6. Antidepressants Flashcards
Clinical aspects
- ____ is a major issue.
- Second leading cause of death for ____.
- There may or may not be signs. Some people might not talk about it and they just do it.
suicide
adolescents
- 5 stages of Grief by Dr. Kubler-Ross
a. She came up with 5 stages as to what happens when you tell somebody something bad
i. Some of you might find oral cancer in patients and people will have different responses: - ____ – “no it’s not true”
- ____ – “why me”
- ____ - “well I’ll be better”
- ____
- ____
a. There are various people who accepts things as cancer survivors.
b. Talks about his experience with GI cancer (Stage 1A) he had surgery
(Tangent). He was happy with close surveillance and not depressed because he was relieved that it was found early before any metastatic disease.
c. There are different ways to handle some of these things
denial anger bargaining depression acceptance
- We have these agents
a. The ideal half life = ____ hrs (but nothing will be exact)
b. The person takes it once a day, it takes ____ half-lives to get to a steady state. c. Fluoxetine (Prozac) has a half life of ____ days.
i. This is the first SSRI. It wasn’t ideal but it had major advantages clinically.
ii. All of the other SSRIs half-lives closer to ____ hours. - Once a day dosing increases compliance.
24
4-5
2-3
24
BIOGENIC AMINE THEORIES of DEPRESSION
A. Early Theory
Depression results from depletion of central ____
Supporting evidence:
• reserpine is an antihypertensive drug
Ø mechanism: depletion of presynaptic ____ at peripheral synapses of adrenergic nerves/smooth muscle of blood vessels
Ø some pts developed ____ with the lowered BP Ø when reserpine was withdrawn, ____ ended
• drugs (e.g., amphetamine; cocaine) which inc synaptic
catecholamine levels do inc ____ (they are NOT effective antidepressants since this action is only acute); they induce ____ and potentially lethal ADRs
e.g., arrhythmias; inc BP])
Legitimate antidepressants (e.g., TCAs, MAO Inhibitors): increase in synaptic catecholamine levels occurs acutely BUT clinical effects require 1 ® 4 wks of therapy. WHY?
catecholamines
NE
depression
depression
mood
tachyphylaxis
B. Current Theory
Depressed pts have up-regulated ____ (possibly 5-HT1A & 5-HT2) and/or ____ (possibly alpha-1 & beta) receptors.
Elevated levels of synaptic ____–as produced by antidepressant drugs–eventually induce ____ of these post-synaptic 5-HT and/or adrenergic receptors.
____ weeks are required for down-regulation process.
post-synaptic 5-HT
adrenergic
biogenic amines
down-regulation
1-4
o Evidence
§ Have PET scans that serve as evidence to this previous theory.
§ Suicide victim (right scan) – when they are depressed, there is an increase ____ receptors.
• Once you increase the levels of neurotransmitters in synapse, the post-synaptic
side decreases in number and gets back to controlled level.
post-synpatic 5HT
TCA’s – tricyclic antidepressants like Amitriptyline
• Mechanisms that may be related to antidepressants is NE or 5HT – they inhibit the ____ which is the major mechanism of terminating catecholamine and 5HT activity is reuptake at the membrane and not
enzymatic (he doesn’t make sense what)
Refinement of these mechanisms and getting down to 5HT and ultimately getting to SSRIs (????!! Sorry)
uptake
Blocking uptake of NE into rat brain synaptosomes
Desipramine
• Blocking uptake of ____
• In this study, Desipramine has more potency than ____.
• Whereas, paroxetine(paxol), sertraline (Zoloft) or fluoxetine (prozac) doesn’t have much effect on blocking the Norpeinephrine.
o Don’t memorize the numbers just understand the concept.
norepinephrine
amitryptiline
Blocking uptake of SE into rat brain synaptosomes
Now going to the 5HT side. This is just looking at blocking serotonin uptake.
• The 3 ____ are greater in potency, then Amitriptyline and then Desipramine.
Once upon a time the only drugs that were there were Desipramine and AMI.
• But they found that AMI is more effective in ____ than Desipramine (clinical observation)
• AMI is roughly 5 times greater in blocking 5HT – so the theory started to involve maybe 5HT is also connected.
SSRIs
OCD
Selectivity of Antidepressants at Blocking Synaptosomal Uptake of Serotonin Over Norepinephrine
SSRIs
• ____ is 64 times greater in blocking 5HT uptake than Norepi
• Fluoxetine is less
• ____ is much more selective than Desipramine.
• “Do not memorize these drugs, just understand that:”
o Someone is on Prozac but its not working properly, but the psychiatrist may try another SSRI – bc they are not the same.
• Most selective in this group is ____ (but he says we don’t have to know)
Sertraline
AMI
Sertraline
- Histamine – Diphenhydramine
o Amitriptyline has a lot of ____ activity but this is not necessary to treat depression.
But what you want is a clean drug with no side-effects/
o This is why SSRIs replaced it.
o Paroxetine, Sertraline – don’t have much activity blocking ____ receptors
o So diphenhydramine’s histamine activity is not really needed for anti-depressant activity - Same thing for muscarinic blockers
o AMI–close to 6
o Desipramine – 10% of that
o So AMI is NOT recommended for treating ____ patients bc it blocks muscarinic, cholinergic
receptors.
§ Problem:
• In terms of brain activity, has an effect on cognition.
• Blocking Acetylcholine will interfere with cognitive function.
• Because it has ____ effect – do not recommend on geriatric patients.
• So SSRIs have less affect so it’s a good thing.
anti-histamine
histamine
geriatric
anticholinergic
- Adrenergic receptors
o Alpha -1 receptors
§ What happens when you block these receptors? = ____
• ____ – can cause fainting
• When you stand up, the blood pulls to the lower legs and the body faints
• Alpha 1 blocking activity is there with ____ and Desipramine but not so
much with the newer ones. - Dopamine
o None of them do this, we’re not talking about ____ effects.
So we use ____, because they are more effective and have less ADRs (I think adverse reactions?).
vasodilation
hypotension
amitriptyline
anti-psychotic
SSRI
THERAPEUTIC USES (General) Depression: Prominent, persistent depressed or dysphoric mood that interferes with daily functioning (> 2 weeks).
Pt will exhibit many of the following symptoms:
- ____, change in
- Fatigue, increase in
- Feelings of guilt or ____
- Loss of interest in usual activities/decreased sex drive 5. Psychomotor agitation or retardation
- ____, change in
- Slowed thinking/impaired concentration
- Suicide attempt/suicidal ideation
appetite
worthlessness
sleep
TYPES of DEPRESSION
Major Depressive Disorder
A. ____; Primary (approx. 25%) No clear identifiable cause Occurs at any ____
Possible ____ factors
B. Secondary (approx. 60%)
____ problems (MI; cancer; arthritis)
Drugs (e.g., antihypertensives)
____ (e.g., death of a child) Psychological Disorders:
Bulimia
____ Disorder
[especially responsive to SSIs & tertiary TCAs] Severe anxiety syndrome (with panic reactions)
____ (Manic-Depression) (approx 15%)
endogenous
age
genetic
physical
stress
obsessive-compulsive
bipolar
Obsessive-Compulsive Disorder
Especially responsive to ____ & tertiary clomipramine
Pain
Best response with ____ (SSIs are under study)
Enuresis
____ more effective (prob. due to anticholinergic)
Other:
Fibromyalgia
Irritable bowel syndrome
Migraine Sleep apnea
SSIs
tertiary TCAs
teritary TCAs
A. TCAs
u ____ Adrenergic Blocking Activity
u Anticholinergic
Greater with ____
u Blockade of Presynaptic Reuptake
Primary blockade of ____ reuptake: Tertiary TCAs; SSRIs
Primary blockake of ____ reuptake: Secondary TCAs
alpha-1
tertiary TCAs
5-HT
NE
TCAs
Anticholinergic
____ vision
Paralysis of accommodation:
Ø may precipitate attack of ____ in pt with narrow- angle glaucoma
Constipation, Urinary retention Dry mouth
Cardiovascular Direct depression of myocardium \_\_\_\_ conduction time: Ø may cause ventricular arrhythmias \_\_\_\_ (anticholinergic) \_\_\_\_ (alpha-1 ABA)
blurred
glaucoma
prolonged
tachycardia
orthostatic hypotension
TCAs
CNS
____** (> 30% in pts > 50 y.o.)
____ ** (> 30% in pts > 50 y.o.)
____ *** (> 30% in pts > 50 y.o.)
*** More likely with ____ TCAs (anticholinergic effect); Dizziness
Hypomanic or manic excitement (‘switch process’)
Seizures (more with maprotiline; less with desipramine)
Tremors (about 10%)
Other Agranulocytosis Interference with orgasm (male and female) Jaundice Rash Sweating (paradoxical) \_\_\_\_: Ø may be related to increased appetite O NS with fluoxetine
confusion
delirium
sedation
tertiary
weight gain
SSRIs
• Comparative pharm (compared to TCAs)
o Any ____ activity is less
o Less ____
o Less ____
o Cardiac conduction – not significantly ____
§ What happens when cardiac conduction cycle is prolonged?
• Normal cycle is very quick. But when you slow down the cardiac conduction with a drug, it takes a while for the ____ to get around the heart muscle. Circus movement. (I recommend listening this part)
o Anorexia
o Only thing that occurs more than the other drugs is ____
cholinergic hypotension sedation prolonged stimulus akathisia
Suicidality and Antidepressant Drugs
• Increased risk of ____ thinking in compared to placebo.
o Increased suicide with anti-depressants???
§ He doesn’t know why this happens but something is increasing the person’s thought process.
§ Most likely in the ____ group, we have these increases (age-related)
suicidal
younger
Serotonin Syndrome
Also occurs in ‘____’ (3,4-methylenedioxymethamphetamine;
MDMA) users.
Possible cause: hyperstimulation of ____ system
Effects include: Ø diaphoresis Ø restlessness (possibly 5-HT-1A receptor) Ø confusion & delirium Ø shivering®tremor®myoclonus Ø \_\_\_\_ Ø \_\_\_\_ Ø acute renal failure Ø rhabdomyolysis Ø disseminated intravascular coagulation (DIC)
Drug interactions producing the Serotonin Sydrome include:
Ø ____ + MAO Inhibitors (e.g., PARNATE)
Ø tryptophan + ____ (PROZAC)
Ø MAO Inhibitors + ____ (contraindicated** combin.)
Ø MAO Inhibitors + ____ (DEMEROL)
Ø ____ & Anti-migraine meds
Nonselective 5-HT antagonists may be useful for treatment:
Ø cyproheptadine (PERIACTIN)
Ø methysergide (SANSERT)
Ecstasy
serotonin
tachycardia
hyperthermia
tryptopham fluoxetine fluoxetine meperidine SSRIs
C. SNRIs
Venlafaxine (EFFEXOR)
Blocks reuptake of both ____ Biotransformed by cytochrome P450-IID6 (CYP2D6)
T1⁄2 »____hrs
T1⁄2 of active metab. (O-desmethylvenlafaxine; ODV) » ____ hrs
No significant activity at following sites: Ø \_\_\_\_ Ø histaminic Ø α-1 Does not inhibit \_\_\_\_
T1⁄2 inc in ____ and renal imairment
ADRs
Sustained ____ (dose-dependent ) Anorexia / N & V
Dizziness
Anxiety
Interactions
____ (TAGAMET): inc in T1⁄2
____ Inhibitors: possibly fatal hyperthermia
5-Ht and NE
5
11
muscarinic
MAO
cirrhosis
hypertension
cimetidine
MAO
SNRIs
Duloxetine (CYMBALTA)
Strong inhibitor of presynaptic uptake of both ____
(similar effectiveness on each type).
Weak inhibition of reuptake of ____;
____ affinity for histamine & cholinergic (M) receptors.
Used not only for depression but also FDA-approved for
treatment of:
____
pain related to ____
T1⁄2 » 10-15 hrs
5HT and NE DA low stress urinary incontinence peripheral neuropathy
SNRIs
Bupropion (WELLBUTRIN; ZYBAN)
Mechanism of action ____. Does not inhibit ____. Weak blockade of ____, serotonin and norepinephrine reuptake.
ADRS include seizures: contraindicated in pts with ____ disorders
unknown
MAO
dopamine
seizure
E. MONOAMINE OXIDASE (MAO) INHIBITORS
Non-selective:
Ø MAO-A: preference for ____ (less for DA)
Ø MAO-B: preference for ____
Isocarboxazid (MARPLAN)
MAO-A Inhibitors
____
Phenelzine (NARDIL)
Tranylcypromine (PARNATE)
MAO-B Inhibitors
____
Selegiline (l-deprenyl; EMSAM) / patch
Greater ____ compared to other psychiatric drugs.
Reserved for pts not ____ to other therapies.
5HT and NE
DA
irreversible
irreversible
toxicity
responding
E. MONOAMINE OXIDASE (MAO) INHIBITORS
Uses
____
Narcolepsy
Phobic-anxiety
ADRs
____
\_\_\_\_ Hypertensive crisis (see Diet Restrictions, below) Orthostatic hypotension
\_\_\_\_ Agitation Dizziness Fatigue Hallucinations Headache Vertigo
Other \_\_\_\_ (may be unrelated to anticholinergic action) Hepatotoxicity (can be very severe) Hyperpyrexia Hyperreflexia Interference with ejaculation Rash
depression
anticholinergic
cardiovascular
CNS
constipation
MAO INHIBITORS (continued)
COMPARATIVE PHARMACOLOGY (continued) In pts with cardiac disease or hypertension, \_\_\_\_ not recommended (other MAO inhibitors should be used with caution, if at all, in these cases).
Diet Restriction
Substances containing ____ (usually > 10 mg) are likely to cause a rapid and potentially lethal elevation in BP.
Cheeses (strong, aged, or natural)
Yeast products (especially if employed as food supplement)
Anchovies Avocados* Bananas* Beans (broad, pods of/fava beans) \_\_\_\_ (including nonalcoholic) \_\_\_\_ \_\_\_\_ \_\_\_\_ Cream Figs (canned) Herring, pickled Liqueurs Liver (beef and chicken) Meat extracts/meat prepared with tenderizers Raisins* Sherry Snails Soy sauce Sour cream Wine (Chianti) *Especially if over-ripe
Drug Restrictions (some examples) Increased risk of hypertension --\_\_\_\_, cocaine and other sympathomimetics --Buspirone --L-dopa
Increased risk of hyperpyrexia
–____ (Demerol) and related narcotics
Increased risk of psychosis
–____
Increases peak & duration by dec biotransformation of:
–Alcohol
tranylcypromine tyramine beer caffeine caviar chocolate
amphetamine
meperidine
dextromethorphan
alcohol
• If you have NE released from pre-synapse
• If you have MAO and it is inhibited, then you have more ____ released
• Tyramine is indirect acting adrenergic agent
o Its mechanism of action is to facilitate release of catecholamines aka NE in this case
• So if you block MAO and intake tyramine, you’ll have a ton of ____ released o This can kill people via ____
NE
NE
hypertensive crisis
Ketamine
____ receptor antagonist.
Several studies demonstrated ____ efficacy.
One limitation of ketamine for Tx depression: requires ____ which dc use for outpts.
NMDA
antidepressant
IV
Esketamine
____ of ketamine
____ affinity for blockade of NMDA receptor than the R-enantiomer
Being developed as ____ formulation for Tx-resistant
depression (TRD).
Rapid onset of antidepressant effects following IV
This study: intranasal esketamine, assessing efficacy and safety compared in individuals with TRD.
____, ____-controlled ____ clinical trial of 67
adults with treatment-resistant depression
Intranasal esketamine, 28 to 84 mg administered twice weekly, with a significant ascending dose-response relationship.
Significant improvement of depressive symptoms observed after 1 week.
Assessed by Montgomery-Åsberg Depression Rating Scale total score
Improvement appeared to be sustained with reduced dosing frequency for up to ____ weeks.
Results of this first clinical trial of intranasal esketamine for
treatment-resistant depression support study in larger trials
S-enantiomer higher intranasal randomized placebo double-blind 9
“Inflammation in Neurocircuitry of Obsessive-Compulsive Disorder”
“Key Question: Is ____ distribution volume, a
marker of the microglial component of neuroinflammation, elevated
in the cortico-striato-thalamo-cortical (CSTC) circuit of
obsessive-compulsive disorder (OCD)?
Findings: In this case-control study, translocator protein
distribution volume was significantly ____ in the CSTC of
participants with OCD compared with healthy control individuals.
The Yale-Brown Obsessive Compulsive Scale measure of distress associated with preventing compulsive behaviors was ____
correlated with translocator protein distribution volume in the orbitofrontal cortex.
Meaning: The presence of neuroinflammation in the CSTC of OCD argues for extending investigations of serum ____ to the entire CSTC and that ____ therapies should be
investigated in adult OCD.”
translocator protein elevated positively autoantibodies immunomodulatory
• History of relapse
o ____ can occur
o Can treat people and help to reduce relapse rate
§ Must remove ____ though for this to happen
• Certain things you cannot remove like a death of a child
o So there’s only so much ____ can do sometimes
relapse
stressor
psychotherapy
• Just want to mention that ____ from antidepressants is not easy
• Point: not easy to get off of
• Clinician must tell patient that withdrawal might be rough
• Point: antidepressants are ____ agents, such as the newer ones, the SSRIs (produce
less side effects)
o “my point is that” they really are better
• ANSWER TO STUDENT QUESTION: More likely being on ____ for life than antidepressant
withdrawal
effective
anti-psychotic
