Drug Treatment of Affective Disorders

Christian Waeber

Vincent van Gogh's painting, "On the Threshold of

Eternity“, is often used to illustrate the despair of
those suffering from Major Depressive Disorder.
 Mood (Affective) Disorders
• The fundamental disturbance is a change in mood or affect, usually to
depression (with or without associated anxiety) or to elation. The mood change
is usually accompanied by a change in the overall level of activity.
• Most of these disorders tend to be recurrent, and the onset of individual
episodes is often related to stressful events or situations (only 25% show a
familial pattern).

• The mood disorders may be subdivided into unipolar and bipolar types:
1. those that are characterized by depression only
2. those that are characterized by manic episode either alone or in combination with
depression, managed with
Lithium: MOA unclear, may involve inhibition of inositol
monophosphatase and glycogen synthase kinase 3, GSK3.
Antiepileptics: valproic acid, lamotrigine, carbamazepine.

2
 Treatment of Depression
• ~30 antidepressants altering levels of central neurotransmitters (?)
are available to treat depression.
• Overall effectiveness: 65-70%
• Mild to moderate depressive episode: SSRIs.
• Severe depression: antidepressants with broader spectrum of effects, like
SNRI or TCA.
• Patients with insomnia or anorexia may do better with more sedating
medication (mirtazapine, trazodone)
• Patients with lethargy, hypersomnia, weight gain and lower levels of tension
and anxiety may prefer the less sedating medications such as reboxetine or
stimulating SSRIs.
• IMAOs or RIMA should be tried in refractory patients or patients with atypical
depression.

“Matching Antidepressants to Patients: Selection Dosing & Cost”

http://www.med.umich.edu/1info/FHP/practiceguides/depress/drugtable.pdf
Evolution
Evoof
lutimajor
on of moclasses
noaminergiof
c aantidepressants
ntidepressants

Enzyme Uptake Receptor

inhibitors blockers blockers

1950s MAOIs TCAs

1960s
Subtype- NA 5-HT selective Mianserin
selective MAOIs selective
1970s Trazodone

1980s SSRIs

Nefazodone
1990s RIMAs SNRIs
NARIs
Mirtazapine
 Antidepressants: serendipitous discovery
A side effect becomes main indication

• 1951: Hydrazine derivative antibiotics isoniazid and iproniazid Isoniazid

tested on tuberculosis patients, who end up “dancing in the halls Iproniazid
tho’ there were holes in their lungs”.
• Isoniazid is still used today for the treatment of TB (inhibits the
synthesis of mycolic acids), and is only a mild MAO inhibitor.
• 1952-53: Isoniazid tested in depressed patients (France, USA); Phenelzine Isocarboxazid
Max Lurie/Harry Salzer coin the term “antidepressant“.
• 1952: Iproniazid found to be a monamine oxidase inhibitor
(prevents the breakdown of NA and 5-HT).
• 1958: N-isopropyl addition led to a clinically
useful antidepressant; it was withdrawn in most
countries a few years later due to a high incidence
of hepatitis, From
PF3012
• Peplaced by less hepatotoxic drugs such as
phenelzine and isocarboxazid.
 MAO inhibitors: Mechanism of action

COMT:
catechol-O-methyltransferase 6
 Monoamine Oxidase Inhibitors
• MAO converts the monoamines into their corresponding carboxylic acid via an
aldehyde intermediate. Note there are 2 isoforms (MAO-A and MAO-B) and most
inhibitors used as antidepressants are non-selective.

• Hydrazines (phenelzine) or nonhydrazines (tranylcypromine, moclobemide, or

selegiline, which is an anti-Parkinsonian and selective for MAO-B)

• Mechanism
Irreversible inactivation of MAO (moclobemide is the exception: its effect is
reversible). The non-hydrazines (especially tranylcypromine) have a significant
indirect sympathomimetic effect.

• Adverse effects (irreversible MAO-A inhibitors)

Well known 'cheese reaction' following ingestion of tyramine-rich foods (e.g.
cheese and red wine) and sympathomimetics (e.g. pseudoephedrine 'cold
remedies')
• In the presence of MAOI, tyramine (normally subject to extensive first-pass)
becomes a potent indirect sympathomimetic causing an acute rise in BP. 7
 Antidepressants: serendipitous discovery (Part II)
• 1950: Chlorpromazine developed as an antihistamine to induce sedation/relaxation in surgery patients.

• 1951-55: Chlorpromazine shown to be effective in psychotic patients (France, Canada, USA).

• 1951: Attempting to improve the effectiveness of chlorpromazine as an antihistamine and tranquilizer for psychotic
patients, Geigy Pharmaceutical Company discovers imipramine, ineffective in schizophrenia, but improved mood
of patients with "depressive psychosis“.

Promethazine Imipramine
(1940s) Chlorpromazine

• Imipramine is a NA and 5-HT reuptake inhibitor. Also acts on histaminergic,

adrenergic and cholinergic receptors.
Psychiatric disorders no longer “alterations of the soul”
→ chemical imbalance / biological psychiatry.
NA and 5-HT Amitriptyline

• 1961: A 2nd tricyclic antidepressant, amitriptyline, was synthesized

9
Tricyclic Antidepressants: Mechanism of action
•Prevent 5-HT and NA reuptake of into neuronal
stores (selectivity ratio varies widely)
•Onset of action is delayed possibly due to down
regulation of presynaptic 5-HT and/or alpha2
receptors.
•Adverse effects
 Antimuscarinic effects: dry mouth, blurred
vision, constipation and urinary retention
 Postural hypotension (through alpha1
blockade)
 Sedation (H1 receptors)
 Weight gain (5-HT2C)
 Lower seizure threshold
 Potentially lethal adverse effects (cardiac
conduction; effect similar to Class 1A: Na+
channels):
 risk of sudden cardiac death in patients with
myocardial disease
 Overdoses are frequently fatal (limited quantities of
tricyclic antidepressants should be prescribed at
any one time). 10
 The Monoamine hypothesis
• Profile of known antidepressants (may be an artefact related to
development history!)
• Reserpine [antihypertensive (not in BNF!)] irreversibly blocks VMAT,
depletes monoamines, suspected to induce depression.
• Patients who respond to serotonergic antidepressants such as
fluoxetine often rapidly suffer relapse when given diets free of
tryptophan.
• Depleting catecholamines in depressed patients who respond to
noradrenergic agents likewise tends to be associated with relapse.
• Studies of depressed patients have sometimes shown an alteration in
monoamine function.
• Polymorphism (Subjects who are homozygous for the short allele of SERT
more vulnerable to developing major depression)

• Why do antidepressant drugs rapidly change monoamine levels but take weeks
to show antidepressant efficacy?
Serotonergic and noradrenergic pathways

5-HT NA
Synapses of biogenic amines are less confined and anatomically structured
(diffuse modulatory system) than Glu, GABA and Gly.
Despite tiny number of neurons producing 5-HT and NA, these amines
affect most brain functions.
 Evolution of major classes of antidepressants

The standard classification of antidepressant drugs is based on a combination of chemical structure

and mechanism of action.
• TCA = tricyclic antidepressant NARI = SNRI = selective serotonin and noradrenaline reuptake inhibitor
• SSRI = selective serotonin reuptake inhibitor RIMA = reversible inhibitor of monoamine oxidase
• SNRI = selective noradrenaline reuptake inhibitor 13
 Evolution of major classes of antidepressants

• The strategy used in the development of these newer drugs also focused on increasing
tolerability and safety especially in overdose
• The selective reuptake inhibitors (SSRIs) were shown to have the same efficacy but are
better tolerated than TCAs
• The improved tolerability of these newer drugs resulted in fluoxetine — the first SSRI
available in the US market — replacing imipramine as the 'gold-standard' for the
treatment of depression.
• More recent members of this class of drugs include serotonin noradrenergic reuptake
inhibitors (SSNRIs), noradrenaline reuptake inhibitors (SNRIs), and a noradrenergic and
specific serotonergic antidepressant (NaSSA) with minimal effects on monoamine
reuptake (a2 and 5-HT receptors antagonists).

• Agomelatine (launched 2009): melatonin receptor agonist and 5-HT (5-HT2C) receptor
antagonist.

14
 Antidepressants and
TCA monoamines 5-HT2/α1 anta

Imipramine TeCA SNRIs

Trazodone
Maprotiline Reboxetine Milnacipran Venlafaxine

Amitriptyline SSRIs SSNRIs

MAOi 5-HT2/H1 anta

TeCA
Tranylcypromine Serotonin Mirtazapine
reuptake
enhancer
reversible

Mianserin
Moclobemide
From my Introduction to PF4014 …

The CNS is the ultimate “integrator“

• It is influenced by all the other systems
• It controls all the other systems

Most CNS disorders poorly understood

Many treatments discovered serendipitously or because of a certain
“let’s see if this will work” attitude.
Same drugs used for different conditions (antidepressants for
depression, but also for anxiety disorders, for migraine, for pain).

You’re in 4th year! I want to see some serious integration.

But a Mind/Concept Map is just … a map; it is not meant to
contain detailed information (content should be presented in
5-10 minutes).
 Antidepressants and monoamines
(5-HT and NE, not DA)
Maprotiline (not in BNF): tetracyclic; NET>>DAT=SERT; potent H1 antagonist; moderate 5-HT2 and α1
antagonist. Potent antagonist of the 5-HT7 receptor (potentially playing an important role in its antidepressant
effectiveness).
Selective Noradrenaline Reuptake Inhibitors (SNRIs) NET>SERT
Reboxetine: only approved for major depression; used off-label for panic disorder and attention deficit
hyperactivity disorder (ADHD).
Atomoxetine (Strattera) is a norepinephrine reuptake inhibitor which is approved for the treatment of ADHD.

Selective Serotonin and Noradrenaline Reuptake Inhibitors (SSNRIs; serotonin–norepinephrine reuptake inhibitor (SNRI))
Venlafaxine: first (1994) and most commonly used SSNRI. It was introduced by Wyeth in 1994 (depression,
Generalised anxiety disorder); SERT=NET>DAT
Duloxetine (Cymbalta): Major depressive disorder; Generalised anxiety disorder; diabetic neuropathy and
fibromyalgia; urinary incontinence. SERT>NET>DAT
Milnacipran: not available in Ireland; only approved in some countries for major depression; used for the treatment
of fibromyalgia.
Sibutramine: Appetite suppressant, discontinued in EU and USA; NET=SERT=DAT, but no antidepressant
activity.
Tramadol: weak μ-OR agonist; SERT=NET>>DAT, also 5-HT releasing agent; for mild to moderate pain.
Bupropion (Wellbutrin): antidepressant in USA (off label here); smoking cessation DAT>NET>>5HT (nAChR anta)
 Antidepressants and
anxiety disorders SSRIs
Maprotiline: NET>>DAT=SERT; potent H1 antagonist; moderate 5-HT2 and α1 antagonist. Potent
antagonist of the 5-HT7 receptor (potentially playing an important role in its antidepressant effectiveness).

Selective Noradrenaline Reuptake Inhibitors (SNRIs) NET>SERT

Reboxetine: only approved for major depression; used off-label for panic disorder and attention deficit
hyperactivity disorder (ADHD).
Atomoxetine (Strattera) is a norepinephrine reuptake inhibitor which is approved for the treatment of ADHD.

Selective Serotonin and Noradrenaline Reuptake Inhibitors (SSNRIs)

Venlafaxine: first (1994) and most commonly used SSNRI. It was introduced by Wyeth in 1994 (depression,
Generalised anxiety disorder); SERT=NET>DAT
Duloxetine (Cymbalta): Major depressive disorder; Generalised anxiety disorder; diabetic neuropathy and
fibromyalgia; urinary incontinence. SERT>NET>DAT
Milnacipran: not available in Ireland; only approved in some countries for major depression; used for the treatment
of fibromyalgia.
Sibutramine: Appetite suppressant, discontinued in EU and USA; NET=SERT=DAT, but no antidepressant
activity.
Tramadol: weak μ-OR agonist; SERT=NET>>DAT, also 5-HT releasing agent; for mild to moderate pain.
Bupropion (Wellbutrin): antidepressant in USA (off label here); smoking cessation DAT>NET>>5HT (nAChR anta)
 Antidepressants and Amitriptyline
pain
Maprotiline: NET>>DAT=SERT; potent H1 antagonist; moderate 5-HT2 and α1 antagonist. Potent
antagonist of the 5-HT7 receptor (potentially playing an important role in its antidepressant effectiveness).

Selective Noradrenaline Reuptake Inhibitors (SNRIs) NET>SERT

Reboxetine: only approved for major depression; used off-label for panic disorder and attention deficit
hyperactivity disorder (ADHD).
Atomoxetine (Strattera) is a norepinephrine reuptake inhibitor which is approved for the treatment of ADHD.

Selective Serotonin and Noradrenaline Reuptake Inhibitors (SSNRIs)

Venlafaxine: first (1994) and most commonly used SNRI. It was introduced by Wyeth in 1994 (depression,
Generalised anxiety disorder); SERT=NET>DAT
Duloxetine (Cymbalta): Major depressive disorder; Generalised anxiety disorder; diabetic neuropathy and
fibromyalgia; urinary incontinence. SERT>NET>DAT
Milnacipran: not available in Ireland; only approved in some countries for major depression; used for the treatment
of fibromyalgia.
Sibutramine: Appetite suppressant, discontinued in EU and USA; NET=SERT=DAT, but no antidepressant
activity.
Tramadol: weak μ-OR agonist; SERT=NET>>DAT, also 5-HT releasing agent; for mild to moderate pain.
Bupropion (Wellbutrin): antidepressant in USA (off label here); smoking cessation DAT>NET>>5HT (nAChR anta)
 Antidepressants with no effect on
serotonin reuptake/metabolism
Trazodone: “Depressive illness (particularly where sedation is required)”, anxiety (BNF);
insomnia; off-label: ED (via metabolite mCPP).
Tetracyclic antidepressant do not inhibit the reuptake of serotonin. They do inhibit the reuptake of norepinephrine
(except mirtazapine). 5-HT2A and α1 receptor antagonists. Clinically relevant antihistamine (H1 receptor) activity.

Mianserin: “Depressive illness (particularly where sedation is required)” (BNF) Tetracyclic

Mirtazepine: Major depression; off-label: various anxiety disorders; migraine antidepressants (TeCA)

Very similar structures but different Ki (nM) Mianserin Mirtazepine

pharmacological profiles, indications:
NET 71 5000
5-HT2A, 2C 1-2 6-9 Increased appetite/weight gain
5-HT2B 2 200
5-HT3 6 9 Nausea - vomiting
5-HT7 50 300

Flupentixol (Flupenthixol): atypical antipsychotic (D2 and/or 5-HT2A antagonism); antidepressant effects at lower
doses (D2/D3 autoreceptor blockade).
 Vortioxetine
Approved for the treatment of MDD (FDA: September 2013; EMA: October 2013)

Serotonin modulator and stimulator (SMS):

1. Blockade of serotonin transporter (Ki 1.6 nM)
2. Agonism of 5-HT1A receptor (15 nM), partial agonism at 5-HT1B receptors (33 nM)
3. Antagonism of 5-HT1D (54 nM), 5-HT3 (Ki 3.7 nM), and 5-HT7 (19 nM) receptors
→ Synergistic effect on increased [5HT]
4. Not NET inhibitor, but also increases [NE] (via 5-HT1A and 5-HT3)
5. Also increase [DA] in frontal cortex and hippocampus, [Ach] and [HA]

Increases cell proliferation in dentate gyrus (only after 1 day, in contrast to the 7+days for SSRIs)
In rats, vortioxetine reverses the LTP reduction induced by stress and is active in several animal
models predictive of pro-cognitive effects.
In humans, effective against cognitive impairment associated with depression.
Patients poorly responding to SSRI/SNRI monotherapy show better response when switched to
vortioxetine than when stitched to agomelatine.
Other SMS: Vilazodone (US: Viibryd): SERT blocker and 5-HT1A partial agonist (related to
21
buspirone)
 SSRI Antidepressants

• First-line and most commonly prescribed antidepressants.

• Selectivity with respect to 5-HT over noradrenaline uptake inhibition,
• As efficacious as TCAs but without the anticholinergic side-effects.
• Side-effects caused by stimulation of different subtypes of 5-HT receptor
– Brain 5HT2 receptor stimulation: insomnia, anxiety, irritability, decreased libido
– Spinal 5-HT2 receptor stimulation: sexual dysfunction
– 5-HT3 receptors: nausea (see PF4014 Lecture on Nausea/Vomiting)
22
SSRI Antidepressants: Mechanism of action
See Fig 46.2 of R&D

5-HT
 SSRI Antidepressants: Mechanism of action

Rang & Dale, 7th ed

Figure 46.2
 Tina Pejchal, Melissa A Foley, Barry E Kosofsky, Christian Waeber (2002) Chronic fluoxetine treatment selectively
uncouples raphe 5-HT1A receptors as measured by [35S]-GTPγS autoradiography, British J Pharmacol 135, 1115–1122.

Selective Serotonin Reuptake Inhibitors (SSRIs) are thought to have a delay in

therapeutic efficacy because of the need to overcome the inhibitory influence
of raphe 5-HT1A autoreceptors. Prolonged SSRI administration has been
reported to desensitize these autoreceptors. We have used [35S]-GTPγS
autoradiography to determine whether this desensitization occurs at the level
of receptor/G protein coupling.
Male mice were injected intraperitoneally once a day with saline or 20 mg kg−1
fluoxetine for either 2 days or 14 days. 5-HT1A receptor binding and coupling
to G proteins were assessed using [3H]-8-OH-DPAT and [35S]-GTPγS
autoradiography, respectively.
The 5-HT receptor agonist 5-carboxamidotryptamine (5-CT) stimulated [35S]-
GTPγS binding in the substantia nigra, as well as in hippocampus and dorsal
raphe nucleus. The 5-HT1A receptor antagonist p-MPPF (4-fluoro-N-(2-[4-(2-
methoxyphenyl)1-piperazinyl]ethyl)-N-(2-pyridinyl)benzamide) blocked this
effect in the latter regions, whereas the 5-HT1B/D antagonist GR-127,935 (2′-
methyl-4′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-
methoxy-3-(4-methyl-piperazin-l-yl)-phenyl]-amide) only decreased labelling in
substantia nigra.
Fourteen-day fluoxetine treatment decreased 5-CT-stimulated [35S]-GTPγS
binding in dorsal raphe (saline: 112±12% stimulation; fluoxetine: 66±13%),
but not in substantia nigra (99±14% vs 103±7%) or hippocampus
(157±3% vs 148±18%). Two-day fluoxetine treatment did not alter 5-CT-
stimulated [35S]-GTPγS binding in any of the brain areas investigated.
Decreased [35S]-GTPγS binding was not due to receptor down-regulation,
since the density of raphe [3H]-8-OH-DPAT binding sites was unaffected by
fluoxetine treatment.
These results suggest that the desensitization of presynaptic 5-HT1A receptor
function occurs at the level of receptor-G protein interaction on dorsal raphe
neurons, and may underlie the therapeutic efficacy of long-term SSRI
treatment.
 Tina Pejchal, Melissa A Foley, Barry E Kosofsky, Christian Waeber (2002) Chronic fluoxetine treatment selectively
uncouples raphe 5-HT1A receptors as measured by [35S]-GTPγS autoradiography, British J Pharmacol 135, 1115–1122.

14 days with saline 14 days with fluoxetine

G Protein activation 5-HT1A binding sites
 Why Do We Need New Antidepressants?
• Delay in onset of action
• Side effect profile and compliance
• Safety issues
• Treatment resistant depression
• Response difficult to predict

The monoamine hypothesis is

only part of a bigger story
involving neuronal life and
death.

27
 Hippocampal atrophy in MDD

To put things in context …

Untreated depression and hippocampal volume loss.

Am J Psychiatry. (2003 )160:1516-8.
 Stress and neurogenesis
• Neurogenesis (birth of new neurons) occurs throughout
adulthood in the hippocampus.

• These new stem cells can functionally integrate into neural

networks
• In animal models,
chronic stress has been
shown to decrease adult
hippocampal
neurogenesis
 Stress and Depression
The hypothalamic-pituitary-adrenal (HPA) axis is upregulated with a down-regulation of its
negative feedback controls.

- • Corticotropin-releasing factor (CRF) is hypersecreted from the hypothalamus

• It induces the release of adrenocorticotropin hormone (ACTH) from the pituitary.
• ACTH interacts with receptors on adrenocortical cells. Cortisol is released from the
- adrenal glands.
• Cortisol receptors become desensitized.
• The negative feedback of cortisol to the hypothalamus, pituitary and immune system is
impaired.
• This leads to continual activation of the HPA axis and excess cortisol release, increased
activity of the pro-inflammatory immune mediators and disturbances in monoamine
transmission.
• Increased activation can lead to hippocampal cell loss and shrinkage.

Antidepressant treatment, in general, shows the ability to

oppose these effects and promote neuroprotection.
30
 Neurotrophic responses in depression
• Brain-derived neurotrophic factor (BDNF), is a protein, member of the
neurotrophin family of growth factors, which are related to Nerve Growth
Factor.

• Stress decreases and all antidepressants increase BDNF in hippocampus.

• BDNF is sufficient to produce an antidepressant response in animal models
• Deletion or blockade of BDNF blocks the effects of antidepressants.
• BDNF heterozygous knockout mice display depressive behavior when
exposed to mild stress that has no effect in wild-type mice.
• The BDNF Val66Met polymorphism is found in 25–30% of humans.
• Val66Met carriers exposed to early life stress or trauma are at increased risk
for depression.
Antidepressants and ECT increase hippocampal neurogenesis
(BrdU* -positive cells)

VEHICLE Tranylcypromine

Malberg et al, J Neurosci 2000

ECT Fluoxetine

*BrdU is a thymidine analog that labels DNA during the S phase

 Pathophysiology of Depression

• Depression involve the HPA axis and the excitotoxic action of glutamate; switches on the expression of genes
that promote neural apoptosis in the hippocampus and prefrontal cortex.
• Antidepressive pathways involve the monoamines and BDNF, which acts on a kinase-linked receptor (TrkB),
switching on genes that protect neurons against apoptosis and also promote neurogenesis.
• Tianeptine produces its antidepressant effects by alterating AMPA and NMDA receptor activity and inducing
BDNF release in turn affecting neural plasticity and protecting against stress induced neuronal remodelling.
Ketamine: A Rapid onset antidepressant?

Cryan and O’Leary, Science 2010

34
"Together with the recently announced results from four other Phase 3 studies, these data provide continued support
for a positive benefit-risk assessment for esketamine nasal spray as a potentially novel treatment approach for
patients living with treatment-resistant depression,"
Indications and dose
Induction and maintenance of anaesthesia, i.v. or i.m.
Analgesic supplementation of regional and local anaesthesia, i.v. infusion
Analgesia in emergency medicine, i.m. or i.v.
Ketamine should only be administered by, or under the direct supervision of, personnel experienced in its use,
with adequate training in anaesthesia and airway management, and when resuscitation equipment is available.
Van Gogh on Prozac