Major Depressive Disorder (MT 2)
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Overview of MDD facts? (3) Approx. percent if adults? Males to female?
- -12 to 20% of adults will be diagnosed with depression at some time in their life
- -2:1 ratio of females to males are likely to have depression or report it than males
Overview of diagnostic features?
- can never have had a manic or mixed episode to be diagnosed with MDD
- one or more Major Depressive Episodes for at least 2 weeks:
- D Depressed mood most of the day, nearly
- every day
- I Interest: loss of interest of pleasure
- G Guilt: feelings of guilt, worthlessness, hopelessness
- E Energy: loss of energy, fatigue
- S Sleep: insomnia or hypersomnia
- C Concentration: diminished ability to think, concentrate or indecisiveness
- A Appetite: decrease/increase in appetite or significant weight gain/loss when
- not dieting
- P Psychomotor agitation or retardation (reported and/or observed)
- S Suicidality: Recurrent thoughts of death or suicide with or without a specific
Disorders that can manifest as Clinical Depression Medical disorders like MDD (broad level)? (6)
- 1. Endocrine disorders
- 2. Infectious disorders
- 3. Metabolic disorders
- 4. Rheumatic and inflammatory disorders
- 5. Neurological disorders
- 6. Other general medical disorders
Primary psychiatric disorders with clinical depression
- 1. Mood disorders
- (MDD & Dysthymia & BD I and II)
- 2. Anxiety disorders (DATA for drugs in this is not good
- (Post traumatic stress disorder & Panic Disorder &OCD (have insight but cannot stop))
- 3. Borderline PD, Dependent PD
- -Will see use of antidepressant medication (ADM) for symptoms or clinical features
What key word systems do these use: 5-HT, 5-hydroxytriptamine; NE, norepinephrine, noradrenaline; Epinephrine, adrenaline; DA, dopamine ?
- 1. 5-HT, 5-hydroxytriptamine (serotonin)
- -Serotonergic (S)
- NE, norepinephrine, noradrenaline
- -Noradrenergeric (NA)
- Epinephrine, adrenaline
- -Adrenergeric (A)
- DA, dopamine
- -Dopaminergic (DA)
Hormonal changes for women that cause depression? (4)
- 1. Menopause,
- 2. post partum depression
- 3. premenstrual
- 4. Female contraceptives : Including birth control pills,
- patches, implants, and intrauterine devices
Drugs and substances of abuse that cause or exacerbate depressive symptoms? (4)
- 1. Alcohol
- 2. CNS depressant and when used regularly can cause or exacerbate depressive symptoms
- 3. Antianxiety drugs: Can cause or exacerbate
- depressive symptoms Especially benzodiazepines
- (4. Antihypertensive medications used to treat high blood pressure)
Other disorders with features of MDD (3)?
- 1. Antiparkinsonism drugs
- 2. Hormone replacement therapy for menopausal women
- 3. Steroids such as cortisone
The Monoamine (MA) Hypothesis defined?
- Depression results from a decrease in monoamines
- at critical synapses (e.g. Norepinephrine, Serotonin, Dopamine. )
Causes of the Monoamine (MA) Hypothesis defined (4)?
- 1. Excessive re-uptake by the presynaptic neurons
- (Instead of neurotransmitter (NT) remaining in synapse and interacting again with postsynaptic receptors, too much is reabsorbed into pre-synaptic neurons)
- 2. Decreased release of a NT by pre-synaptic neurons
- (Reduction in synthesis of a NT Impaired ability to store a NT Abnormalities in vesicle migration and fusion with the cell membrane)
- 3. Monoamine oxidase (MAO) excess ( Enzyme In pre-synaptic neurons Breaks down NTs into amino acids
- If this MAO enzyme is too active and breaks down excessive amounts of NTs insufficient amounts of NTs for release into the synapse)
- 4. Abnormalities in postsynaptic neuron receptors related to second messenger systems ( These receptor abnormalities include Changes in the number of receptors (reregulation - down or up) Altered (increased or decreased) receptor sensitivity )
Abnormalities in postsynaptic neuron receptors related to
second messenger systems: These receptor abnormalities include?(2) <- for the Monoamine (MA) Hypothesis
- 1. Changes in the number of receptors (reregulation - down or up)
- 2. Altered (increased or decreased) receptor sensitivity
What is the problem with this theory?
- The time-lag issue:
- It takes 2-3 HOURS for drugs to exert effect on synapse BUT…It takes 3-5 (or more) WEEKS for drugs to exert their antidepressant effect
- INCREASE 5-HT at terminal ending (the desired THERAPEUTIC effect), (give signal autoreceptor and postsynaptic.. Too many in autoreceptor there will be a blocking). Over stimulation in postsynaptic = down regulation. but also…INCREASE inhibition at dendritic autoreceptors
Indirect evidence leading to Monoamine (MA) Hypothesis proposal?
- 1. Lowered amines
- 2. Reserpine (Effective treatment for hypertension by reducing peripheral adrenergic activity Induced depression in a significant number of patients Found to inhibit vesicularstorage of monoamines, thus allowing metabolism by Monoamine Oxidase (less MAOI))
- 3. Other Early Drugs (Reduce biogenic amine levels andprecipitated depression)
- 4. Early Effective Antidepressants (Found to acutely increase intracellular monoamine levels Also reversed reserpine-induced depression)
Definition, function and relevance of autoreceptors and transporters in MA hypothesis and use of ADMs?
- l. TCAs or SSRIs administered (block reuptake) Increase in NE & 5-HT levels primarily detected initially at autoreceptors Detected by the receptors on presynaptic neuron. Autoreceptors on the presynaptic membrane (Provide feedback to presynaptic neuron about rate of neurotransmitter synthesis and release)
- 2. Monoamine transporters are neurotransmitter transporters that transfer monoamine neurotransmitters in or out of cells. remove neurotransmitters from the synaptic cleft and prevent their action or bring it to an end.
- _look at notes for more detail!!!
Evidence that the amine hypothesis is too simple
- 1. Affective disorders are too complex (e.g., changes in mood, sleep, sexual activity, appetite, body temperature, motor activity, cognitive function, etc.)
- 2. A disconnect between pharmacology
- (hrs) and therapeutic benefit (weeks) (clinical effect 3/5 week but flood CNS
- and no change.. Disconnect)
- (While monoamine level are immediately influenced by antidepressants, any therapeutic benefit may be
- delayed for weeks.)
- 3. Lack of correlation between drug potency and effective therapeutic dose (The most potent drugs at influencing monoamine levels in vitro are not necessarily the most potent drugs for treating depression in vivo. Potency doesn’t matter?)
- 4. No evidence for amine depletion
- in depressed individuals (no differnce in MAOI (No consistent findings when measuring amine or metabolite concentrations in various fluids from untreated
Where does one find Monoamine Oxidase Inhibitors (MAOIs)?
- Found mainly on the outer mitochondrial membrane in cells
- throughout the central nervous system
MAO-A vs MAO-B?
- l. MAO-A (responsible for “Red Wine and Cheese Effect”) Know if we inhibit MAO irreversibly Take Wine etc increase Preferentially metabolizes serotonin, but also will metabolize
- dopamine, epinephrine, norepinephrine, and others
- 2. MAO-B Preferentially metabolizes dopamine, but also many other amines
- (MAO-A inhibitors act as antidepressant and antianxiety agents, whereas MAO-B inhibitors are used alone or in combination to treat Alzheimer’s and Parkinson’s diseases- Wiki)
Issue of non-selective and irreversible MAOIs?
- 1. MAO-A Inhibitors E.g., Moclobemide selectively and reversibly inhibit MAO-A. Inhibition results in a rise of norepinephrine, dopamine, & serotonin in
- the synaptic cleft
- 2. MAO-B Inhibitors E.g., L-deprenyl selectively and irreversibly inhibits MAO-B Results in a rise in dopamine primarily Used in combination with levodopa to treat Parkinson’s
Pharmacokinetics of MAOIs? (6)
- l. Oral Administration
- 2. Rapid absorption from the GI tract (2 to 4 hours)
- 3. Hepatic (liver) metabolism
- 4. Half-life: 2 to 3 hours for iproniazid
- 5. Protein (depot) binding is variable (50 to 80%)
- 6. Excretion is mainly via the urine
Side effects (6)?
- 1. Hypertensive crisis
- 2. Orthostatic hypotension, weight gain
- 3. Anorgasmia, impotence, urinary hesitancy, constipation
- 4. Seizures
- 5. Sometimes insomnia (Parnate)
- 6. Anticholinergic effects
Food and over the counter medication problematic interactions with MAOIs – the name for the this and what causes it (basically)
- Irreversible MAOIs cause rise in amine levels and
- hypertensive crisis
- Strong interactions with SSRIs, over the counter cold
- medications Called the red wine and cheese effect: Notably hazardous interactions with foods containing tyramine, among them.
General issues of herb and supplement pills that may have similar functions as MAOIs
- If a person taking MAOIs experiences 2 or more of the
- following symptoms, they should be taken to emergency medical services immediately
- (Severe headache Excessive sweating/perspiration
- Lightheadedness Vomiting Increased heart rate without
- Some herbs and supplements that may perform similar functions as a MAO inhibitor (i.e., interaction)
Cyclic Antidepressants: How they function with NE
and 5-HT (pharmacodynamics)?
- -Block of
- reuptake of NE and 5-HT (block Sertonin lSNaRIs )
Effects and side effects of Cyclic Antidepresant medications? (4)
- l. Strong anticholinergic effects
- (blurred vision at close range dry mouth, dry eyes
- rapid heart rate (tachycardia) urinary hesitation)
- 2. Hypotension problems (fuzzy headed feeling, dizzy,
- nauseous sedation)
- 3. manic “switch over”
- 4. These drugs are very lethal (IF OD)
Use of sedating vs stimulating TCAs and when they would be employed?
- 1. Tertiary amine tricyclics = SEDATING
- -Old school Tricyclics sedating (drugs can help and make worse) depression is accompanied by sleep disturbance, agitation and restlessnes
- 2. Secondary amine tricyclics = STIMULATING where the depressed patient is fatigued, withdrawn, apathetic and inert.
SSRIs: Pharmacokinetics and dynamics of these?
- l. Theoretically the effects are seen much faster (within 3 weeks) (This is not always the case)
- 2. SSRIs don’t have same side effects as
- other tricyclics
- 3. Function by blocking serotonin reuptake
Side effect profile including sexual side effects?
(symptoms and management) (4)
- l. Apathy syndrome (not a lot of data): *After several months of treatment and symptom reduction patient experiences symptoms superficially similar to reemergence of MDE but patient usually denies sad mood
- * This syndrome is best treated by reducing the SSRI dose
- 2. Serotonin syndrome (lot of data) *Serious event and can become a life-threatening medicalemergency Caused by excessive activation of the serotonin system Usually seen in people who are taking two or more serotonergic medications
- aaociated with death
- * MUST discontinue immediately
- 3. SSRI Discontinuation syndrome (issue): Stopping SSRIs
- Neurologic sxs, Somatic sxs , Gastrointestinal,
- Motor sxs, Psychiatric sxs.
- *Gradually taper all serotonin reuptake inhibitors except fluoxetine
- 4. Sexual dysfunction: This can be augmented with other
- medications Some discussion of permanent sexual dysfunction following SSRI discontinuation
Interaction effects with MAOIs, TCAs, lithium?
l. MAOIs: Risk of serotonin syndrome
- 2. TCAs: Paroxetine or fluoxetine prescribed with Cyclic
- antidepressants can raise blood levels of the cyclics into overdose ranges
3. Lithium Lithium taken with SSRIs may increase lithium levels into the toxic range
Na R blocker/ DA R blocker (DaNaRIs) - Wellbutrin (bupropion)?
- Stimulating effects
- l. Seizures (esp. with ETOH)
- 2. Weight loss (28%)
- 3. No sexual problems
- 4. Drug interactions: (SSRIs (Increases SSRI levels (Serotonin syndrome) TCAs: Increases TCA levels Decreased liver metabolism (inhibited with TCAs) Will produce seizures)<-put together not good thing!!)
NaSSAs (noradrenergicspecific serotonergic antidepressants)-Remeron (mirtazapine)?
- l. SSRI gains:
- 2. less sexual side effects
- 3. weight gain/increased appetite (Can be quite pronounce in some patients)
- 4. sedation
- 5. “abnormal thinking/abnormal dreams”
SNaRIs - Effexor(venlafaxine)?
- Serotonin-norepinephrine reuptake inhibitor
- 1. Fair effectiveness (Seizures Dizziness
- Headache, nausea, sleepiness Seizures possible High rate of sexual side effects)
- 2. High SSRI discontinuation syndrome (side effects after discontinue with use)
NRI (NorepinephrineReuptake Inhibitors; NRIs) - Vestra (reboxetine)?
- Side effects: lNRI (Norepinephrine Reuptake Inhibitors; NRIs) lInsomnia lLoss of appetite lExcessive sweating lDizziness, vertigo and hypotension
- Loss of libido, impotence and other urological problems
- (Urinary retention in men, pain on ejaculation), increased
- orgasm intensity, and premature/quickened ejaculation
- -Note that Straterra (atomoxetine) is an NRI on label for ADHD but did not have any clinical effect of MDD in trials
SSNaRI - Cymbalta(duloxetine)?
- SSNaRI (tricyclic like this also)
- Selective serotonin and norepinephrine reuptake inhibitor
- actions are believed to be
- related to its potentiation of serotonergic and noradrenergic activity in the CNS.”
- “duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake”
Use of Deseryl (trazodone)?
- (the little antidepressant that couldn’t )
- Not clear what mechanisms of action are (TCA or SRI)
- Not the best antidepressant
- Typically used to aid sleep (Very commonly prescribed for this Need to look for interactions Does have some serious side effects)
- Some heart problems (tachycardia)
Considerations for drug treatment of MDD? (4)
- l. Not everyone wants to be on a medication
- 2. Not all patients are accurately diagnosed
- 3. Medications are expensive
- 4. There is much variability with regard to individual responses
Understand the difference between responders, non-responders, remission and relapse rates?
- 1. Responders – at least 50% reduction in symptoms
- 2. Non-responders – less than 50% reduction in symptoms
- 3. Remission – full reduction in symptoms
- 4. Relapse – return to depressed state
Placebo analysis data, how much is drug effect, how much is placebo?
- drug better but control did do well
- Drug versus manupulation… not a HUGE effect..!!!Is the cost work it?
How do Kirsch & Sapperstein (1998) drug effect vs placebo effect size ratio?
- l. Meta-analysis of drug studies: Combining many studies into one finding across them
- 2. Comparison of effect of treatment to no treatment
- 3. End up with a percentage of improvement that is due to:
- Treatment condition AND Waiting, Placebo
- Divide the placebo condition effect size (D-Placebo) by the drug condition effect size (D-Drug)
- This is a ratio of drug to placebo effect
- For example: Placebo D = 1.24 divided by SSRI
- D = 1.68 Ratio = 1.24/1.68 This is .74
What is the number that they come up with (ratio or percentage) and what does this mean?
- Ratio of placebo to drug effect is consistently equivalent to
- .75 or ¾
- Across drugs
- What does this mean? (placebo over lap treat versus no
- treatment accounts for 75%)
- -> 75% of drug benefit is due to psychological effect 24% maturation or history 51% expectancy/placebo
Kirsch & Sapperstein History vs. placebo effects (what is this number and how was it calculated?)
- From psychotherapy vs. wait-list studies
- Look at comparison of effect of treatment to no treatment (create a ratio again)
- End up with a percentage of improvement that is due to waiting This is 25%
- Total inactive placebo effect =
- 75% (waitng around/ maturation)
Issues with the active placebo – what is it and what are the results?
- lCompare antidepressants with “active” placebos
- (lPlacebos with side effects Give drug but NOT with main treatment effects (just side
- Meta analysis by: (Moncrieff et al. (2003) (reduced effective of active drug)
- Reduces clinical effectiveness of active drug
- See essentially no difference between active placebo and real drug
- -> DOUBLE blind-more than likely going to be biased
Moncrieff et al.’s (2003) conclusions from the
active placebo research?
Small differences were found in favour of antidepressants in terms of improvements in mood. This suggests that the effects of antidepressants may generally be overestimated and their placebo effects may be underestimated.”
SSRIs and the placebo effect with children?
- 1. The FDA is still evaluating reports of increased risk of suicidal thinking and attempts in kids who use it
- -NOT approved by FDA for treatment
- of depression in non-adult populations: Both the FDA and
- British authorities recommend children under 18 not take it
- 2. In January the FDA approved Prozac for use in children 7 to 17 Only drug approved by FDA for children dx with depression
The data on SSRIs and suicidality ?
- FDA requires a caution on all SSRIs and Efexor, Wellbutrin , Remeron, & Serzone (start stop change elevate antidepres)
- Issued warning March 2004
- Requires close observation of all patients on these drugs for
- emergence of SI
- Especially important when beginning drug, switching dose, and discontinuing drug MUST watch for anxiety,
- agitation, panic, insomnia, irritability, hostility, impulsivity
- -The data on Effexor (atypical antidep SNaRI) Elevation of suicidal ideation (8.8 times); NO increased rate of actual completed suicides.
Psychotherapy for depression clinical
efficacy trials What are the relapse rates for therapy, cessation from meds, continuing on meds for 16 wk and 1 yr follow up?
- 16-weeks antidepressants (SSRIs) and visit to professional
- placebo and visit to professional cognitive therapy alone
- End of 16 weeks: CT = 57% response rate (CBT NOTjust CT); SSRIs = 57% response rate
- 16-week follow up - relapse rate: CT = 25% Meds = 40% Placebo = 81%
- 2. 16 weeks of drugs cost $2,590
- 16 weeks of individual CT $2,250 Tx largely cheaper in long run because patients have to continue taking antidepressants.
One year follow up post-treatment: CBT = 31% relapse rates Discontinuation (GET off) of Medications = 76% relapse If stayed on medications = 47% relapse (Stopping more in meds)
APA report (NB critically) During an 8-week clinical trial?
patient receives an average of 20 hours of “having been examined by top expertsand highly trained professionals”(- lot of contact!! May impact placebo) How does this affect drugresponse? How might this figure intoplacebo response? Now, revisit the Effexor data – concerns?-research kids looked a lot, real life only seen for refill)
Psychopharmacologic treatment guidelines for MDD
1. Patient with BD history – no ADM only Choice of ADM may be based on symptomotolgy of patient
Recommendations about when, starting, and discontinuing (6) ?
- 1. Start antidepressants at a low dose and gradually increase the dose over 10 to 14 days until within the therapeutic range for the specific drug
- 2. Most antidepressants require 2 to4 weeks of treatment before reduction of vegetative depressive symptoms begins )
- 3. ->Patient will likely experience side effects within the first week of treatment
- 4. Antidepressants should not be discontinued suddenly except in the case of a medical emergency
- 5. Alcohol and benzodiazepine intake should be reduced dramatically or avoided completely when a patient is taking
- an antidepressant
- 6. If patient does not respond to an initial trial of an antidepressant, even after an increased dose has been tried, treatment may be switched to another one of the newer antidepressants from another class
Phases in the pharmacologic treatment of depression?
- l. Acute Phase: Begins with the first medication dose and extends until the
- patient is asymptomatic (usually 6 to 8 weeks)
- 2. Continuation Phase: To avoid acute relapse into
- depression, patients should continue drug treatment for a minimum of 6 months
- after they become asymptomatic (after the Acute Phase)
- 3. Maintenance Phase: To prevent relapse the guidelines for maintenance (First Depressive Episode At the end of the Continuation
Other disorders treated like MDD?
- Dysthymic Disorder:
- SSRIs used frequently
- 62% response rate to SSRIs Up to 44% response rate to
- Patients on SSRIs :Treatment response increases if believe Dysthymia is a biological disorder Sullivan, et al (2003)
- 2.Anxiolytics have been used: No effect over placebo Have been noted to worsen
“Organic” Alternatives (general issues here)?
- FDA says be careful
- All can have interactions with
- other prescribed (and non-prescribed) drugs
- e.g.Hypericum or St. John’s Wort
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