepinephrine and dopamine).
Monoamine depletion causes the post-synaptic receptors to upregulate which causes depression. Suspected that there is an abnormally functioning gene that causes depression.

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5
Q

Comment on the MOA and use of SSRIs and give some examples of SSRIs.

A
  • The postsynaptic receptor for serotonin is 5-HT receptors (many subtypes)
    - Serotonin is synthesized from amino acid called tryptophan and then stores in vesicles awaiting release
    - Reabsorbed from the synapse by SERT (serotonin reuptake transporter)
    - Once reabsorbed, they are partially repackaged into the presynaptic vesicles and partially broken down into inactive metabolites by MAO - monoamine oxidase
    - SSRIs inhibit the reuptake of serotonin from the synapse and accomplish this by blocking the serotonin transporter
  • Fluoxetine, Paroxetine, Citalopram, Escitalopram, Sertraline, Fluvoxamine

ADVANTAGES
- safe in pregnancy except paroxetine (safest is sertraline)
- drug of choice in the elderly and adolescents (fluoxetine)
- safer than other antidepressants when taken in overdose

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6
Q

Why do SSRIs take weeks to take effect?

A

§ G-proteins tend to cluster in parts of the brain cell membranes rich in cholesterol called lipid rafts
§ While clustered in these rafts, the G-proteins do not have access to CAMP which is needed for them to function and use serotonin.
§ Found that SSRIs also build up in these lipid rafts and gradually displace the G-proteins to other areas of the brain cell membrane where they are able to function better.

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7
Q

What are some side effects of SSRIs and withdrawal of SSRIs?

A
  • SHORT TERM SIDE EFFECTS
    § Insomnia (brain)
    § Anxiety and agitation (brain)
    § Irritability (brain)
    Headache (brain)
    § Sexual dysfunction (spinal)
    § N and V (GIT)
    § Diarrhoea (GIT)
    Abdominal pain (GIT
    - Abrupt withdrawal leads to a temporary deficiency in serotonin in the synapse which can cause headache, N and V, sleep disturbances
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8
Q

What are some drug interactions for SSRIs and the black box warning?

A
  • MAOIs (high risk of serotonin syndrome)
  • NSAIDs and Aspirin - increased risk of bleeding
  • diuretics - increased risk of hyponatremia

BLACK BOX
Increased suicidal thinking and behavior in the short term.

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9
Q

Comment on the MOA and use of SNRIs

A
  • Postsynaptic receptor for norepinephrine are Beta and alpha 1 receptors
    - Norepinephrine is synthesized from an amino acid called tyrosine and then stored in vesicles to await release
    - Reuptake is by transporter called NET (norepinephrine transporter)
    - Once reabsorbed, they are partially repackaged into the presynaptic vesicles and partially broken down into inactive metabolites by MOA - monoamine oxidase
    - Works in the same way as SSRIs but also inhibit the NET transporter. Venlafaxine is the common RSA option.
    Shown to be effective in the same conditions as SSRIs but also in reducing the pain associated with fibromyalgia and pain caused by neuropathy. This is due to the increase in noradrenergic activity in the CNS.

INDICATIONS:
- 2nd line treatment for MDD or for treatment augmentation, treatment resistance or prominent pain symptoms
- SAD, PD, persistent depressive disorder, diabetic neuropathic pain

INTERACTIONS
- MAOIs - serotonin syndrome

EXAMPLES
- Venlafaxine, duloxetine, milnacipran, desvenlafaxin, levomilnacipran

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10
Q

What are some side effects of SNRIs?

A

GIT - nausea, anorexia

ANTICHOLINERGIC - constipation, blurred vision, dry mouth

CNS - sedation, dizziness, anxiety

OTHER - sweating, hypertension, erectile dysfunction, increased BP, increased PR

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11
Q

Comment on the MOA and use of TCAs and Tetracyclic ADs

A
  • Core chemical structure is 3 rings connected together
    - Not a straightforward MOA
    - Inhibits reuptake of both serotonin and norepinephrine by blocking both of the transporters
    - Different TCA agents do this with different levels of selectivity
    - Also block many other receptors such as alpha receptors, histamine receptors and muscarinic receptors - this causes the side effects rather than the antidepressant activity
    - Mainly used for depression but also treats pain and migraine prevention, insomnia, childhood enuresis, OCD, narcolepsy and cataplexy, agoraphobia and panic attacks

INTERACTIONS:
- MAOIs (serotonin syndrome)
- Clonidine (hypertensive crisis)
- CNS depressants (over sedation)

CONTRAINDICATED:
- pregnancy
- recent MI
- cardiac arrythmias

EXAMPLES:
- amytriptyline
- clomipramine
- imipramine
- trimipramine
- lofepramine
Tetracyclic:
- maprotiline
- Amoxapine

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12
Q

What are some of the side effects of TCAs and what receptor blockade are they associated with?

A
  • SIDE EFFECTS
    § Inhibition of alpha receptors leads to orthostatic hypotension and dizziness.
    § Inhibition of histamine receptors leads to sedation and weight gain
    § Inhibition of muscarinic receptors leads to anticholinergic side effects such as blurred vision, dry mouth, constipation and urinary retention.

TCAs block cardiac sodium channels - produce effects similar to antiarrhythmic agents. Palpitations, orthostatic hypotension and reflex tachycardia

Sexual dysfunction

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13
Q

Comment on the MOA and use of MAOIs

A
  • Monoamine oxidase is the enzyme that degrades both serotonin and norepinephrine
    - Exists in two subtypes, namely A and B with different distribution in the different tissues such as the brain, gut and liver
    - MAO subtype A preferentially metabolises serotonin - blocking is responsible in the primary antidepressant effect of the MAOIs
    - MAO subtype B preferentially metabolises dopamine
    - Irreversible inhibitors and selective inhibitors.
    - Some of the agents will block both subtype A and B
    - Selegiline is a selective inhibitor of just MAO subtype B - this means that it is effective in Parkinson’s symptoms which are the result of dopamine depletion
    - Are a last choice for antidepressants as they not only have a LOT of drug drug interactions but also drug food interactions as they are also present in the GUT and are responsible for the breakdown of monoamines that we ingest. This means that it can’t metabolise tyramine which is in aged and fermented foods. This Tyramine is then taken up into the synaptic nerve terminals where it acts as a catecholamine releasing agent. The release of large amounts of catecholamine due to Tyramine leads to hypertensive crisis and potentially a stroke.

BLACK BOX WARNING: Tyramine-induced hypertension
- concomitant ingestion of MAOI and substance containing tyramine can lead to severe hypertension, death or stroke. This is found in fermented foods. This is why those taking MAOIs need to wear a medic alert bracelet.

INTERACTIONS:
- most antidepressants
- CNS depressants
- anti-asthmatics
- antihypertensives

SIDE EFFECTS:
- orthostatic hypotension
- insomina
- weight gain
- oedema
- sexual dysfunction
EXAMPLES:
- Tranylcipromine, phenelzine, isocardoxazid, selegiline

Remeber selegiline as it preferentially inhibits MAO subtype B which is mostly responsible for the degradation of dopamine which makes it useful in the treatment of Parkinson’s disease which is due to dopamine depletion.

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14
Q

What are some examples of atypical antidepressants?

A

Bupropion
Mirtazapine
Trazadone
Nefazodone
Vilazodone
Vortioxetine

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15
Q

Briefly comment on the MOA and use of bupropion

A
  • BUPROPION - weak norepinephrine and dopamine reuptake inhibitor. Can also use in nicotine cravings and withdrawal symptoms.
  • 2nd line treatment for depression
  • treatment augmentation
  • used in cases that have prominent hypersomnia and fatigue as symptoms of depression
  • used in those patients who have sexual dysfunction with other antidepressants
  • can also be used in tobacco-use disorder, ADHD and persistent depressive disorder

ADVANTAGES: minimal effect on weight gain, cardiac conduction and sexual desire

INTERACTIONS:
MAOIs - hypertensive crisis
Drugs that decrease the seizure threshold

SIDE EFFECTS:
Headache, insomnia, dry mouth, tremor, nausea, increased sweating

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16
Q

Briefly comment on the MOA and use of mirtazapine

A

Serotonergic and Noradrenergic antidepressants

  • MIRTAZEPINE - alpha 2 receptor antagonist. Blocks the presynaptic alpha 2 receptors. This increases noradrenergic and serotonergic neurotransmission. Also has some post-synaptic serotonin receptor blocking activity as well as antihistaminic activity which explains the sedating effects.
    The 5HT2 and 5HT3 blocking increases the release of norepinephrine and 5HT1A mediated serotonergic transmission.

INDICATIONS: can be first or second line depending, treatment augmentation, in depression with prominent insomnia. GAD, PD, SAD, SD

ADVANTAGES:
- Limited sexual side effects
- limited interactions so can be used in cardiac patients

INTERACTIONS: MAOIs - hypertensive crisis

SIDE EFFECTS:
Increased appetite, weight gain, dry mouth, constipation, dizziness, headache, sedation, oedema

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17
Q

Briefly comment on the MOA and use of trazadone and nefazodone

A

Serotonin receptor antagonist/reuptake inhibitors
- TRAZODONE AND NEFAZODONE - blockage of the SERT (just like SSRI) and also the 5-HT 2A (this is the “bad” serotonin receptor) - activation of this receptor is thought to contribute to depression. Also blocks histamine receptors and alpha 1 adrenergic receptors which is thought to account for their sedative effects.
Causes indirect increase in noradrenaline release

INDICATIONS: MDD and insomnia

BLACK BOX WARNING: risk of hepatotoxicity associated with nefazodone

SIDE EFFECTS: sedation, dizziness, orthostatic hypotension, tachycardia, headache, nausea and vomiting, priaprism

18
Q

Briefly comment on the MOA and use of vilazodone

A

VILAZODONE - serotonin partial agonist AND a SERT inhibitor

19
Q

Briefly comment on the MOA and use of vortiozetine

A
  • VORTIOZETINE - inhibits serotonin reuptake and also activates and blocks different serotonin receptors involved in mood regulation
20
Q

Comment on the MOA and use of norepinephrine reuptake inhibitors

A

EXAMPLES
Atomoxetine, reboxetine

INDICATIONS:
MDD, ADHD

INTERACTIONS:
MAOIs - type A - causes serotonin syndrome

SIDE EFFECTS:
Abdominal discomfort, anorexia, sexual dysfunction

21
Q

What is an example of a melatonin agonist?

A

Agomelatine

22
Q

What is considered a treatment failure with ADs and what are the options?

A
  • no response after 4 weeks
  • taper down and then switch to an AD from another class
  • augmentation with lithium, an antipsychotic such as Aripiprazole, Olanzapine, Quetiapine or another AD such as mirtazapine or bupropion

Ketamine

ECT

23
Q

Describe antidepressant cessation syndrome and its treatment

A
  • symptoms after the abrupt withdrawal of an antidepressant, especially those with short half-lives such as paroxetine, fluvoxamine and venlafaxine
  • symptoms usually appear after 6 weeks of antidepressant discontinuation and resolve spontaneously within 3 weeks
  • symptoms include dizziness, weakness, nausea, rebound depression, anxiety, insomnia, poor concentration, headache, migraine, paranesthesia, upper resp symptoms

Restart the medication at the same dose and taper down slowly.
Choose drugs with a longer half life
Treatment of symptoms.

24
Q

Define a Major Depressive Episode

A

(A) Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from the previous functioning; at least one of the symptoms is either: (1) depressed mood or (2) loss of interest or pleasure.

MSIGECAPS
M - mood - depressed
S - sleep - increased or decreased
I - interest - decreased
G - guilt
E - energy - decreased
C - concentration - decreased
A - appetite - increased or decreased
P - psychomotor - agitation or retardation
S - suicidal thoughts

Must meet criteria B and C
(B) the symptoms cause clinically significant distress or impairment in social, occupational or other areas of functioning.
(C) The episode is not attributable to the physiological effects of a substance or to another medical condition.

25
Q

How many supporting symptoms are needed in making the diagnosis of depression in addition to one of the core symptoms?

A

4

26
Q

What are the specifiers for MDD?

A

With anxious distress
With mixed features
With melancholic features
With atypical features
With mood-congruent psychotic features
With mood-incongruent psychotic features
With catatonia
With peripartum onset
With seasonal pattern

27
Q

In which common condition should you avoid Venlafaxine?

A

Hypertension

28
Q

What are the age specifiers for persistent depressive disorder?

A

Early onset - onset before the age of 21 years
Late onset - onset at 21 years or older

29
Q

What are the symptoms in the DSM associated with Premenstrual Dysphoric Disorder?

A

Marked affective lability
Marked irritability, anger or increased interpersonal conflicts
Marked depressed mood, feelings of hopelessness or self-deprecating thoughts
Marked anxiety, tension or feelings of being keyed up or on edge

Decreased interest in usual activities
Subjective difficulty concentrating
Lethargy, easy fatiguability or marked lack of energy
Marked change in appetite, overeating or specific food cravings
Hypersomnia or insomnia
A sense of being overwhelmed or out of control
Physical symptoms such as breast tenderness or swelling, joint or muscle pain, a sensation of bloating or weight gain

30
Q

Which substances are included in the DSM as specifiers for substance/medication induced depressive disorder?

A

Alcohol
Phencyclidine
Other hallucinogen
Inhalant
Opioid
Sedative, hypnotic or anxiolytic
Amphetamine
Cocaine

Specify whether there is a substance use disorder associated.
Specify whether the onset is during intoxication or onset during withdrawal.

31
Q

What are the features of the (with anxious distress) specifier for depressive disorder?

A
  • feeling keyed up or tense
  • feeling unusually restless
  • difficulty concentrating due to worry
  • fear that something awful will happen
  • feeling that the individual may lose control of himself or herself

Severity:
Mild - 2 symptoms
Moderate - 3 symptoms
Moderate-severe - 4 or 5 symptoms
Severe - 4 or 5 symptoms with motor agitation

32
Q

What are the criteria for the (mixed features) specifier for a depressive disorder?

A

A - at lease 3 of the following manic/hypomanic symptoms are present nearly every day during the majority of days of a major depressive episode
- elevated, expansive mood
- inflated self-esteem or grandiosity
- more talkative than usual or pressure to keep talking
- flight of ideas or subjective experience that thoughts are racing
- increase in energy or goal-directed activity
- increased or excessive involvement in activities that have a high potential for painful consequences
- decreased need for sleep

B - mixed symptoms are observable by others and represent a chance from the person’s usual behavior

C - for individuals whose symptoms meet full criteria for either mania or hypomania, the diagnosis should be bipolar 1 or bipolar 2 disorder

D - the mixed symptoms are not attributable to the physiological effects of a substance

33
Q

Describe the (melancholic features) specifier for depressive disorders?

A

Criterion A - one of the following is present during the most severe period of the current episode
1- loss of pleasure in all, or almost all, activities
2- lack of reactivity to usually pleasurable stimuli

Criterion B - with three or more of the following
1 - a distinct quality of depressed mood characterized by profound despondency, despair and/or moroseness or empty mood
2 - depression that is regularly worse in the morning
3 - early morning awakening
4 - marked psychomotor agitation or retardation
5 - significant anorexia or weight loss
6 - excessive or inappropriate guilt

34
Q

Describe the (with atypical features) specifier for depressive disorders.

A

Criterion A
Mood reactivity - the depressed individual’s mood brightens in response to actual or potential positive events

Criterion B
Two or more of the following:
- significant weight gain or increase in appetite
- hypersomnia
- leaden paralysis
- a long-standing pattern of interpersonal rejection sensitivity that results in significant social or occupational impairment

Criterion C
Criteria are not met for (with melancholic features) or (with catatonia)

35
Q

Describe the (with psychotic features) specifier for depressive disorders.

A

Can have mood congruent psychotic features or mood incongruent psychotic features

36
Q

Which antidepressant is indicated in patients who are wishing to stop smoking?

A

Bupropion

37
Q

Which is the most sedating antidepressant with minimal sexual side effects?

A

Trazodone

38
Q

Which antidepressant is the most appropriate choice for patients with medical comorbidity?

A

Citalopram

39
Q

Which antidepressant blocks histamine receptor?

A

Amitriptyline

40
Q
A