WEEK 8 - DEPRESSION

Question 1

Historically, mental disorders have had three major “explanations”

Answer 1

1. SUPERNATURAL
2. BIOLOGICAL
3. PSYCHOLOGICAL, SOCIAL AND CULTURAL FACTORS

Question 2

What causes depression? = 3 + EXPLANATIONS

Answer 2

1. ‘Genetic factors’
   - Human disease genes
2. ‘Environmental challenges’
   - Chronic stress, trauma, social factors
3. ‘Acquired Pathology’
   - Abnormal circuitry, brain lesions, dementia

Question 3

The DSM-5 outlines the following criterion to make a diagnosis of depression. The individual must be
experiencing five or more symptoms during the same 2-week period and at least one of the
symptoms should be either (1) depressed mood or (2) loss of interest or pleasure.

Answer 3

1.Depressed mood most of the day, nearly every day.

2.Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day.

3.Significant weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day.

4.A slowing down of thought and a reduction of physical movement (observable by others, not merely
subjective feelings of restlessness or being slowed down).

5.Fatigue or loss of energy nearly every day.

6.Feelings of worthlessness or excessive or inappropriate guilt nearly every day.

7.Diminished ability to think or concentrate, or indecisiveness, nearly every day.

8.Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt
or a specific plan for committing suicide.

‘To receive a diagnosis of depression, these symptoms must cause the individual clinically significant
distress or impairment in social, occupational, or other important areas of functioning. The symptoms
must also not be a result of substance abuse or another medical condition.’

Question 4

What can the pharmacology of anti-depressants tell us about depression?

3 AND EXPLAIN THEM = 8

Answer 4

1. ‘Monoamine hypothesis of depression’
2. Most common drug targets
3. Remission rates are low (often less than 60%)
4. Delayed onset
5. ‘New targets: Glutamatergic systems’
   
   6. NMDA antagonist ketamine
6. ‘Brain connectivity’
   
   8. rTMS and ECT (not really pharmacology…)

Question 5

Explain the ‘MONOAMINE HYPOTHESIS’ =

Answer 5

Predicts that the underlying PATHOPHYSIOLOGIC BASIS OF DEPRESSION is a

• DEPLETION in the LEVELS of ‘serotonin, norepinephrine, and/or dopamine’ in
  the
• IN CENTRAL NERVOUS SYSTEM

Question 6

WHAT ARE THE FEATURES OF ‘MONOAMINE TRANSPORTERS’ = 3

Answer 6

1. localized to PRESYNAPTIC SITE ,
2. where they are CRUCIAL FOR TERMINATION OF MONOAMINE TRANSMISSION AND THE MAINTENANCE OF of PRESYNAPTIC monoamine STORAGE.
3. Several selective pharmacological agents acting at each monoamine transporter are shown. Amph., amphetamine; DA, dopamine; DAT, Dopamine transporter; LDOPA, L-3,4-dihydroxyphenylalanine; 5-HT, 5-hydroxytryptamine; MPP+, 1-methyl-4-phenylpyridinium; MDMA, (+)-3,4-
   methylenedioxymethamphetamine; NA, noradrenaline; NET, noradrenaline transporter; SERT, 5-HT transporter.

Question 7

Monoamine hypothesis -

‘But we should also pay attention to the transporters!
And the breakdown enzymes!’ = 4

Answer 7

1. Transporters MOVE MONOAMINES ACROSS MEMBRANES: they areNOT RECEPTORS, they DO NOT TRIGGER ANY EVENTS
2. They are just
   ‘SHUTTLES’
3. MONOAMINE OXIDASE is an ENZYMES that
   BREAKS DOWN ‘MONOAMINES’ INTO ALDEHYDES
4. It is LOCATED on the SURFACE OF MITOCHONDRIA

Question 8

Monoaminergic hypothesis
Evidence part 1 = RESERPINE

= 4

Answer 8

1. Reserpine, a PLANT ALKALOID was utilized as a TREATMENT FOR HYPERTENSIVE VASCULAR DISEASE IN THE 1950S
2. Reserpine PRECIPITATED DEPRESSION IN SOME PATIENTS
3. Reserpine INHIBITS VESICULAR MONOAMINE TRANSPORTER AND THEREFORE ‘DEPLETE BRAIN MONOAMINES’
4. (i.e. serotonin, norepinephrine, and dopamine)

Question 9

Monoaminergic hypothesis
Evidence part 2 — ISONICOTINYL HYDRAZIDE (IPRONIAZID) = 4

Answer 9

1. Isonicotinyl hydrazide (iproniazid) was developed to TREAT TUBERCULOSIS,
2. SIDE EFFECTS included EUPHORIA, INCREASED APPETITE, AND IMPROVED SLEEP
3. 70% of patients with depression treated with iproniazid
   showed SIGNIFICANT IMPROVEMENTS
4. Iproniazid was the first successful pharmacological
   treatment for depression and is a ‘MAO INHIBITOR’.

Question 10

Monoamine inhibitors

INHIBITING MAO =

GOAL =

Answer 10

Inhibiting MAO = MONOAMINE NEUROTRANSMITTER CONCENTRATIONS INCREASE IN PRESYNAPTIC TERMINAL AND ARE AVAILABLE FOR RELEASE WHEN ACTION POTENTIALS REACH THE NERVE TERMINAL

GOAL = to INCREASE MONOAMINE NEUROTRANSMITTERS
in the SYNAPTIC SPACETO ACTIVATE POSTSYNAPTIC RECEPTORS

Question 11

MAO-A is also found in the gut…

Answer 11

1. DMT
   (Dimethyltryptamine)
   is a very strong
   psychedelic found in a
   number of animals and
   plants
2. DMT (HALLUCINOGENIC EFFECT) IS RAPIDLY METABOLISED BY MONOAMINE OXIDASE (MAO) IN THE GUT FOLLOWING ORAL ADMINISTRATION
3. Beta-carboline alkaloids harmine, tetrahydroharmine and harmaline in ayahuasca are potent MAO inhibitors (MAOIs), preventing the 1st- pass oxidative deamination of DMT

Question 12

AYAHUASCA = MECHANISM OF ACTION = 3

Answer 12

1. DMT (the major alkaloid present in the leaves of ‘Psychotria viridis’ - hallucinogen

+

2. B-carboline alkaloids harmine, tetrahydroharmine, and harmaline

+

3. trace alkaloids i the bark and stems of the vine ‘Baisteriopis caapi’

Question 13

Another target: monoamine transporters - SEROTONIN = 4

Answer 13

1. Significant role of serotonin: DECREASED CONCENTRATIONS
   of serotonin in the brains of DEPRESSIVE SUICIDES
2. 1974: selective serotonin reuptake inhibitor (SSRI)
   LY110140 (fluoxetine)
3. WEAK AFFINITY for the NOREPINEPHRINE TRANSPORTER:
   SEPARATED FLUOXETINE pharmacologically from other antidepressant drugs.
4. Fluoxetine was approved by the FDA in December of
   1987 and was launched to the market in January 1988
   under the trade name ‘Prozac®’

Question 14

SSRIs: hardcore pharmacology = 5

Answer 14

1. 20-1500 fold more SELECTIVE for INHIBITING SEROTONIN OVER NOREPINEPHRINE TRANSPORT
2. MINIMAL BINDING AFFINITY FOR OTHER POSTSYNAPTIC RECEPTORS: adrenergic α1, α2, and β, histamine H1, muscarinic, and dopamine D2 receptors

3.DO NOT STIMULATE THE PRESYNAPTIC RELEASE OF SEROTONIN OR NOREPINEPHRINE

4. Have WEAK OR NO DIRECT PHARMACOLOGICAL ACTION AT POSTSYNAPTIC SEROTONIN RECEPTORS
   (e.g. 5-HT1A, 5-HT2A, and 5-HT2c)
5. Specificity of action!

Question 15

Serotonin modulator and stimulator (SMS): EXPLAIN

why developed?

Answer 15

simultaneously MODULATE ONE OR MORE SEROTONIN RECEPTORS and INHIBIT THE RE- UPTAKE OF SEROTONIN

SMSs were DEVELOPED because NOT ALL SEROTONIN RECEPTORS are INVOLVED IN THE ANTIDEPRESSANT EFFECT OF ‘SSRIs’

Question 16

SMSs were DEVELOPED because NOT ALL SEROTONIN RECEPTORS are INVOLVED IN THE ANTIDEPRESSANT EFFECT OF ‘SSRIs’

4 = explain

Answer 16

1. Some receptors are oppositional (5-HT1A autoreceptors)
2. Some are responsible for side effects (5-HT3 –regulation of nausea, vomiting, and the gastrointestinal tract )

E.g. vortioxetine: SRI and agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors.

E.g. vilazodone, SRI and 5-HT1A receptor partial agonist

Question 17

What are Tricyclic antidepressants (TCA) = explain 3

Answer 17

1. Inspired by CHLORPROMAZINE (schizophrenia drug), many novel compounds were based on the classic ANTIHISTAMINE STRUCTURE
2. Prototype: imipramine: marked improvements
   in patients suffering from severe depression.
3. The classification of TCAs was based on the THREE BEZENE RING MOLECULAR CORE, IN PART, BECAUSE THE MECHANISM OF ACTION WAS UNKOWN AT THE TIME OF DISCOVERY

Question 18

TCAs: a diverse pharmacological profile

ACT?
INHIBITS? = 2
BLOCK? = 3

Answer 18

1. Act at reuptake transporters and receptor proteins

• inhibit presynaptic NOREPINEPHRINE REUPTAKE TRANSPORTERS;
• inhibit presynaptic SEROTONIN REUPTAKE TRANSPORTERS;
• block postsynaptic ADRENERGIC α1 and α2 receptors (DIZZINESS);
• block postsynaptic MUSCARINIC receptors; (MEMORY IMPAIRMENT)
• block POSTSYNAPTIC HISTAMINE H1 receptors (DROWSINESS)

Question 19

Atypical drugs = 4
‘Bupropion’

Answer 19

1. unique chemical class (AMINOKETONE)
2. primarily a DOPAMINE-NOREPINEPHRINE REUPTAKE INHIBITOR
3. 2x HIGHER for DOPAMINE than for norepinephrine
4. MINIMAL OR NO BINDING AFFINITY FOR SEROTONIN TRANSPORTERS OR OTHER PRE- AND POSTSYNAPTIC RECEPTORS

Question 20

Atypical drugs… ‘Venlafaxine’
= 2

Answer 20

1. Like TCAs, selectively targets the serotonin and norepinephrine transporters (SNRI).
2. Unlike TCAs, minimal or no pharmacological action at adrenergic (α1, α2, and β),
   histamine (H1), muscarinic

Question 21

Although there are seven antidepressant drug classes that produce an immediate
increase in monoamine neurotransmitter concentrations in various ways, there is
still a population of patients that do not respond to any of these medications

Answer 21

1. Depleted concentrations of serotonin, norepinephrine, and dopamine do not
   produce depressive symptoms
2. Monoamines likely play a modulatory role or become relevant in the context of
   stressors

Question 22

Glutamate

Answer 22

Glutamate is the most abundant neurotransmitter in the brain

Glutamate

1. Ion channel-associated
   - ionotropic (iGluR)
   - ndma, ampa, kAINATE
   - fast - excitatory
2. G-protein coupled
   metabotropic (mGluR)
   Group I,
   slow - excitatory
   Group II, Group III
   slow - inhibitory

Question 23

Evidence for glutamate involvement in depression = Plasma and CSF = 6

limitations?

Answer 23

1. Increased concentrations of glutamate in plasma, cerebrospinal fluid of patients.
2. Antidepressant drug treatment reduces the serum and plasma glutamate concentrations as well as cerebrospinal fluid glutamine concentrations
3. Monoamine-based antidepressant drugs are
   modulating the glutamatergic system?

4.Limitations:
5. Inability to distinguish central and peripheral substrates and metabolic effects.
6. Blood brain barrier

Question 24

Evidence for glutamate involvement in depression =

‘Proton magnetic resonance spectroscopy (1HMRS):’ 4

limitations?

Answer 24

1. reduced glutamate/glutamine exchange (Glx) in subcortical and cortical brain regions
   of MDD patients.
2. Following ECT treatment, Glx concentrations were significantly increased back to healthy control levels
3. ECT responders had a greater increase of Glx
   compared to non-responders
4. Limitations: measuring glutamate/glutamine cycle rather than glutamate exclusively

Question 25

But its not just about glutamate – contradictions …NMDA = 6

Answer 25

1. Contradictions: is high or low glutamate associated with depression?
2. MDD patients have shown an increase in glutamate binding in the hippocampus
3. Postmortem studies: changes in the expression of NMDA receptor subunits in
   MDD patients
   4. • hyperfunction of NMDA receptors in subcortical regions (i.e. hippocampus, locus coeruleus, and amygdala)
   5. • hypofunction of NMDA receptors in cortical regions (i.e. prefrontal, perirhinal and temporal cortices).
4. Limitations:
   Previous drug treatment – potential for long term neurobiological changes

Question 26

Glutamatergic drug targets = 4

Answer 26

1. Ketamine
2. NR2B subunit
3. Glycine
4. EAAT2 (transporter)

Question 27

Ketamine = 6

Answer 27

1. Derivative of phencyclidine
2. Short-acting dissociative anaesthetic in humans and animals
3. Ketamine, also known as “Special K,” became popular as a recreational drug in the mid- 1990s.
4. Noncompetitive NMDA receptor antagonist (aka channel blocker) that binds to the phencyclidine site, blocking the channel in a way that is similar to how Mg2+ blocks NMDA receptors
5. Non-selective for the NR2A-D subunits of the NMDA receptor channel
6. Relatively low affinity (Ki = 659-1190 nM)

Question 28

Ketamine = Low selectivity

EXPLAIN = 3

Answer 28

1. • higher receptor affinity for in vitro human cloned dopamine D2 receptors (Ki = 55nM) than for NMDA receptors (Ki = 659-1190 nM) (but no functional activity)
2. • 12 and 20-fold more selective for NMDA receptors as compared to serotonin 5-HT2A and mu opioid receptors, respectively.
3. • weak binding affinity for sigma, muscarinic, and κ and δ opioid receptors, as well as
     dopamine, norepinephrine, and serotonin transporters

Question 29

Summary of ketamine effects =

Answer 29

1. A single, subanesthetic dose of ketamine (0.5 mg/kg) was intravenously (i.v.)
   infused over 40 minutes, and the antidepressant effects of ketamine were
   assessed using the Hamilton Depression Rating Scale (HDRS) and Beck Depression
   Inventor (BDI).

• (an anaesthetic dose for ketamine in humans ranges from 1.0 mg/kg to 4.5 mg/kg intravenous and
  from 6.5 mg/kg to 13.0 mg/kg intramuscular)

2. Ketamine produced rapid, within four hours, antidepressant effects that lasted up to 72 hours as compared to placebo control.
3. The hallucinogenic (or psychotomimetic) effects (e.g. out of body experience,
   hallucinations, etc.) of ketamine subsided within two hours, prior to the onset of the antidepressant effects

Question 30

Other drugs targeting the NMDA receptor =

Answer 30

1. Memantine, low affinity antagonist
   - No anti-depressant effects, although ketamine and memantine possess similar binding affinity for the
   NMDA receptors,
2. AZD6765 (lanicemine): low affinity and low trapping open-channel blocker
   lack of efficacy in Phase II clinical trials.
3. CP-101,606 (traxoprodil): potent and NR2B subunit selective NMDA receptor antagonist
   Not effective, but NR2B selectivity may reduce psychotomimetic effects
4. MK-0657: NR2B subunit selective antagonist
   first oral formulation
   inconsistent antidepressant effects, no psychotomimetic or adverse side effects
5. D-cycloserine: partial agonist, binds to the glycine binding site no psychotomimetic or adverse side effects
6. GLYX-13 partial agonist, binds to the glycine binding site
   - Antidepressant action of rapastinel, but high placebo effect and the small sample size

Question 31

Riluzole = 2

Answer 31

1. EAAT2 glutamate reuptake enhancer approved for the treatment of amyotrophic lateral sclerosis (ALS)
2. Evaluated under a number of conditions for the treatment of MDD including
   monotherapy, adjunctive therapy, and ketamine relapse prevention.

Question 32

Inflammation and infection = 5

Answer 32

1. Activation of microglia can release pro-inflammatory cytokines, leading to

    2. (1) activation of the hypothalamic-pituitary adrenal axis, generating an imbalance in the serotonergic and noradrenergic circuits;

   3. (2) increased activity of the enzyme indoleamine-2,3-dioxygenase, resulting in depletion of serotonin levels
      and the production of quinolinic acid.
2. Non-steroidal anti-inflammatory drugs can have benefits in depressed patients with inflammatory
   comorbidities or an elevated immune profile,
3. Evidence for anti-inflammatory properties of standard antidepressants.