involves drastic mood swings from extreme highs to extreme lows and will be discussed at another time.

hypothyroidism

nutritional deficiencies

neurological and psychiatric disorders

Dysthymia - less severe, not disabling form; can be chronic (month - years); predisposes you to MDD

Seasonal affective disorder - alters circadian rhythm; sleep deprivation

Postpartum depression - 

A less severe, less disabling form of depression that shows a prolonged time course(months to years). Predisposes an individual to MDD.

Depression is often triggered by a combination of genetic, psychological and environmental factors.

low self-esteem

 women > men

age 25-44

substance abuse

heterogeneous 

For examples, there is some evidence that women experience depression differently than men. This along with the higher risk in women is suggestive of different etiologies. 

1. 5HT transporter (5-HTT, SERT) 

A polymorphism was identified in the promoter of SERT that is a 44 bp insertion/deletion. This affects expression of the gene with the short allele (S) producing less SERT than the L allele. S/S homozygotes are at greater risk of developing MDD.

2. Trp Hydroxylase-2 (TPH2):  A hypomorphic allele in the enzyme that catalyzes the rate-limiting step in 5HT synthesis in brain

3. Brain-derived Neuronotrophic Factor (BDNF): This protein regulates synaptic plasticity and neuronal survival/differentiation. It is reduced in hippocampus by stress

the efficacy of SSRIs and NRIs gave rise to the monoamine hypothesis, which states that depression is due serotonergic and noradrenergic hypofunction.

____has a role in behaviors such as attention and vigilance; also seems to be critically involved in the processes of hunger and satiety through innervation of the hypothalamus.

    The importance of monoamines is also underscored by the fact that _____can induce depression

Reserpine (rauwolfia serpentine) 

causes monoamines to be released from synaptic vesicles and destroyed, thus causing depletion of the neurotransmitters.

1. There is no specific brain region that controls mood.

2. Antidepressants take weeks to work, but since the concentrations of 5HT and NE increase immediately, that means that 5HT and NE presence are not all that is needed to achieve the antidepressant effects (needs neural remodeling?)

The delay in response is suggestive of a genomic response, that is, changes in gene regulation that alter the pattern of receptors and ion channels in the affected neurons. Another possibility is the delay occurs because structural changes occur, such as neuronal plasticity, and these take time (and genomic changes).

Limbic system and prefrontal cortex.  

Dysfunction of ____leads to inability to solve complex problems, lack of motivation, lack of focus, impulsivity and inappropriate social interactions.

Activation of the ____system is associated with pleasure, “warm fuzzy” feelings. Activation of _____is associated with anxiety, fear and anger.

hypothalamus 

 lateral hypothalamus = elicit a rage display

ventromedial hypothalamic nuclei =  elicits satisfaction.

The Dexamethasone Suppression Test has been used to test hypothalamic function in MDD. Treatment with dexamethasone would be expected to reduce ACTH levels and thereby cortisol levels. Some patients, termed nonresponders, do not suppress cortisol production upon dex treatment. The DST may be a way of separating patients into different groups, but the utility has yet to be demonstrated.

____is involved in inner emotions such as joy, anger, hope, fear, and anxiety, and applies emotion to cortical information.

____is best known for its role in memory consolidation. It has other roles including positional memory and timing mechanisms and inhibition of hypothalamic function.

This the so-called “reward center” which is activated by DA neurons located in ventral tegmentum. It responds to novelty and applies positive reinforcement to thoughts and actions.

This region of cortex functions to provide emotional awareness.

Cerebral metabolic rate of ____metabolism is lower in cortical regions making up this network in MDD. Antidepressant treatment can reverse the deficiency.

This adult neurogenesis is important for hippocampal function, such as formation of new memories. Many years ago, it was shown that elevated cortisol levels cause hippocampal atrophy (Cushing’s disease) and recent experiments have demonstrated that cortisol impairs hippocampal neurogenesis. Neuroinflammation also impairs neurogenesis. On the other hand, exercise and antidepressants enhance hippocampal neurogenesis and elevated BDNF levels mediate this enhancement. By itself, BDNF is an important regulator of hippocampal function. 

List the brand names:

fluoxetine

paroxetine

sertraline

citalopram

escitalopram

venlafaxine

desvenlafaxine

duloxetine

bupropion

mirtazapine

vilazodone

selegiline patch 

(a) fluoxetine – Prozac

(b) paroxetine – Paxil

(c) sertraline – Zoloft

(d) citalopram – Celexa

(e) escitalopram – Lexapro

(f) venlafaxine – Effexor

(g) desvenlafaxine – Pristiq

(h) duloxetine – Cymbalta

(i) bupropion – Wellbutrin

(j) mirtazapine – Remeron

(k) vilazodone – Viibryd

(l) selegiline patch – EmSam.

q  Diagnostic and Statistical Manual of Mental Disorders, 5^th Edition

q  Most widely accepted and important diagnostic reference used in the care of mentally ill patients

q  General information on all mental disorders recognized by the American Psychiatric Association

·         Age of onset

·         Clinical course

·         Complications

·         Predisposing factors

·         Prevalence

·         Differential diagnoses

·         Diagnostic criteria

Number of symptoms/time course required

q  Direct patient interview

q  Combined with other components of patient work-up (hx of illness, physical exam, appropriate lab work, medical/psych history) to give full picture of the presenting psychiatric problem

q  Appearance

·                                                      Age, dress, grooming, hygiene, use of cosmetics

·                                                      Facial expressions

·                                                      General state of physical health

q  Attitude

·      Cooperative, mute, hostile, paranoid, guarded, withdrawn

q  Motor Activity

·      Overactivity, underactivity, catatonia

q  Speech/Language/Eye Contact

·      Does speech flow in a logical goal-directed manner?

·      Blocking – stops speaking without any obvious reason (hallucinations/delusions intrude?)

·      Circumstantial – lacks clear direction but patient eventually answers question

·      Tangential – ultimate point is never made

·      Perservation – repetition of an answer to multiple questions

·      Flight of ideas – jumps from one idea to the next rapidly.

·      Pressured speech – talking very fast to where interviewer has difficulty interrupting.

q  Mood

·      Depressed, euphoric, euthymic

q  Affect

·      Appropriate, reactive, blunted, restricted, flat, labile

q  Thought content/process

·      Hallucinations, delusions, paranoia

·      Organized , answers thought-out, goal-directed

·      Disorganized, superficial

q  Insight/Judgment

·      Awareness of mental illness and impact of illness

·      Ability to make appropriate decisions

q  Neuropsychiatric Evaluation

·      Sensorium – level of consciousness

·      Attention and Concentration

·      Intelligence

·      Memory

·      Orientation

Medical Conditions that Cause Depression

- Hypothyroidism                                                        - Alzheimer’s disease

- ¯vitamin B12 or folate                                             - Parkinson’s disease

- Severe anemia                                                           - Malignant disease

- Infections                                                                  - Autoimmune disorders

- Post-stroke                                                                - Menopause

- Heart failure                                                              - Electrolyte imbalance

-Coronary artery disease

Substance Disorders that Cause Depression

-    Alcoholism                                                               - Marijuana use and dependence

-    Nicotine dependence                                               - Opiate abuse and dependence

-    Stimulant abuse and dependence

Medications that Cause Depression

Beta blockers                                                  - Benzodiazepines

- Opioids                                                                     - Clonidine

- Barbiturates                                                              - Anticonvulsants

- Reserpine                                                                  -Interferon

-    Oral contraceptives                                                  - Isotretinoin

S - How is your SLEEP?  How many hours?

I - Are you still INTERESTED in your normal daily activities?

G - Do you have feelings of - GUILT/worthlessness/hopelessness?

Describe your ENERGY.

C - Do you have problems with CONCENTRATION or memory?

A - How is your APPETITE?

P - Do you feel agitated or have problems with getting motivated? (PSYCHOMOTOR retardation/agitation)

S- Any thoughts of wanting to harm yourself? (SUICIDE)

q  Short-term studies have shown an increased risk of suicidal thinking and behavior with antidepressant therapy in people under the age of ____

Highest risk of suicidal behavior was found to be during the ____.

q  All antidepressants carry this black box warning.

Why is it important to treat depression?

q  Increases quality of life

q  Decreases suicide risk

q  Decreases morbidity and mortality of other disease states

5 Treatment Options for depression

q  Psychotherapy

q  Electroconvulsive Therapy (ECT)

q  Light Therapy

q  Vagal Nerve Stimulation

q  Pharmacotherapy

According to the American Psychiatric Association (APA) Treatment, what are the initial pharmaco treatment fo depression

o  Choose SSRI, SNRI, bupropion, or mirtazapine

o  Titrate to a therapeutic dose and assess for efficacy in 4-6 weeks

SSRIs:   Serotonin Selective  Reuptake  Inhibitors

               (e.g., fluoxetine, sertraline, paroxetine)

SNRIs:   Serotonin Norepiphrine Reuptake Inhibitors

 (e.g., duloxetine, venlafaxine)

Mirtazapine= Noradrenergic SpecificSerontonergicAntidpressants (NSSA)

Buproprion = Norepinephrine Dopamine  Reuptake Inhibitors (NDRI)

·         Partial Response

o  Step 1:    Increase dose if not at maximum dose

o  Step 2:    Add psychotherapy if patient is not already participating and agrees   AND/OR

§   Add augmentation agent

·      Modest to good evidence

o                        A non-MAOI antidepressant with a different mechanism of action

o                        Lithium

o                        Thyroid hormone (T3 or T4)

o                        2^nd generation antipsychotics

·      Less supporting evidence

o                        Folic acid

o                        Omega 3 Fatty Acids

o                        Anticonvulsant

o                        Stimulants

o  Discontinue the initial antidepressant and try another non-MAOI antidepressant

§   May switch to another drug within the same class or one with a different mechanism of action

o  MAOI should be reserved as last line therapy but should not be forgotten

For treatment of depression ____should be reserved as last line therapy but should not be forgotten

7 Factors Influencing Drug Selection

q  History or familial history of response

q  Concurrent diseases

q  Concurrent medications

q  Adverse effects

q  Compliance

q  Cost

q  Neurotransmitter specificity

Fluoxetine (Prozac)

Paroxetine (Paxil)

Sertraline (Zoloft)

Fluvoxamine (Luvox)

Citalopram (Celexa)

Escitalopram (Lexapro)

·         Serotonin adverse effects - GI side effects, sleep disturbances, initial agitation, anorexia, sexual dysfunction

 This SSRI holds a warning for prolonged QT interval – doses > 40mg not recommended and try to avoid CYP 2C19 inhibitors (e.g. omeprazole)

  Fluoxetine (prozac) , Fluvoxamine (Luvox), Sertraline (Zoloft), Escitalopram (Lexapro)

FFSE

Venlafaxine (Effexor)

Duloxetine (Cymbalta)

Levomilnacipran (Fetzima)

VDL

q  Norepinephrine adverse effects – tachycardia, elevated BP, insomnia, tremor, sweating, pseudo-anticholinergic adverse effects (urinary retention, dry mouth, constipation)

q  Serotonin side effects

____ is A SNRI associatedf with elevated LFT

____ is A SNRI associatedf with QT prolongation

Duloxetine (Cymbalta) = LFT

Venlafaxine (Effexor) = QT prolongation

Venlafaxine (Effexor)

·      Desvenlafaxine (Pristiq) – active metabolite of venlafaxine (more noradrenergic compared to venlafaxine)

Duloxetine (Cymbalta)

Levomilnacipran (Fetzima)

1. Avoid MAOI

2. other serotonergics

3. other sympathomimetics and stimulant - raise NE

4. Can decrease effects of antihypertensives

• Patients with apathy, low motivation
• Patients suffering from hypersomnia
• Obese patients
• Pain patients

Patients with HTN

Ptn with cardiovascular disease 

q  Decreases seizure threshold (higher than 450mg/day)

q  Norepinephrine adverse effects – tachycardia, HTN, insomnia, tremor, wt loss, sweating, pseudo-anticholinergic adverse effects (dry mouth, constipation, urinary retention)

q  Dopamine adverse effects – psychotic symptoms, bad dreams

1. Bupropion

2. TCAs

q  Decreases seizure threshold (higher than 450mg/day)

q  Norepinephrine adverse effects – tachycardia, HTN, insomnia, tremor, wt loss, sweating, pseudo-anticholinergic adverse effects (dry mouth, constipation, urinary retention)

q  Dopamine adverse effects – psychotic symptoms, bad dreams

q  Use with monoamine oxidase inhibitors is contraindicated

q  Use caution with medications that augment dopamine (Parkinson’s Meds)

q  Use caution with medications that increase NE levels

q  Use caution with other medications that lower seizure threshold

False - Sustained and Extended release products preferred

q  Extended release (XL) product is taken once daily in the morning.

q  Sustained release (SR) product is taken twice daily. Do not take pm dose right before bedtime.  Separate doses by at least 8 hours and do not exceed > 200mg per dose.

• No serotonin side effects       
• Smokers
• Patients with low motivation/energy
• Obese patients

• Patients predispose to seizures
• Anorexia Nervosa
• Cardiovascular disease

Secondary amines – nortriptyline (Pamelor), desipramine (Norpramin) 

Tertiary amines – amitriptyline (Elavil), imipramine (Tofranil), doxepin (Adapin), clomipramine (Anafranil)

q  Norepinephrine adverse effects – tachycardia, elevated BP

q  Serotonin adverse effects – GI upset, sexual dysfunction

q  Anticholinergic adverse effects (due to M1 blockade)

q  Sedation and weight gain (due to H1 blockade)

q  Orthostatic Hypotension (due to alpha-1 blockade)

q  Arrhythmias (due to Na+ and K+ channel blockade in the cardiac tissue)

q  Decreases seizure threshold

This class of antidepressants cause arrhythmia (due to Na+ and K+ channel blockade in the cardiac tissue) and Orthostatic Hypotension (due to alpha-1 blockade)

Imipramine(Tofranil)  and desipramine ((Norpramine)

    Withdrawal symptoms in the infant have been reported with this antidepressant class

• Patients with migraine headaches
• Patients with insomnia
• Patients with decreased appetite
• Patients with neuropathic pain

• History of arrhythmias
• Cardiac disease
• Elderly
• Suicidal patients
• Predisposed to seizures

q  Use with monoamine oxidase inhibitors is contraindicated

q  Sedating medications

q  Use caution with medications that increase NE

q  Use caution with other serotonergic medications

Decreases the effectiveness of clonidine

Less serotonin side effects

Patients with loss of appetite

Patients with insomnia

Obese patients

Patients with elevated cholesterol

Patients with hypersomnia

q  Use with other antidepressants is absolutely contraindicated

q  Use with other serotonergic medications is contraindicated

q  Use with other medications that increase NE and dopamine is contraindicated

q  May decrease the effect of clonidine and guanethidine

q  no longer a first line agent, absolutely contraindicated in patients who have difficulty understanding or remembering medication instructions.

q  Acute Phase:   6-10 weeks; Goal is to reach remission

q  Continuation Phase: 4-9 months after remission is achieved; Prevent relapse

q  Maintenance Phase: 12 months - ???? Prevent recurrences

q  symptoms of depression are no longer present

episode of depression, which occurs years after normal functioning returns

o  1^st episode (50% recurrence)

o  3 or more episodes (90% recurrence) – Lifetime management

  Elderly should be dosed at____ dose for ____ week(s) then increase to therapeutic dose if side effects are not seen.

qRemission is associated with ___ and ___

less disability;

lower risk of relapse

T/F: L-dopa is the active form of dopamine

Cardidopa: Inhibits the peripheral metabolism of L-dopa to dopamine, which increases amount of L-dopa

Sinemet = ___+ _____

Lodosyn = _____

Sinemet = carbidopa + L-dopa

Lodosyn = carbidopa only

Name the 3 peripheral NS enzyme inhibitor that increase dopamine.

Tolcapone & Entacapone = COMT inhibition

Carbidopa = AADC

Name the 3 central NS enzyme inhibitor that increase dopamine.

selegiline (low dose) & Rasagiline = MAO-B

Tolcapone = COMT

Indirect pathway (D2)

Direct pathway (D1) 

Activate direct pathway (D1)

Inactivate indirect pathway (D2)