Mood Disorders I and II

Cognitive-Behavioral Model

*More here and now, what is going on in the present - current THOUGHTS (kind of like- who gives a frick why they're here in the first place. the fact is- they're here, and let's address them... pardon my french) a) Postulates that depressed patients tend to express similar types of "unconscious" thoughts - automatic thoughts. Automatic thoughts: i) Selective abstraction - drawing a conclusion based on only a small portion of the data (mental filter) ii) Arbitrary inference - drawing a conclusion based on inadequate data or ignoring contradictory data iii) Absolutist - Rigid dichotomies. Perfect or flawed, success or failure, etc iv) Magnification and minimization - overvaluing flaws, undervaluing strengths v) Personalization - taking blame or self-criticizing for events outside of ones control vi) Catastrophic thinking - predicting worst possible outcome and ignoring more likely events. goal of CBT (cognitive-based therapy): correct these patterns of thinking -focusing on thoughts themselves -automatic thoughts contain cognitive distortions, which in turn reflect maladaptive cognitive schemas Summary: Psychodynamic: unconscious; past experiences; classical psychoanalytic theory (anger turned inward) vs object relations theory (early disappointment/loss --> later depression); goal of psychotherapy= provide corrective emotional experience thru 1) classical psychoanalysis (free association, therapist neutral) or 2) short term therapy (highly focused on a few main issues) CBT: "here and now", goal = focus on automatic thoughts to determine maladaptive cognitive schemas;

Distinguish between post-partum "baby blues" and full-blown post-partum major depressive disorder.

+postpartum "baby blues" -- crying, irritability, mood swings. onset: 3-10 days postpartum, resolves in ~1 week. thought to be due to hormonal changes, stress, sleep deprivation. +true full-blown postpartum major depressive disorder -- meets full dx criteria= for major depressive episode (but basically, depressed mood, lack of interest/pleasure in activities, wt loss/gain, change in appetite, insomnia or hypersomnia, fatigue, feelings of worthlessness, etc. think SIG E CAPS) ● greatest risk is first 2 weeks postpartum but can be up into several months out ● women who've had a previous depressive episode are more likely to experience postpartum depression ● women with postpartum depression are more likely to have future postpartum depression ● also hormonally related but you would not just treat with hormonal therapy, need antidepressants!

Serotonin (5-HT2) antagonist/reuptake inhibitor

- azodone Trazodone (Desyrel) Nefazodone (Serzone)

MAO Inhibitors

-Indications: Dysthymic disorder, atypical depression, seasonal affective disorder, (maybe) bipolar disorder, medication-refractory depression -Mechanism of Action: Inhibit MAO-A and -B (responsible for dopamine and tyramine metabolism) thus inhibiting its breakdown (remember that low dopamine is seen in depression, so you want to keep it high) Increase synaptic monoamine --> down regulate post-synaptic receptors -Benefits: Good for medication refractory depression (otherwise not commonly used- 0.1% of all antidepressant prescriptions) -Side effects: "Cheese reaction"- inhibiting MAO --> high levels of tyramine (potent releaser of NE)--> high norepinephrine --> hypertension Serotonin Syndrome: overactivation of 5-HT receptors --> abdominal pain, diarrhea, flushing, hyperpyrexia/hyperthermia (high fever), CV shock, confusion, myoclonus, seizures -Receptors/ Enzyme: On MAO enzyme

Tricyclics

-Indications: lots of side effects, not good for people with heart problems especially -Mechanism of Action: "Dirty/slutty"- binds to multiple receptors This leads to high efficacy, but lots of side effects, too Main idea: increase available monoamine in synaptic cleft--> down regulate postsynaptic receptors Specifically, inhibit reuptake of 5HT and NE -Benefits: very effective -Side Effects: Can be lethal in overdose! Based on receptor: Histamine: sedation, weight gain, hypotension, delirium ACh (muscarinic): dry mouth/eyes, blurred vision, decreased memory, constipation, resting tachycardia Alpha: orthostatic hypotension, reflex tachycardia, potentiation of prazosin antihypertensive effects Alpha 2: block antihypertensive effect of clonidine, methyldopa, guanfacine 5HT2: anxiety, insomnia, sexual dysfunction, hypotension 5HT3: nausea, cramps, diarrhea

Selective Serotonin Reuptake Inhibitors (SSRI)

-Indications: not a lot of side effects, generally well tolerated over months -Mechanism of Action: Selective for serotonin receptor--> block reuptake of serotonin with little effect on other neurotransmitters -Benefits: fewer side effects--> lower rate of discontinuation, little cardiotoxicity, safe in overdose -Side Effects: increased serotonin --> insomnia many patients end up needing sleeping pills Common side effects: anxiety, nervousness, restlessness, insomnia, GI distress, headache, dizziness Sexual side effects (70% of pts): decreased libido, anorgasmia, impotence Hypofrontality/apathy: not sad, but "feel like a zombie" SSRI-discontinuation syndrome: anxiety, restlessness, emotional lability, "electrical zap" sensation through head -Receptors/ Enzymes: Selective for serotonin receptor

Mirtazapine Serotonin (5-HT2 and 5-HT3) antagonist and alpha-2 antagonist

-Mechanism of Action: 5HT2 antagonist but also blocks the 5HT3 receptor and also increases both norephinephrine and serotonin release; blocks the presynaptic a-2 autoreceptor and increases release of both serotonin and norepinephrine; dual mechanism of action (serotonergic and noradrenergic) -Benefits: a lower rate of sexual side-effects (due to serotonin-blockade); doesn't interfere with sleep architecture; Low anticholingeric and anti- a-1 adrenergic receptors, leading to an improved side-effect profile; Not cardiotoxic, and safe in overdose; dual MOA might translate into a slightly higher remission rate -Side Effects: significant antihistaminergic activity and so is both sedating and can cause significant weight gain *The "unique" mechanism of action is that this drug increases intrasynaptic levels of serotonin and norepinephrine by increasing their RELEASE from the presynaptic neuron, rather than just inhibiting their reuptake

Trazodone Serotonin (5-HT2) antagonist/reuptake inhibitors

-Mechanism of Action: A weak 5HT reuptake inhibitor, but a direct 5-HT2 antagonist; Used to treat depression (or depression with anxiety); The reuptake inhibitor increases the serotonin in the synapse; The 5-HT2 antagonist keeps the receptors from being indirectly downregulated due to increase synaptic serotonin; Also acts at postsynaptic alpha-1 receptor (orthostatic hypotension) -Benefits: By directly affecting the receptor, it avoids side-effects related to raising the overall level of serotonin (nervousness, GI symptoms and sexual problems); useful in agitated demented patients; used as hypnotic; Doesn't have anticholinergic side-effects and overall safe in cardiac patients; safe in overdose -Side Effects: Can cause orthostatic hypotension and sedation; Priapism (erect penis); sedation

Buspirone Serotonin (5HT1A) partial agonist

-Mechanism of Action: Directly interacts with presynaptic and postsynaptic serotonin 5HT1A receptors, where it is a partial agonist (precise mechanism of action remains unclear); POST-SYNAPTIC RECEPTORS: At LOW doses, competes with serotonin receptors and has less activity so acts like an ANTAGONIST (used for anxiety); At HIGH doses, it reaches more receptors and acts like a WEAK AGONIST (uses for serotonin depletion in depression) PRE SYNAPTIC RECEPTORS: 5HT1A autoreceptors decrease serotonin release through feedback inhibition - so this drug can act as an autoreceptor agonist and slow neuronal firing (decreasing serotonin release - quiet neuron for anxiety); OR chronic stimulation by drug can desensitize neuron and enhance serotonin output (for depression) -Benefits: Antianxiety effects at lower doses (15-30 mg/day) but also antidepressant properties when used at higher doses -Side Effects: Relatively benign side-effect profile (dizziness, nausea, headache, nervousness, lightheadedness or excitement)

Stimulant Agents (Monoamine Releasing Agents) (Includes: Dextroamphetamine (Dexedrine) Methylphenidate (Ritalin, Concerta, Metadate) Pemoline (Cylert) Amphetamine Mixture (Adderall)

-Mechanism of Action: Increase synaptic release of dopamine (also NE and 5HT to some extent) -Benefits: Increase attention, concentration, energy, and motivation; Effect is RAPID; Their antidepressant effects may be short-lived -Side Effects: Headache, appetite suppression, nervousness, and insomnia; At higher doses, their dopaminergic effect can lead to psychosis (RARE); Dextroamphetamine and methylphenidate are controlled substances. However, no reports of patients being treated for depression becoming addicted to these agents or using them in an abusive way

Nefazodone Serotonin (5-HT2) antagonist/reuptake inhibitors

-Mechanism of Action: Similar to trazodone but modified to decrease the alpha-adrenergic antagonist effect -Benefits: Less sedating and doesn't cause orthostatic hypotension or priapism; Doesn't cause the anxiety, restlessness, and sexual side-effects that the SSRIs do, (avoids increased serotonin); Isn't cardiotoxic. Safe in overdose -Side Effects: sedation, weakness, headache, dry mouth, nausea, and constipation, but these effects are much less than what is seen with tertiary TCAs; higher rate of liver failure

Bupropion (aka Wellbutrin) Dopamine-Norepinephrine Reuptake Inhibitor (DNRI)

-Mechanism: Inhibits NE reuptake (and Dopamine to lesser extent) -Benefits: Can have stimulant effect in depressed patients; also can be used to ADHD; can treat nicotine dependence; no anticholinergic or antihistaminergic side effects -Side Effects: No benefit for comorbid OCD or comorbid panic disorder or comorbid impulse-control problems (benefit is less "broad-spectrum" than with the SSRIs); sexual side effects minimal; risks of seizures

Describe the prevalence of post-stroke depression and which stroke locations are most commonly associated with post-stroke depression.

-Post-stroke depression is seen in 30-50% of stroke patients. - Most common stroke locations associated with post-stroke depression are left frontal and left basal ganglia regions. **Quick review: Stress Thermostat problems - Hippocampus Post-Stroke depression - L Frontal and L Basal Ganglia

Minimizing Tyramine Reaction:

1) Selective MAO-B inhibition: Selegiline, or deprenyl (Eldepryl) -requires high doses for antidepressant effects, and loses MAO A/B specificity at those doses -transdermal patch (Ensam) can interfere less with MAO-A in gut/liver by avoiding first pass metabolism 2) Reversible MAOIs (RIMA): moclobemide (not approved in US) - tyramine competes RIMA off of MAO, avoiding "cheese reaction"

4 Key Components of Stress Thermostat:

(1) Glucocorticoid system -- recall glucocorticoids are secreted from the adrenal system as part of the "fight or flight" response to brief stress Adaptive/protective -- aid survival when secreted transiently (increase CO, stimulate immunity, mobilize energy) Maladaptive in chronic/excessive glucocorticoid secretion -- contribute to diabetes, hypertension, ulcers, immunosuppression Neurotoxic -- excessive amts can also cause dendritic atrophy, impaired neurogenesis, neuron death. Hippocampal neurons are esp. susceptible!!! handout mentions that both PTSD and Major Depressive Disorder pts have loss of hippocampal volume (ie stress affects hippocampus a lot) (2) Excitatory AA system -- recall glutamate is an excitatory NT and binds NMDARs, allowing calcium influx Adaptive -- synaptic plasticity/LTP/memory (every neuron in the brain has Glu receptors) Maladaptive -- excessive excitation is "too much of a good thing" --> neuropath! The balance btw excitation and inhibition is what leads to neuronal plasticity. Neurotoxic -- too much calcium influx and you excite the neuron to death with free radical production (seen in stroke, Parkinson's, HD, Alzheimer's, ALS). Hippocampus is sensitive again. (Not a coincidence though: excessive glucocorticoids increase hippocampal [glutamate] and sensitivity. (positive feedback of death)) can't find stuff on GABA/inhibitory synapses in resources + SMD15 googledoc... will hopefully add after class. welps, there didn't seem to be any discussion of this in class. will email dr cohen. (3) Neurotrophic system -- recall neurotrophic factors are released by neurons to affect activity of neighboring neurons, and are involved in neurogenesis (telling neurons to grow/survive)- while the absence of neurotrophins essentially signals other neurons to die (favoring the growth of certain synapses) Adaptive -- help neurons survive, favor the growth of certain synapses- mediates synaptic plasticity. Maladaptive/neurotoxic -- inadequate neurotrophic activity (cannot overcome glutamate toxicity, which competes for the neurons "attention"). Note that excessive glucocorticoids inhibit release of neurotrophic factors and interfere with their effectiveness. This system has close connections to the monoamine system -- e.g. antidepressants (monoamine system) stimulate downstream effects like increasing txn of neurotrophic proteins. Specifically, antidepressants increase hippocampal levels of CREB and BDNF (CREB is the cAMP response-element binding protein which is a TXn factor that regulates neuronal gene expression. BDNF is Brain-Derived Neurotrophic Factor, a gene that codes for neurotrophins.) (4) Endocrine system -- (doesn't say much except:) dysregulation of hypothalamic-pituitary-adrenal (HPA) axis (which BTW involves glucocorticoids), hypothalamic-pituitary-thyroid (HPT) axis, and hypothalamic-growth hormone axis = associated with depression ***Summary: Our body's way of adapting to stress sometimes goes awry and can contribute to us getting depressed. Glucocorticoids can directly cause neuronal death and affect plasticity; and indirectly affect plasticity by lowering neurotrophin levels; lack of neurotrophic factors in turn causes neurons to die/prune. Glutamate can excite a neuron to death (due to too much Ca++). Imbalances in the hormonal axes are likely centrally mediated (ie partially caused by NT imbalance, which itself is a response to stress). The hippocampus is especially vulnerable. <-- This is great! Agree- thank you

Psychodynamic Model

*Focuses on unconscious, look to the past to get perspective on current problems *goal is to provide a corrective emotional experience a) postulates that depressive symptoms reflect an internal, unconscious conflict i) Classical Psychoanalytic Theory - depression results from the loss of an ambivalently loved object and from anger turned inward. The theory postulates that depressed patients have a hard time expressing their anger towards others, and therefore turn it inward against themselves. In this model, early loss directly causes depression. ii) Object Relations Theory - this theory places the emphasis on disturbed interpersonal relations in early life, usually involving disappointment or loss. These disturbed relations cause the patient to become depressed. In this mode, early loss indirectly causes depression by contributing to character pathology. Ex: we end up mirroring the relationship we have with our parents on the relationship we have with other people later in life (guilty!) -introjection and identification -deprivation of a parent or inconsistency leads to increased attachment -Insecure attachments earlier in life cause increased vulnerability to a stress, including low self-esteem, anxiety, and depression in future relationships b) Psychotherapies (provide a "corrective emotional experience") i) Classical psychoanalytic psychotherapy - intensive. -Frequent patient-therapist interactions (several times/week). -Broad, ambitious goals. -Attempts to tap into patient's unconscious thoughts by discouraging censoring of unacceptable or embarrassing material (free association). -Therapist remains neutral. -interpretation of transference -avoidance of acting on countertransference ii) short-term therapies (ex: IPT= interpersonal psychotherapy) -Greater degree of participation by therapist (active collaboration). -Scope of therapy is more limited - focus only on certain issues, hit them hard, hit them fast and then stop therapy -Free association is discouraged (can contribute to regression and acting out). -Transference is more explicitly addressed from the outset of therapy. -Interpersonal Psychotherapy (IPT) - Emphasizes depression as a medical illness with biological and psychological roots; encourages medication and psychotherapy. - emphasis on recent history: unresolved grief, interpersonal disputes, role transitions, and interpersonal deficits

Describe how major depressive disorder may present differently in children and teenagers.

Increasing age is a risk factor for developing mood disorder. Children -- present with prominent somatic complaints, irritability, social withdrawal. less likely to have sleep disturbance, wt loss, delusions. They're less prone to say "I feel sad." It manifests in other ways (low grades, etc.) Adolescents -- appear to present like adults with major depressive disorder. Both commonly occur with comorbid conditions like Generalized Anxiety Disorder (adults/teens), Separation Anxiety Disorder (children), Conduct Disorder (children), Substance-related Disorders (adults/teens). Avg length of depressive episode in both is ~9 months.

MAO Inhibitors:

Irreversible Inhibitors of MAO A and B: Phenelzine (Nardil) Tranylcypromine (Parnate) Reversible Inhibitors of MAO A (RIMAs): Moclobemide

Serotonin (5-HT2 and 5-HT3) antagonist and alpha-2 antagonist

Mirtazepine (Remeron - Rem for REM sleep)

Describe the monoamine theory of depression and its limitations. With regard to the latter, list other, non-monoamine systems that also are impaired. Describe how antidepressants that act on monoamine systems can indirectly affect these non-monamine systems. Describe how this relationship may help explain the delay of up to several weeks between the initiation of an antidepressant medication and the onset of clinical antidepressant effect.

Monoamine hypothesis - clinical depression is the result of a monoamine deficiency -evidence in favor of this hypothesis: (a) MAOIs and TCAs (tricyclic antidepressants) successfully treat depression (both increase brain levels of serotonin and norepinephrine - albeit via different mechanisms!). (MAOIs inhibit breakdown of NE and 5-HT, whereas TCAs inhibit the NT reuptake from synaptic cleft.) (b) Drugs that deplete biogenic amines cause depression in about 15% of people -limitations of hypothesis- (a) while some mood disorder patients do indeed have decreased CSF levels of monoamine metabolites, others have shown no change or an increase. (b) most research subjects with depleted biogenic amines do NOT become depressed (c) synaptic monoamine levels rise rapidly on therapy, but clinical response doesn't occur for up to several weeks Non-monoamine Systems also impaired in depression: Glucocorticoid system Excitatory amino acid system (Glutamate) Neurotrophic system Endocrine system Antidepressants cause persistent increases in brain monoamines, which stimulate post-synaptic monoamine receptors, which trigger second messenger transduction systems. For the Neurotrophic system, the transcription factor is cAMP response-element binding protein (CREB), which activates neurotrophic genes. I will expand more on this after class. The handout discusses only how monoamines affect the neurotrophic system, and does not go into how it contributes to the delay. Answer to third part of LO: How antidepressants act indirectly on monoamine systems and how this explains the delay in medication work: Point 1: Because of the limitations named above that show there isn't a direct correlation between levels of monoamine in the CSF and depressed state, scientists thought that the "clinical response to antidepressant medication isn't caused by increases in monoamine levels per se but by later-onset adaptations in brain functioning to this shift in monoamine homeostasis." In other words, its not the amount of NT itself but the downstream effects that correlate with us being depressed or not. Point 2: From the conclusion highlighted above, scientists came up with the Neuroreceptor Hypothesis of Depression: a modified monoamine hypothesis, where instead of focusing on absolute levels of NTs, they noticed that the level of receptors was modified with antidepressants- but that it took a few weeks- which corresponds with the few weeks of delay that meds take to start working clinically!!! Specifically, they saw a downregulation of the Beta-adrenergic NE receptor and the 5-HT2A serotonin receptor. Point 3: Animal models have shown that administering antidepressants leads to increased hippocampal levels of CREB (a cAMP dependent protein) with a delay that is similar to the clinical response delay seen in humans on antidepressants. -animal models of ECT (electroconvulsive therapy) show hippocampal BDNF expression (gene TXn factor), again with a comparable clinical response delay.

Depression and neuronal plasticity

Normally, our brain responds to life events such that we can interact and change with our environment (adaptive). This can happen either through altering [NT] or [neuroreceptors], # or complexity of dendritic branches, strength/weakness of synaptic connections, and/or influencing the amount of neurotrophic/neurotoxic substances released (allowing for fertilizing of some synapses and pruning of others -- aka neuronal plasticity). These factors are controlled by genes (so someone can be genetically predisposed/vulnerable to certain kinds of adaptation). But sometimes - in face of adverse life experiences, both single events and chronic stressors - our "stress thermostat" becomes set too high for too long (maladaptive).

Describe the stress diathesis model of mood disorder and define the "kindling theory."

The stress diathesis model is an integrative theory that combines genetic traits and life experiences to explain why some people get depressed. Inborn/hereditary/constitutional factors, gender, and early loss all contribute to "affective temperament", which can make certain individuals more vulnerable to particular life stressors. A combination of temperament and stress can lead to limbic-diencephalic dysfunction (aka dysfunction of the communication between thalamus and limbic system components, such as insular cortex), which can trigger an affective episode. Kindling Model - Initial episodes of affective disorders have long intervals between them, but they get progressively shorter. Psychosocial stressors appear to be more important in the earlier episodes than later in the course of the illness. (ie - initial episodes seem to have direct triggers. Eventually, episodes become autonomous and turn into a mood disorder.) Early (social) triggers kindle the fire of the illness until it burns on its own.<< great statement of analogy. Thats it. This "kindling," in literal terms, means: (a) even small life stressors can begin to trigger episodes; (b) episodes can start arising spontaneously; (c) stress causes micro-anatomical changes to take place (dendritic branching patterns, etc) (d) kindling affects gene transcription (ex: c-fos oncogene levels increase with life stressors)

Tricyclics

Tricyclic Antidepressants -ipramine, -iptyline Tertiary Amine Tricyclics: Imipramine (Tofranil) Amitriptyline (Elavil) Doxepin (Sinequan) Trimipramine (Surmontil) Clomipramine (Anafranil) Secondary Amine Tricyclics: Desipramine (Norpramin) Nortriptyline (Pamelor) Protriptyline (Vivactil) Maprotiline (Ludiomil)

Be able to counsel a patient who has had 1, 2, or 3 past major depressive episodes in major depressive disorder with regard to their likely risk of having a subsequent episode of illness and the implications of this with regard to whether to discontinue treatment versus continue maintenance treatment over the longer-term.

Up to 85% of depressed patients experience multiple episodes of illness. First episode is usually associated with a stressful life event, but eventually the mood disorder progresses independent of life events (Kindling Theory? LO13). Duration of episodes increases while duration between episodes decreases. Dr Cohen says he wants you to know these stats: In absence of tx, 50% pts will recur after 1 major depressive episode After 2 episodes --> recurrence is 70% After 3 episodes --> recurrence is inevitable (90%)! In a 20yr period, a patient averages 5-6 depressive episodes. Counseling: prefer to not discontinue tx (continue maintenance therapy)

Serotonin-Norepinephrine Reuptake Inhibitor (SNRI):

Venlafaxine (Effexor) Duloxetine (Cymbalta)

Describe augmentation strategies, switching strategies, and combination strategies. If presented with a case of a patient who has been treated with one antidepressant with either limited or no benefit, describe how you might decide to either switch to a different agent or add a second agent and how you would justify the choice based on mechanism of action.

a First need to know the stage of treatment i Defined by patient's current degree of symptom severity ii Five R's = response, relapse, remission, recurrence, recovery iii b Acute Phase i Physician makes diagnosis and decides treatment strategy ii Physician considers: 1 The patient's risk of becoming delirious 2 The patient's risk of overdosing on medicine 3 Whether the patient has responded (or failed to respond) to particular types of medication or psychotherapy in the past 4 Whether the patient has a bipolar diathesis that places her at greater risk of becoming manic or of rapid cycling 5 Whether family members who have had similar symptoms have responded to particular forms of treatments 6 The presence of comorbid medical or psychiatric conditions iii Physician guesses (that's what this all seems like) based on symptoms and above considerations which class of medicine will have the most benefits to patient iv Goal is to help patient adhere to the treatment c If patient has not responded to a single agent, there are several options: i Increase dose ii Switch to a different medication iii Combine two classes of medications iv Augment the first medication with a second medication 1 Difference between "combine" and "augment - combine means using two primary treatments; augment means adding a second medication that has lesser efficacy when used as monotherapy but can give the primary medication a "boost". a Example of augmenting: add lithium (calming agent), thyroid hormone, a stimulant, or an atypical antipsychotic medication in treating depression v What to consider: 1 Has the patient demonstrated "some" response to the first medication (so maybe just increase dose or augment; if not then switch or combine) 2 Is the patient willing to take more than one antidepressant (if yes then augment or combine; if no then increase dose or switch) 3 Is the patient able to withstand adverse drug reactions that might arise 4 If patient is already experiencing significant side effects, then probably switch vi Know that there is a potential for pharmokinetic and pharmodynamic interactions when using combination strategy d Response = decrease in clinically significant symptoms following the initiation of treatment e Remission = if response to treatment lasts for at least 1-3 months, then the patient is considered to be in remission i Patient has entered the continuation phase of therapy (lasts between 4 and 9 months, and is typically 6 months) 1 Goal - to monitor for completeness of response, for relapse, and for any late-appearing side effects f Relapse = return of some symptoms during or upon cessation of treatment i Avoid rapid discontinuation of medication (instead use a slow taper) g Recovered = patient does not relapse and remains in a more extended state of clinical remission i Entered the maintenance phase of therapy 1 Goal - to prevent future episodes from occurring 2 If symptoms return in this phase it is considered a "recurrence" (as opposed to relapse) 3 Watch closely for signs of "roughening" of mood (patient might complain of difficulty sleeping, mild fatigue, increase procrastination)

Stimulant agents

b These are still used for treatment of depression, particularly with medically ill patients as they are generally safe and have rapid onset. Also, they are used to combat the "apathy" associated with SSRI use. And they are often used as antidepressant augmenting agents, rather than as monotherapy (so used in combo with other drugs instead of just alone). Sometimes they are used to treat apathy and impaired concentration in patients with subcortical dementia, TBI, or stroke. One reason they may not be approved for depression is because their antidepressant effects are very short-lived.

Dysthymic Disorder

i at least 2 years of continuous depressed mood and at least 2 additional depressive symptoms ii does not meet full criteria for Major Depressive Episode iii Chronic lower grade depression, characterized by nihilism ("existence is senseless and useless") and pessimism iv Double depression = major depressive episode superimposed on dysthymic disorder

Major Depressive Disorder

i more than 1 major depressive episodes (>2wks of depressed mood or anhedonia, + 4 associated depressive symptoms) (anhedonia= inability to experience pleasure from activities previously found enjoyable) ii Five (or more) of the following symptoms over a 2-week period; at least one of the symptoms is either (1) depressed mood or (2) anhedonia 1 associated symptoms of depression = SIG E CAPS (Sleep changes, decreased Interest in activities, Guilt, diminished Energy, decreased Concentration, Appetite changes, Psychomotor retardation, Suicidal ideation) iii Not due to Bipolar Mixed Episode iv Clinically significant impairment v Not due to substance use or general medical condition vi Not due to bereavement *5 or more SIGECAPS symptoms over a 2 week period not due to other disorders or causes

Bipolar II Disorder

i one or more major depressive episodes and at least one hypomanic episode (patient never has full blown manic or mixed episode) ii hypomania = Not severe enough to cause marked impairment in social or occupational functioning, or to necessitate hospitalization, and there are no psychotic features ***The major difference between Bipolar I and Bipolar II is the grade of mania "how high the high is". The grade of depression may be the exact same! If you have full on Mania - Bipolar I If you have hypomania - Bipolar II

Bipolar I Disorder

i one or more manic or mixed episodes (mixed episode = meets criteria for depression and mania simultaneously) ii no, don't need to have depressive symptoms, but FA says depressive symptoms always occur eventually iii Manic episode (>3 of the following): manics DIG FAST 1 distractibility 2 irresponsibility (hedonistic) 3 grandiostic 4 flight of ideas 5 increase psychomotor Agitation/goal directed Activity 6 less Sleep 7 Talkativeness

Serotonin Syndrome:

overactivation of central 5-HT receptors --> mild and severe side effects Mild effects: abdominal pain, diarrhea, sweating, fever, tachycardia, hypertension. delirium, myoclonus, irritability, hostility, mood change Severe effects: hyperpyrexia, cardiovascular shock, death Consequences: discontinue MAOIs 2 weeks before starting SSRI (and stop SSRI 5 half lives before starting MAOI); avoid combinations with opiates and amphetamines Why aren't they used more often? Risky cardiovascular side effects, difficult diet to maintain

Cyclothymic DIsorder

■ at least two years of periods of hypomanic symptoms and dysthymia-level symptoms but no full-blown depressive or manic episodes ■ low grade depression and low grade mania

Substance Induced Mood Disorders

■ can be caused by intoxication or withdrawal of a substance ■ substance could be illicit drugs, prescribed medications or over the counter meds ■ common meds that can cause mood symptoms include: ● anesthetics, analgesics ● anticholinergics ● anticonvulsants ● antihypertensives ● antiparkinsonian meds ● anti-ulcer meds (H2-blockers) ● cardiac medications, (esp. β-adrenergic antagonists) ● isotretinoin (Accutane) ● oral contraceptives ● muscle relaxants ● steroids ● sulfonamides ■ high doses of reserpine (antihypertensive), corticosteroids, and anabolic steroids are especially likely to cause depressive symptoms

endogenous vs. reactive depression

■ endogenous depression = no recent stressors and prominent vegetative symptoms (problems with basic bodily processes, such as eating, sleeping, feeling pleasure, and elimination) ● biological depression ■ reactive depression = recent stressors, like a significant loss, and fewer vegetative symptoms ● psychological depression ■ problem: determining if the stressor is the cause (people with Major Depressive Disorder also report recent stressors prior to their depression) ● basically, everyone experiences stressors and it is hard to determine causality ■ dichotomy influenced distinction between Major Depressive Disorder and Adjustment Disorder

Mood Disorder due to General Medical Condition

■ medical conditions can cause pathologic mood changes, including: ● degenerative neurological conditions (Parkinson's, Huntington's) ● cerebrovascular disease (strokes) ● metabolic conditions (B12 deficiency) ● endocrine conditions (hyper/hypo- thyroidism, parathyroidism, etc.) ● autoimmune conditions (lupus) ● infections (hepatitis, HIV) ● certain cancers (pancreatic carcinoma)

primary vs. secondary depression

■ primary depression = "idiopathic" or "psychogenic" depression (no apparent etiology) ■ secondary depression = has a medical or "organic" etiology, such as hypothyroidism or stroke ● problem: begs the question of ultimate etiology prematurely (there could be an underlying medical cause that is not apparent at the time) ○ ignores the fact that people who suffer from "idiopathic" depression and those that suffer from an "organic" etiology may be experiencing similar pathologic changes (and thus could benefit from similar treatments) ■ dichotomy influenced category of Mood Disorders due to general Medical conditions ○ personality traits, biologic factors and life events are not easy to separate and it can be too simplistic to make these dichotomous designations

psychotic vs. neurotic depression

■ psychotic depression = acute severe depression ■ neurotic depression = more chronic and "characterologic" ■ Problem: continuum of illness, both longitudinally (ie patients with lifetime sadness are more likely to experience acute depressive episodes) and genetically ■ dichotomy Influenced distinction between major depressive disorder (analogous to psychotic) and dysthymic disorder (analogous to neurotic; milder and more chronic form of depression associated with temperament)

Distinguish between Major Depressive Disorder and Adjustment Disorder with Depressed Mood. If presented with a case vignette, be able to assign the most likely diagnosis.

○ Adjustment disorder with depressed mood: defined as the development of emotional or behavioral symptoms in response to an identifiable stressor occurring within 3 months of the onset of the stressor ■ distress in excess of what would be expected or significant impairment in social/occupational functioning ■ symptoms don't meet the criteria for any other specific Axis I disorder and are not due to bereavement ■ once the stressor has terminated, the symptoms do not persist for more than an additional 6 months ■ its a diagnosis of exclusion ○ DISTINCTION from Major Depression Disorder: Adjustment disorder with depressed mood is milder (aka does not have multiple SIG E CAPS Sx) and course of symptoms is limited by appearance/disappearance of a particular stressor (6 month grace period)

Describe how major depressive disorder may present differently in the elderly

○ depression is less common in the elderly than in the general population ■ prevalence of depression of those living in community: 1-2% (with another 2% having dysthymic symptoms) ■ in hospitals and nursing homes: 12% with another 25%-30% having dysthymic symptoms ■ i.e. elderly in nursing homes more likely to be depressed ○ presentation ■ more anxiety and somatic complaints, weight loss, and anhedonia ■ less guilt or lowered self esteem ■ more likely to have psychotic symptoms ■ may be "subsyndromal" and therefore might not meet criteria for depression ■ Higher morbidity & mortality, even though lower incidence

Distinguish major depressive disorder from bereavement. If presented with a case vignette, be able to assign the most likely diagnosis.

○ major depressive symptoms are considered part of the normal grief response to death of someone ■ 10-20% of patients suffer from "severe, unremitting depression" during the year following the death of a spouse ○ some distinguishing factors between bereavement and major depressive disorder: ■ grieving patients without major depression generally don't display pathological changes in self-attitude or guilt ● they may experience survivor's guilt or regrets about things that could have been different before the loved one's death, but they do not generally describe themselves as bad people in general or worthless ■ grieving patients with severe psychomotor retardation or functional impairment likely have a superimposed major depressive episode ■ any hallucinations or delusions beyond the patient reporting very transiently having "heard" or "seen" the deceased are beyond the scope of normal grief and suggest the presence of a psychotic depression ■ sadness due to grief tends to be circumscribed and focuses on the deceased and is triggered by reminders of that person, whereas sadness from clinical depression can be about anything and everything (it is pervasive) and is not triggered by specific reminders (it can arise anytime = autonomous) ■ sadness due to grief tends to be self-limited and improves with time (usually several months) ■ patients who develop major depressive disorder after a loss tend to have a personal history or family history of depression

Describe the mechanism of action, potential benefits, and side effects associated with the serotonin-norepinephrine reuptake inhibitors (SNRIs), venlafaxine and duloxetine.

● Mechanism of action: inhibits uptake of serotonin and norepinephrine ○ low doses- resemble SSRI, but more noradrenergic effects at higher doses ● Potential benefits: resembles TCA in therapeutic effects, but without antihistamine, antiadrenergic, and anticholinergic effects ○ not cardiotoxic, safe in overdose! ○ Greater chance of total remission than with normal SSRI (45% of pts with SNRI, opposed to 35% of pts with SSRI) ● Side effects: resemble SSRIs, including sexual side effects ○ anxiety, nausea -Venlafaxine (Effexor) in particular: 10% of pts had increase in diastolic blood pressure -Duloxetine (Cymbalta) in particular: lower degree of sexual side effects, good for chronic/neuropathic pain pts

Depression mediated by neuronal plasticity in the stress thermostat:

4 key components: (1) glucocorticoid system (2) excitatory and inhibitory synapses: mediated by glutamate and GABA (3) neurotrophic factors (4) endocrine factors

Selective Norepinephrine Reuptake Inhibitor (NRI):

Atomoxiten (Strattera) [approved for ADHD] Reboxetine (Vestra)

Describe the prevalence of suicidality in children and adolescents treated with antidepressants versus placebo in clinical antidepressant trials.

Average risk of suicidality on antidepressants = 4% Average risk of suicidality on placebos = 2% *only relevant for children/adolescents (those less than 24 years old)

Dopamine-Norepinephrine Reuptake Inhibitor (DNRI):

Bupropion (Wellbutrin)

Serotonin (5HT1A) partial agonist

Buspirone (BuSpar)

Monoamine Releasing Agents ("Stimulants")

Dextroamphetamine (Dexedrine) Methylphenidate (Ritalin, Concerta, Metadate) Pemoline (Cylert) Amphetamine Mixture (Adderall)

Describe how it is possible that major depressive disorder can be approached from a dimensional model or from a disease model, and how research on the genetic and biological factors that contribute to depression could apply equally well to either model.

Dimensional model -- depressive personality spectrum Disease model -- depression is an abnormal state due to imbalance of brain chemistry (e.g. monoamine hypothesis, see LO#11) Research into genetic factors (mood disorders tend to show inheritance) and biological factors (e.g. CSF levels of monoamine metabolites) can apply to BOTH models: ● Dimensional -- disease model doesn't seem to always apply (see LO#11). perhaps there is a spectrum of how depressed someone is, and this depends on genetic/biological factors. ● Disease (kind of obvious) -- do you have low levels of serotonin? then you are more likely to become depressed!

Selective Serotonin Reuptake Inhibitors (SSRIs):

Fluoxetine (Prozac) Sertraline (Zoloft) Paroxetine (Paxil) Fluvoxamine (Luvox) Citalopram (Celexa) Escitalopram (Lexapro)