DYSTHYMIA – Chronic depression, less severe but longer lasting symptoms.

HYPOMANIA – Patient experiences persistent and altering euphoric and irritable feelings along with all the associated emotions. May become very creative but lowers sense of risk.

Blockade of:

Tricyclic antidepressants inhibit transporters for amines (NE

& 5HT) which are located on the presynaptic plasma membrane & are responsible for reuptake of aminergic neurotransmitters from synaptic clefts into presynaptic cells. 

Inhibition of synaptic reuptake leads to increased levels of NE

& 5-HT in the synaptic cleft, which leads to stimulation of postsynaptic receptors (increased NE & 5HT neurotransmission)

Maprotilin

Desipramine

Protriptyline

Nortriptyline

AMitriptyline

Clomipramine

Imipramine

Paroxetine (Paxil)
Fluvoxamine (Luvox)
Sertraline (Zoloft)

Fluoxetine (Prozac)

Venlafaxine (Effexor)

Citalopram (Celexa)

Tertiary Amines

 Secondary Amines

At high (suicidal) Doses TCA‘s induce:

  Imipramine is partially metabolized todesipramine (below)

  Amitryptiline is partially metabolized to nortryptiline

Phenelzine (Nardil) 

Tranylcypromine (Parnate)

Moclobemide (investigational drug; approved in Europe)
  Reversible competitive inhibitor

1. MAOI works faster

2. Delayed downregulation of NE and 5-HT receptors - effect lasts longer

Because of these problems MAO-Is are

2nd choice drugs for patients who do not

respond well to _____ 

SSRIs:   Serotonin SelectiveReuptakeInhibitors

               (e.g., fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine)

SNRIs:   Serotonin NorepiphrineReuptakeInhibitors

                (e.g., duloxetine, venlafaxine)

NDRIs:   NorepinephrineDopamineReuptakeInhibitors

                 (e.g., bupropion)

NRIs:     NorepiphrineSelectiveReuptakeInhibitors

                 (e.g., atomoxetine, reboxetine)

SARIs:   Serotonin Antagonist ReuptakeInhibitors

                 (e.g., trazodone, nefazodone)

NaSSA:  NoradrenergicSpecificSerontonergicAntidpressants

                 (e.g., mirtazapine

Same efficacy but SSRI have better safety profile and no tyramine ("cheese syndrome) interaction.

Serotonin syndrome is higher in SSRI

T/F: SSRIs work well in patients with positive and negative affect

False: SSRIs work well in patients with negative affect

SSRI > MAOI > TCA > Lithium salts

Worst (potentially lethal) Combination: MAO inhibitors + SSRIs

SSRI

Mechanism: development of syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

  ADH (= vasopressin) is over-secreted Þ Enhanced   reabsorption of water and decreased serum   

           osmolality

Net Result: Disinhibits NE and DA

Increased NE & DA in PFC

Activating:Leads to Energizing and

Fatigue reducing effect

Good for Depressed patients with

reduced positive effect

    anorexia and antibulimia therapeutic

    actions at high doses

         May improve energy and motivation

         Weakly “activating”

         May be caused by weak M1  

         antagonism

          May contribute to efficacy

           against depression

     sexual dysfunction in males

                (e.g., GI upset, akathisia, restlessness, dizziness, tingling)

Mild CYP 2D6  inhibition(R)

Which SNRI has these properties:

Which SNRI has these properties:

• Has a poorly defined MOA
• 
  
•      Weak inhibitor of both NET          and DAT
•       Metabolites are more potent   NET & DAT inhibitors and are more conentrated in brain
• Goldilocks drug solution
•  CNS-activating & stimulating (proconvulsive in higher doses) 
• - Is also marketed as an anti-smoking drug (Zyban)
• - Metabolism via CYP 2D6!
•  

Which SNRI has these properties:

Novel atypical and sedative antidepressant (H1 and alpha 1 blocker)

Mostly inhibit 5-HT transport

substrate of CYP3A4

Antidepressant with strong sedative  (H1) properties

  - Potent antagonist of a2 (presynaptic), receptors →

enhances NE neurotransmission

- Is an antagonist at H1, 5-HT2 & 5-HT3 receptors

- Weight gain is a typical adverse effect

-  SSRI combined with 5HT 1A

partial agonist

   -  Improved mood within one

week

   -  No reduction in sexual

functioning

   -  Minimal or no weight gain

α2 receptor /Gi coupled receptor;

5-HT1B/1D receptor /Gi coupled receptor

Blockade of

Hyper-excitability by:

Pharmacokinetic Properties of Classical AEDs: – CYP Induction by ____, ___ and _____

CYP induction: phenobarbital, phenytoin, carbamazepine

CYP inhibition by valproic acid

skeletal, CNS, limb and orofacial                          

This AED causes: 

Ataxia, nervousness

Topiramate

Oxcarbazepine 

Lamotrigine

Felbamate 

    - modified Atkins diet

    - low glycemic index diet

False: Benzodiazepines (BZ) do not directly activate the GABA(A) receptor.

BZs potentiate the action of GABA → increase flux of Cl- (GABA-A receptors)  → more pronounced hyperpolarization → less excitable neurons

BZD

Barbiturates

Ethanol

Benzodiazepines are allosteric activators of GABA(A) receptors containing  a1, a2, a3 or a5 subunits; they do not bind to a4 & a6 subunits. 

ØGABA(A) receptors with a6 subunit are abundant in the cerebellum – an area involved in motor & balance coordination
Ø Ethanol binds well to the GABA(A) receptors with a4/6 subunits.
ØBenzodiazepines do not have much effect on motor coordination and  balance! but ethanol does.

a2  = anxiolytic

a1  = sedative/hypnotic/anticonvulsant/anterograde amnesia

flumazenil = competitive antagonist at benzodiazepine (not ethanol) binding site

 Thiopental (Pentothal) 

  Pentobarbital (Nembutal)

  Secobarbital (Seconal)

BZDs do not open the ion channel directly while barbiturates open them directly

False:

Benzodiazepines as the drugs of choice

Ramelteon (Rozerem) is used to treat insomnia - MT1 and MT2 agonists

CYP1A2 in cigarette smokers

Positivesymx of schizophrenia: presence of abnormal behaviors

Negative syx : absence of normal behavior found in healthy individuals

Cognitive syx:

Actions of classical antipyschotics on mesolimbic dopaminergic pathways in schizophrenia is it improves ___symptoms

positive  – reduces hallucinations

but  

Little or No Improvement

in Negative & Cognitive

Symptoms

1. extrapyramidal system  - control of motions
2. Tardive dyskinesia

D2 blockage- antipsychotic, extrapyramidal sx; hyperprolactinemia

H1 blockage- weight gain; drowsiness

M1 blockage - constipation; blurred vision; dry mouth; drowsiness

and alpha-1 receptor blockage - hypotension; dizziness; drowsiness

Thioridazine (Mellaril)

Fluphenazine (Prolixin)

a) D2 receptors are blocked & negative inhibitory feedback on presynaptic release is compromised

b) other DA receptors are ~stimulated

c) overall reduction in DA neurotransmission is  blunted. 

Only partially reduced or unchanged

a) D2 receptors are blocked & there is limited  negative feedback

b) Eventually, DA storage & release overwhelmed or depolarization blockade comprises activity

 c) DA neurotransmission is further decreased

Pseudoparkinsonism 

Bradykinesia, rigidity, tremor, face mask, shuffling gait

  Dystonia

Spasm of muscles of face and neck

Akathesia

Subjective and objective restlessness; Inability to sit still

Tardive Dyskinesia

Stereotyped, repetitive abnormal 

Other Adverse Effects

            Dyslipidemia(Elevated TG, Chol), Diabetes, Metabolic Syndrome,        

Dermatologic Reactions (Allergic, Photosensitivity, Skin Coloration),      

Hematologic (Neutropenia, leukopenia),   Thermoregulatory Problems,

              Ophthalmologic problems (glaucoma, corneal deposits),

                                Urinary retention and Sexual Dysfunction

Significant Antidopaminergic Side Effects in Striatal and Tuberoinfundibular Pathways

First generation antipsychotics have 60-80% brain striatal D2 receptor occupancy for therapeutic antipsychotic effect.  With over 80% occupancy, ____becomes problem

First ‘Atypical’ 2nd Generation Antipsychotic.

2nd gen has:

Less ExtrapyramidalSide Effects or

Tardive Dyskinesia

Less Hyperprolactineamia

2nd gen has more 5HT2A/C antagonist activity 

Hematotoxicity → 1% agranulocytosis

  -  IncreasedSeizurerisk (3-5%)

    -  WarningforMyocarditis

  -  Metabolicsyndrome, Weightgain (>7% Body Weight),

         Impairedglycemiccontrol

• 5HT2A Neurons function as Dopaminergic “Brake”
• Their activation reduces DA activity in some pathways

• 5HT2A blockade can release brake and increase DA communication

  
  

  This means more dopamine release and less EPS (less Tardive symx) and less prolactinemia 

Developed from and similar to clozapine
ØComparable 5HT2A and 2C affinity, but better 5x better affinity against D2
ØMuscarinic and H1 Receptor (+++), α1 (Less ++)
ØGenerally does not cause EPS or raise prolactin
ØBut, low incidenceof agranulocytosis
ØMain adverse effects:
  wSomnolence (drowsiness), dizziness
  wWeight gain; Increased appetite
ØBlockade of H1 receptors
ØBlockade of 5-HT2A receptors
  wDry mouth, constipation (blockade of muscarinic receptors)

ØAlso useful for bipolar disorder

Olanzapine (Zyprexa)

Very High affinity for the 5-HT2A receptor

  w10X better affinity for the D2 receptor than olanzipine

  wNo affinity for muscarinic receptors

    wH1  receptor (++)      α1 (+++)

    w Very effective against Positive symptoms

          Low EPS & wt gain  but can raise prolactin

  Unwanted effects:  Hypotension, Sedation,                               Muscle pain,  Photosensitivity,   possible Arrhythmias (long QT),     Prolactin (++++)                                                                           Metabolism:   P-450 2D6 (polymorphism!)

               Active metabolite    =  9-Hydroxyl  risperidone  

w Causes little or no EPS or prolactin

     w Short half life and rapid dissociation

  w Can cause weight gain & sedation

     w  Norepinephrine reuptake inhibitor (NRI)

     w  5HT1A partial agonist

Quetiapine (Seroquel)

More pronounced antagonist of the 5-HT2A   

                   receptor; 5HT1A partial agonist

  w Low EPS & prolactin elevation.

       Little or no propensity for weight gain or

       dyslipidemia or insulin resistance

  w Parenteral form available

Ziprasidone (Geodon)  

(→ anxiolytic effect)

while bound to the receptor the drug also stimulates it (agonist), but to some extent: Partial Agonist  & Partial Antagonist of D2!

  serotonin: 5-HT1A&B, 5-HT2A,B&C, 5-HT5, 5-HT6 & 5-HT7

  dopamine: D1, D2, D3 & D4  histamine: H1 & H2

  adrenergic: a1 & a2  muscarinic: noaffinity

Orthostatic hypotension      Metabolic syndrome & weight gain
QT prolongation       Hematotoxicity (agranulocytosis!)
EPS & hyperprolactinemia       Increased seizure threshold