Pharm - Drugs for Mood Disorders Flashcards Preview

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Flashcards in Pharm - Drugs for Mood Disorders Deck (41):
1

Major Depressive Disorder, Dysthymia, Bipolar Disorder

MDD --> Tends to be recurrent, presents more commonly in WOMEN (but may be reporting erro) and does NOT INVOLVE MANIA OR HYPOMANIA

Dysthymia -- Less severe than depression, but is still a depressive disorder that NEVER REMITS and can last for YEARS ON END

Bipolar Disorders - Treated extremely differently and include both periods of depression and mania/hypomania

2

How many patients with an affective disorder attempt suicide?

15%

3

What is the biogenic amine hypothesis?

Specific neurotransmitters play a role in depression --> NE, DA, 5HT

The hypothesis argues that low levels of NT (specifically NE, DA, 5HT) activity result in the DEPRESSED MENTAL STATES seen in MDD

Reducing the release of these chemicals may cause depression, and further enforce the chemical basis of the hypothesis

Also a strong genetic component

4

Serotonin Review

Produced by cell bodies in the MIDBRAIN (RAPHAE NUCLEI) that project into almost every part of the cortex and basal ganglia

5HT is diffusely distributed throughout the brain, and excites these areas.

5

Norepinephrine Review

Generated in neurons within cell bodies of the LOCUS COERULEUSS -- this is also a diffusely released NT that gets to most areas of the brain

6

Dopamine Review

Much more LIMITED in its distribution --> only really reacts within the LIMBIC SYSTEM and the BASAL GANGLIA to affect motor coordination and the reward systems

7

Production and release of Serotonin?

TRYPTOPHAN - consumed in the diet --> enters neurons and is transformed to 5-hydroxytryptamine (5HT) --> stored in vesicles that respond to depolarization-dependent calcium influx, fuse with the nerve membrane and is then released into the synaptic cleft

The 5HT then binds with any number of receptors (14 overall - 1a and 2a seem most implicated) to cause post-synaptic depolarization

Removed from the synapse b Na/K/Cl ATPase reuptake pumps that are selective for 5HT, but otherwise identical to NE reuptake pumps

NE is the exact same way, just with different intermediaries

8

Selective Serotonin Reuptake Inhibitors Overview

Highly selective reuptake inhibitors

Increase the concentrations of NT in the synaptic cleft of 5-HT synapses to ameliorate some of the symptoms of depression

Typically take 4-12 WEEKS TO SHOW AN EFFECT and there is a LARGE PLACEBO EFFECT for each

Much lower side effect profiles than TRICYCLIC ANTIDEPRESSANTS

As a result, they are a MAINSTAY OF DEPRESSION TREATMENT and have been for 30 years --> these aren't necessarily better drugs, but they are FAR better tolerated, which leads to better compliance and better outcomes

9

What makes SSRI more effective?

Combining with PSYCHOTHERAPY!!!

10

What is the only anti-depressant that can show abuse symptoms?

BUPROPRION -- has activity for NE as well as DA reuptake

Because of blocking the DA, it may interfere with reward pathways leading to abuse!!! (Like the article for SDL #5 said!)

Note: this is NOT an SSRI

11

Why does it take so long to see an effect?

There is a relatively QUICK onset, so why would it take long?

The axons of 5HT neurons that project to the forebrain have RECURRENT COLLATERAL PROJECTIONS that synapse with its own cell body

Serotonin 1a Receptors - INHIBITORY G PROTEIN RECEPTORS - fill the synapse

Just like all synapses, there are also reuptake pumps

If you BLOCK the pumps, there is excess 5HT and this is true at these inhibitory pumps too!!! OVER INHIBITS! REDUCES CELL FIRING!!!!!!

Even though the 5HT remains at the target synapses for longer periods, then neurons themselves ARE NOT FIRING AT HIGH RATES

Overall, the release of 5HT is lowered (ACUTELY)

***This accounts for the initial DEEPENING of depression that is first observed when prescribing SSRI***

12

So, how do we overcome this autoinhibition?

After long periods of stimulation, the 5HT 1a receptors DOWN REGULATE due to over stimulation!

This results in a RETURN TO NORMAL FIRING RATES OF THE NEURON

Meanwhile, the blockade of 5HT reuptake remains strong in the target synapse!

Thus, SEVERAL WEEKS AFTER STARTING SSRI THERAPY, 5HT levels at the target synapse will INCREASE (more firing of the formerly inhibited neurons!), resulting in the POSITIVE THERAPEUTIC EFFECTS

13

Adolescents and SSRI?

Adolescents are more at risk for suicide, so SSRI ARE NOT APPROVED FOR YOUNG PEOPLE DUE TO THAT INITIAL DEEPENING!!!!

14

What is the ONLY SSRI approved for children?

FLUOXETINE!

15

Is the delay between therapeutic effects limited to SSRI?

NO!

This happens with SNRI and TCAs too!

***All anti-depressants therefore have ESSENTIALLY EQUAL EFFICACY AND DELAY IN CLINICAL EFFECT***

16

Pharmacokinetics of SSRI

All have VERY LONG HALF LIVES and thus take several days/weeks to REACH STEADY STATE in the body

Stopping or switching these medications needs to be taken seriously and slowly, over the course of a few weeks!

17

FLUOXETINE

Has a half life of 4-6 DAYS!

LONGEST OF THE SSRI --> Since we allow 4 half lives for drug clearance, it means that it is about 4 WEEKS for FLUOXETINE -- as a result, it takes a long time to reach steady state and thus a longer time to see therapeutic benefit!

18

What are other SSRI (names)

SERTRALINE (zoloft)
CITALOPRAM
FLUVOXAMIDE

19

Side effects of SSRI?

When taken alone, SSRI are NOT FATAL in overdose

But, as with ANY antidepressant, activity shifts before mood does --> this can be bad --> more active, still depressed --> MAY result in more suicide (again, only Fluoxetine for kids)

Acute Side Effects --> ANXIETY, SLEEP DISTURBANCE, AGITATION; some LOSS OF LIBIDO (> 30%); weight GAIN (but NOT AS MUCH because they DONT block histamine receptors which is commonly associated with gaining weight)

Taper when coming OFF the medication (for a month) due to concerns of WITHDRAWAL


There are NO CARDIAC SIDE EFFECTS (like TCAs!) -- they don't block Na, K or Ca ions in heart tissues, so NOT associated with arrhythmias

These drugs also do NOT block adrenergic or muscarinic receptors, so they don't interrupt the normal autonomics

20

What is the most important thing to consider with SSRI and drug interactions?

SEROTONIN SYNDROME

Fever, sweating, HTN, anxiety, seizures, hyperreflexia and coma --> leading to DEATH

21

Drug Interactions

Again, can cause SEROTONIN SYNDROME if the drug increases the SSRI concentration

OTHER ANTIDEPRESSANTS (TCAs, SNRI)
**MAO INHIBITORS**
TRIPTANS
DEXTROMETHORPHAN (OTC cough suppressant)
MEPERIDINE/DEMEROL
ST JOHN'S WORT (herbal)

****Also, even MODERATE amounts of alcohol can lead to COMA****

SSRI are all HIGHLY PROTEIN BOUND (90%), and therefore they COMPETE AVIDLY FOR BLOOD PROTEIN BINDING SITES which can lead to higher levels of other drugs!!!!!

22

SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS

Inhibit reuptake of BOTH 5HT and NE so they resemble older TCAs, but DON'T prduce the same side effects (no heart effects!)

These drugs have NOT been shown to be any better than SSRI and carry the same precautions (with interactions, etc)

23

VENLAFAXINE

Inhibits 5HT > NE reuptake, but at therapeutic doses, BOTH ARE INHIBITED

24

DULOXETINE

Inhibits 5HT more potently than NE reuptake, but it's metabolite DESVENLAFAXINE inhibits BOTH and is available for prescription!!!!

25

Non-SSRI/SNRI --> BUPROPRION

This is a drug that INHIBITS DA and NE REUPTAKE but probably NOT 5HT

It is a STIMULANT --> only antidepressant with SIGNIFICANT DA effects --> sold as WELLBUTRIN for depression and ZYBAN for smoking cessation!!!!

Side effect profile compares favorably to SSRI --> NO DECREASED LIBIDO (heavily advertised claim; sometimes used WITH SSRI because of this)

Implications of stimulant activity? Could cause BEHAVIORAL ACTIVATION (lots of NE and DA) --> insomnia, decreased appetite, agitation --> especially in the EARLY stages --> good to avoid evening doses

Also implicated in ABUSE (only anti-depressant)

26

TRICYCLIC ANTI-DEPRESSANTS OVERVIEW

These drugs block THREE NT RECEPTORS --> ACh, HISTAMINE, and NE!!!!

In general, these drugs are MUCH LESS POPULAR than SSRI (side effects)

27

DESIPRAMINE

Strong, very specific norepinephrine reuptake inhibitor --> STILL USED TODAY because of its specificity

28

AMITRIPTYLINE

May be used to treat ***NEUROPATHIC PAIN*** as well as depression

Diabetic neuropathy, other nerve injuries

Not nearly specific like Desipramine

29

SIDE EFFECTS OF TCAs

Increased CARDIAC EXCITABILITY AND ARRHYTHMIAS (block Na, K channels in heart), HTN (beta block), DRY MOUTH (muscarinic block), GI disturbances (muscarinic), MEMORY dysfunction (muscarinic), WEIGHT GAIN (histamine), ORTHOSTATIC HYPOTENSION (alpha adrenergic)

While the therapeutic effect takes WEEKS, THESE SIDE EFFECTS OCCUR VERY QUICKLY, which is why there is such a big issue with compliance

Don't use in patients with known cardiac abnormalities, or those who have had heart attacks within a year of administration!!!!!

30

TCAs and OVERDOSE

These drugs can be FATAL IN OVERDOSE and have been used for suicide!

They are HIGHLY and TIGHTLY BOUND to plasma proteins, so it is DIFFICULT TO REMOVE FROM THE BLOODSTREAM AFTER OVERDOSE

Recommended that NO MORE THAN 2 WEEK SUPPLY of TCAs be prescribed until we KNOW the patient and TRUST their ability and willingness to follow directions properly!

31

What is the only drug that has any effect of DA again?

BUPROPRION!

32

MAO INHIBITORS

These drugs DECREASE METABOLISM of NE, 5HT and DA thus INCREASING their concentrations at the synaptic terminals --> this ALSO increases release by REVERSING THE REUPTAKE PUMPS!

This can be highly problematic because of the NUMEROUS INTERACTIONS with other drugs and even TYRAMINE CONTAINING FOODS (too much tyramine - not broken down when MAO is inhibited - will DISPLACE NE, causing it's release, and HYPERTENSIVE CRISIS!)

PHENELZINE, TRANYLCYPROMINE, CHLORGYLINE are all indicated for depression (don't need to know names)

Deprenyl is a MAO-B inhibitor approved as an adjunct for PD

Remember - combinations of MAOI, TCA or SSRI can CAUSE SEROTONIN SYNDROME!

Not widely used today

33

What is the most effective and quickest therapy for MDD?

ELECTROCONVULSIVE THERAPY

Not very popular, but it is more effective than any alternative therapy that exists for unipolar depression or bipolar disorder!

Acts on the same pathways --> INCREASE 5HT and NE release

Much fewer side effects, FASTER

34

KETAMINE

Offers RAPID RELIEF OF DEPRESSION SYMPTOMS

Clinical trials looking into it as an emergency treatment or for depression that doesn't respond to other medications

35

General Recommendations for Anti-Depressants?

In general, need to be started ONE AT A TIME (lots of interactions) and wait for UP TO A MONTH TO SEE IF THEY ARE EFFECTIVE OR NOT!

After that, it is appropriate to change classes or to use another drug in the same class (switching is common)

Only if these show NO EFFECTS, should LITHIUM, MAOI or ECT be considered

Generics are preferred (due to cost)

36

What are the three types of Bipolar Disorders?

CYCLOTHYMIC -- Alternating between hypomania and mild-moderate depression; 1% lifetime risk; A significant number go onto develop FULL BLOWN BPD

Bipolar II --> Alternations between MAJOR DEPRESSION and HYPOmania --> 0.5% life time risk; Significant number go onto develop...

BIPOLAR II --> CLASSIC BIPOLAR - with FULL MANIC EPISODES after alternating with MAJOR DEPRESSION

0.5-1.5% lifetime risk

37

LITHIUM

Mainstay as an effective PROPHYLACTIC against BOTH mania and depression

This is a MOOD STABLIZER

Usually takes about 7-10 days to work

NOT USUALLY EFFECTIVE IN DEPRESSION PHASE or in UNIPOLAR DEPRESSION

38

Lithium Mechanism of Action

Two mechanisms:

Inhibits adenylyl cyclase --> lowering cAMP; this might contribute to some therapeutic effects via reducing NE or DA stimulated cyclic AMP

Inhibits inositol phosphatase --> stopping regeneration of PIP2 in Phospholipase C G protein reactions

This has a greater effect on the BRAIN because it relies on the regeneration cycle heavily --> NT receptors that are couple to this system include ALPHA 1 ADRENERGIC, 5HT, some muscarinic, some glutamate

In the body, PIP2 is also made by the liver, so this drug won't completely reduce body levels

39

Side Effects of Lithium

Has a very narrow therapeutic index! (0.6-1.5 mEq/L = therapeutic --> 2.5 mEq/L = TOXIC)

LIKELY TERATOGEN during 1st Trimester (possible tricuspid valve malformation)

Excreted via the KIDNEY --> reabsorbed in PCT --> THIAZIDE DIURETICS increase excretion of sodium and potassium at the distal tubule, and therefore INCREASE LITHIUM REABSORPTION DUE TO LESS COMPETITION!!!!

Also, Lithium inhibits the action of ADH --> resembling Diabetes Insipidus (kidneys can't conserve water!)

NSAID use and INTENSE EXERCISE will INCREASE LITHIUM LEVELS

Causes WEIGHT GAIN

May also alter THYROID FUNCTION and DEPRESS THE SINUS NODE

40

Lithium ALTERNATIVES

Acute MANIC episodes --> usually controlled by an ANTIPSYCHOTIC (aripiprazole, risperidone, haloperidol) or a BENZO

Usually added CONCURRENTLY with Lithium so that it can STABILIZE MOOD!

41

Anti-Epileptic Drugs?

VALPROIC ACID, CARBAMAZEPINE, LAMOTRIGINE

These antiepileptic drugs can be effective as mood stabilizers also, although they may not be as effective as Li and they cost more. Valproic acid or carbamazepine can be combined with Li in refractory patients.

These drugs are worrisome for a few reasons --> they INTERACT WITH MANY DRUGS THROUGH p450 interactions, specifically oral contraceptives to below effective ranges (increase estradiol!)

Associated with NEURAL TUBE DEFECTS