-A behavioral or psychological syndrome that occurs in an individual

-  The consequences of which are clinically significant distress (e.g. a painful symptom) or disability (e.g. impairment of function)

-  Must NOT be merely an expectable response to common stressors and losses (e.g. loss of a loved one) or a culturally sanctioned response to an event (e.g. trance states in religious rituals)

- That reflects an underlying psychobiological dysfunctions

-          That is not primarily the result of social deviance or conflict with society (referring to the communist countries where all dissenters are considered to have neurosis) 

-Major depressive Disorder & Dysthymia, Bipolar disorder

• Negative Emotionality
• Positive Emotionality
• Cognitive Processes
• Social Processes
• Arousal/regulatory systems

What are the 4 functions of the association cortex?

•    Emotion- most altered component in mood disorders
•    Cognition-recognition of self
•    Thought
•    Behavior

What NT changes in Alzheimer's disease and in what way?

dopamine, INCREASE 

*Only disease caused by an increase in NT

4 sites of serotonin in the body

•Enterochromaffin cells (90% of all 5-HT)-          found in the gut

•Platelets (actively transport and store    serotonin).

•Raphe magnus nuclei of brainstem (part of  endogenous analgesic system)

•Around blood vessels

• Phenoxybenzamine
• Cyproheptadine-carcinoid and uticaria
• Ritanserin-reduce thromboxane, treatment of psychedelic drugs

• Cispride-GE reflux
• Tegaserod(partial)-IBS
• Morphine-Respiratory depression in Pre-Boetzinger complex

Life cycle for monoamine NTs like serotonin and NE

1. Synthesis
2. Packaging
3. release
4. reuptake
5. degradation

location of MAO_A and MAO_B

• MAO_A- brain, placenta, liver and gut
• MAOB^{-  brain, platelets, lymphocytes, and liver}

5 classes of antidepressants

1.     Selective Serotonin Reuptake Inhibitors (SSRIs) Block SERT

2.     Serotonin-Norepinephrine Reuptake Inhibitors

a.     Selective serotonin-norepinephrine reuptake inhibitors (SNRIs) Block SERT + NET

b.     Tricyclic Antidepressants (TCAs) Block SERT + NET + M + alpha1+ H1- block muscarinic, histamine, & α₁ receptors

3.    5-HT2A Antagonists  

4.     Tetra-/Uni- cyclic Block SERT + NET + 5-HT2/3 + alpha2 + H1- also block non CNS serotonin receptors, α₂ receptors, & histamine

5.   Monoamine oxidase inhibitors (MAOI).

Major Depressive- 2 months

Dysthymic- 2 years (chronic)

•≥Five symptoms nearly every day over 2-weeks

•At least one is  depressed mood or apathy /anhedonia.

1.Depressed mood (irritable in children) most of the day

2.Apathy or anhedonia

3.Weight loss/weight gain or anorexia/bulimia.

4.Fatigue or loss of energy

5.Insomnia or hypersomnia

6.Feelings of worthlessness /guilt  (DDx Normal grief)

7.Suicidal ideation

8.Impairment in functioning  (social or occupational)

9. Psychomotor agitation /retardation

10.Diminished ability to think or concentrate, or indecisiveness

Fluoxetine (Prozac);

Fluvoxamine (Luvox)

Paroxetine (Paxil)

Sertaline (Zoloft)

Citalopram (Celexa)

• Mental disorders
• Major Depression
• Anxiety
• Panic
• Obsessive Compulsive
• Posttraumatic Stress
• Eating (Bulimia)
•  
• Perimenopausal vasomotor symptoms 

• Drug interactions occur when an MAOI is given with an SSRI or after recently stopping SSRI – fluoxetine requires 1-3 month delay before initiating treatment with an MAOI

•Relatively well tolerated

• Adverse effects of SSRI mediated via 5-HT₃

    • GIT (nausea/ diarrhea)

    • Sexual dysfunction (anorgasmia)

•Adverse effects of SSTI mediated via 5-HT_2C

 _{• Restlessness, Insomnia}

• Beneficial effects may require 2-3 weeks

•May work when TCA’s fail

• In general, all have long t ½

•CYP2D6 metabolizes fluoxetine→ norfluoxetine( inc t_1/2)
•CYP 2D6 metabolizes codeine → morphine
• Concomitant administration of fluoxetine and codeine decreases the analgesic effect of codeine

Mechanism of action of Serotonin-NE Reuptake Inhibitors (SNRIs)

and 

Selective Serotonin-NE reuptake Inhibitors

(SSNERIs)

Venlafaxine (Effexor)

• Major Depression

• Perimenopausal vasomotor symptoms

• Chronic Pain

• Venlafaxine: Sedation, Hypertension

• Amitryptaline-prototype drug
• Imipramine

• Major depressive disorder not responsive to other drugs

• Enuresis (bed-wetting)

• Panic disorder and agoraphobia

• Anxiety

• OCD (Cloipramine)-drug of choice

•Potent    anti - M

•Weak     anti α₁

•Weak     anti - H1

•Anti-M effects

   •Xerostomia

   •Decreased sweating

   •Constipation

   •Increased intraocular pressure

   •Blurred vision

   •Memory dysfunction (CNS)

•Anti-H1 effects

   •Sedation

   •Potentiation of CNS depressants

•Anti-alpha1 effects:

 •Hypotension

Cardiovascular effects:

•Elevated NE: Tachycardia

•Anti-α₁ effects

TCA contraindicated in:

• MI

• Congestive heart failure

• Orthostatic hypotension

• Advanced Cardiovascular disease 

Nefazodone (Serzone) and Trazodone

Bupropion (Wellbutrin)

and

Mirtazapine (Remeron)

• Block SERT + NET + 5-HT2/3 + alpha2 + H1

• Increased NE and Dopamine activity

Indications for Bupropion

• Major Depression
• Smoking cessation

Adverse affects of Bupropion

• Seizures 
• Agitation
• Insomnia

• Block SERT + NET + 5-HT2/3 +alpha2 + H1

• Increased NE & 5-HT release 

• Sedation
• Weight gain

MAO produces the most reactive free radical, •OH, which then reacts with any available molecule causing oxidative damage

• MAO is found in the outer mitochondrial membrane
• MAO_A in the gut
• MAO_B in the CNS and platelets

Substrates for enzyme but intermediates covalently bind to and inactivate MAO

Adverse effects of MAOIs

• CNS: Pro-psychotic; proconvulsive (due to ↑dopamine)
  • Hypomania, agitation, hallucination
  • Hyperpyrexia, hyperreflexia and convulsions
• Anti-α1
  • Orthostatic hypotension
• Anti-M:
  • Impotence, dry mouth and constipation
• PNS
  • Phenelzine can produce peripheral neuropathy 
• Rx - vitamin B6

• Most inhibitors irreversible (except moclobemide)

Clinical response:

• Clinical response correlates with 85% inhibition of

   platelet MAO_B. (This is a useful mechanism for           determining effectiveness of drug)

• Elevation of mood

MAOIs that inhibit MAO_A and MOA_B

• Phenelzine
• Tranycypromine

MAOI that inhibits only MAO_B? 

Adverse effects?

Selegiline

anxiety and insomnia

Mechanism of interaction with Tyramine and MAO_A inhibitor(or non-selective MAOI)

*Tyramine Effect

• Tyramine is a naturally occurring amine found in    cheese and other foods. 

• Tyramine is oxidized by MAO_A in the gut.

• Tyramine induces norepinephrine release from sympathetic neurons (sympathomimetic).

• When an MAOI_A is given, there is no way to breakdown Tyramine→ uninhibitied induced release of NE from sympathetic neurons

Symptoms of Tyramine effect

• Hypertension

• Severe occipital headache, temporal headache, neck    stiffness

• Diaphoresis, Mydriasis, Pallor

• Neuromuscular excitation, Palpitations, &/or chest pain

• Hyperthermia

Lower blood pressure

•Short-acting a1 blockers  phentolamine

•Vasodilator nitroprusside

•Ca2+ channel blocker  nifedipine

Lower body temperature

Prophylaxis:

•Advise patients not to take food containing tyramine.

•Use MAO_B inhibitors (Selegiline)

•Use reversible MAO_A inhibitors (Moclobemide).

• Serotonin syndrome occurs after a dose increase of MAOI or SSRI or after a addition of a second SSRI
• Idiosyncratic drug-induced complication of antidepressant therapy
• Serotonin receptors 5-HT_1A & 5-HT₂ are involved

• Akathisia-like restlessness
• Sweating, Shivering, Tremor
• Confusion/disorientation
• Hyperthermia
• Hypertension
• Muscle rigidity in the lower extremities, Penile erection
• Delirium, Seizures, Coma

• Cyproheptadine (5-HT₂ and H₁ antagonist) -  MOST EFFECTIVE antiserotonergic 
• Benzodiazepines are nonspecific serotonin antagonists – decrease patient discomfort and favor muscle relaxation
• Dantrolene- non-specific muscle relaxant (inhibits Ca²⁺release from SR), used occasionally in Serotonin syndrome.  Primary use in hyperthermia caused by excess Succinylcholine

Symptoms seen with the drug interaction of

MAOI+L-DOPA?

Symptoms seen with the drug interaction of

MAOI + TCA

Serotonin Syndrome

(because both drugs increase serotonin in your body)

• Stupor
• Rigidity
• Agitation
• Hyperthermia
• Death 

• General anesthetics, sedative/hypnosis
• Antihistamines, ethanol, analgesics
• Anticholinergics
• TCA

• Malignant hyperthermia
• cause:Inhalation anesthetics + succinylcholine

Tyramine reaction

cause: Tyramine + MAOI

Neuroleptic malignant syndrome 

cause: Antipsychotics

Serotonin syndrome or tyramine rxn

causes: SSRI+MAOI or Tyramine+MAOI

Serotonin Syndrome

causes: SSRI + MAOI

What are the types of Manic-Depressive disorders

(Bipolar)

• Type I: Depression with full mania
• Type II

• Mania
• Mood ranging from euphoria to irritability
• Insomnia
• Hyperactivity
• Racing thoughts
• Grandiosity
• Variable psychotic symptoms

 
Four episodes per year is called rapid cycling 

How do you diagnose Type I bipolar disorder

• Depression with full Mania
• Mania
  • Persistently elevated, expansive or   irritable mood.
  • Grandiosity, decreased need for sleep, talkativeness, racing thoughts, distractibility,psychomotor agitation, excessive involvement in pleasurable activities.
• Marked impairment of social or occupational function
• Duration >1 week.

•One major depressive episode

•No full manic episode

•One hypomanic episode

-Manic syndromes with mild to moderate severity

•Duration  >   4 days

mechanism of action of Lithium in the treatment of Biopolar Disorder

• Blocks NE release

•reduces hydrolysis of inositol phosphate, blocks Protein   Kinase C

•Alters metabolism of NT’s

•Does not exert psychotropic effects in normal state, but elicits adverse effects

• Acute treatment of manic phase

•6-12 month prophylactic treatement for both manic and  depression phases

At therapeutic levels (.8-1.2mM)

• Nephrogenic diabetes insipidus (↑serum osmolarity, ↓ urine osmolarity)- exam q.

• Hypothyroidism- goiter (↑TSH)

•Hyperparathyroidism

At Toxic levels (> 1.2- 1.5 mM)

• Narrow margin of safety

• Dose: Lithium carbonate 900-1500 mg/day up to 2400mg/day

• Serum level in fasting morning blood= .8-1.2mM

• Lithium
  • As carbonate, citrate, aspartate, oroate salts 
• Anticonvulsants
  • Valproate  (Depakote)
  • Lamotrigine (Lamictal)
  • Carbamazepine (Tegredol) 
• Atypical Antipsycotic
  • Olanzapine (Zyprexa)

• suicidal ideation
• depressive stupor
• neuroleptic malignant syndrome

• Advantage: immediate effect

• Complications: Memory loss and Muscle pain

Fenoprofen            - NSAID

Fentanyl                - Opioid Analgesic

Flurazepam            - Sedative (GABAA receptor agonist) - benzodiazepine

Flunitrazepam        - Sedative (GABAA receptor agonist) - benzodiazepine

Flumazenil              - Antidote for benzodiazepine overdose (GABAA  receptor antagonist)

Fluoxetine              - Antidepressant (SSRI)

Fluvoxamine          - Antidepressant (SSRI)

Phenelzine             - Antidepressant (Nonselective MAOI)

Fluphenazine         - Antipsychotic (D2 Receptor blocker)

A monoamine has one amino (-NH₃) group connected by -CH₂-CH₂ to an aromatic ring

Examples:  Serotonin

NE

Phenylalanine

        Tyrosine

        Tryptophan 

Thyroxine (T₄)

Triiodothyronine (T₃)

• Serotonin (5-HT)
• Histamine
• tyramine
• T3
• melatonin

• Dopamine
• NE
• Epinephrine

Serotonin creates a _________ signal and

transmits __________

Normal rate of neuronal depolariztion/repolarization

cycle

Tyrosine-3-monooxygenase (Tyrosine Hydroxylase)

cofactor: BH₄

enzyme: Aromatic L-Amino Acid Decarboxylase (AAD)

cofactor: Vitamin B₆

What enzyme and cofactor are needed to go from

 dopamine to NE?

enzyme: Dopamine hydroxylase

Cofactor: Vitamin C

What enzyme and cofactor are needed to go from

NE to Epi?

enzyme: Phenylethanolamine-N-methyltransferase

cofactor: S-adenosylmethionine