Drug Treatment of Depression and

Bipolar Disorder

Dr. Barry Boland, PhD

Dept. of Pharmacology and
Therapeutics, UCC

Learning Resources
• Rang and Dale: Ch. 48 (9th Ed.)
• Nestler et al Mol. Neuropharm.: Ch. 14

“Portrait of Dr Gachet”,
Vincent van Gogh (1890)
 Affective Disorders
What are Affective Disorders?
• Disorders of mood rather than disturbances of thought or
cognition.

• Psychiatric Condition

Main Affective Disorders:

• Major Depressive Disorder (MDD) (Unipolar)
Treatment: Anti-depressants

• Bipolar Disorder (Alterations between depression and mania)

Treatment: Anti-depressants + Mood stabilisers
 Major Depressive Disorder (MDD)

• Highly prevalent disorder: 21% of world population affected

• > 300,000 people in Republic of Ireland suffer from depression

• Depression is currently the leading cause of leading cause of disability as ”At Eternity’s Gate”
by Vincent Van Gough
measured by Years Lived with Disability (YLDs). Source: WHO

• Females almost twice as likely as men to develop depression: Source: Mayo Clinic
 Biological Basis of Depression

Key brain regions involved in

depression:

(a) Orbital prefrontal cortex

(pink) and the ventromedial
prefrontal cortex (green)

(b) Dorsolateral prefrontal cortex

(c) Hippocampus and amygdala

(d) Anterior cingulate cortex

Brain Imaging: Complex changes involving increases and decreases in certain networks
Link to article on depressive thought “rumination” in Depressive patients:
https://www.psychologytoday.com/blog/the-athletes-way/201508/the-brain-mechanics-rumination-and-repetitive-thinking
 Theories on the Biological Cause of Depression

1. The Monoamine Theory (Schildkraut, 1965)

What are Monoamines?

Monoamine NTs contain one amino group (-NH2)

connected to an aromatic ring by a two-carbon chain. Noradrenaline (NA)

• Catecholamines: Derived from tyrosine

Examples: Dopamine, Noradrenaline (NA), Adrenaline (A)
• Tryptamines: Derived from tryptophan
• Examples: Serotonin (5-hydroxytryptamine; 5HT), Melatonin
Catechol
• Histamine: Derived from histidine

Note: Single amino group in Glutamate is not

connected to an aromatic ring → Not Monoamine
Glutamate
 Theories on the Biological Cause of Depression
1. The Monoamine Theory
Joseph Schildkraut (1965):
• Depression is caused by a functional deficit of the monoamine neurotransmitters,
noradrenaline and 5HT, at certain sites in the brain.
• Mania results from a functional excess of monoamine transmission.
 Theories on the Biological Cause of Depression
2. Neuroendocrine Mechanisms
Pro-Depressive Pathway Anti-Depressive Pathway
 Theories on the Biological Cause of Depression
2. Neuroendocrine Mechanisms

Altered Stress Axis in Depression:

• Stress causes an upregulation in the hypothalamic-pituitary-adrenal (HPA)
axis.
• Excessive release of cortisol into the circulation has a number of effects,
including elevation of blood glucose.
• 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.

• Cortisol receptors become desensitized leading to increased activity of the

pro-inflammatory immune mediators and disturbances in neurotransmitter
transmission.

• Increased activation can lead to hippocampal cell loss and shrinkage.

 Theories on the Biological Cause of Depression

3. Reduced Neuroplasticity

Evidence of neuroplasticity deficits in

brain imaging studies of people with
depression + in post-mortem brains.

From: Berton and Nestler, 2006

Hypothesis:
(i) Lower levels of BDNF (brain derived neurotrophic factor)
(ii) Malfunction of BDNF receptor, TrkB
(iii) Excessive glutamate damages neurons in the brain
 Anti-Depressant Treatment Strategies
• All available antidepressants act via the monoamine neurotransmitters,
serotonin (5HT) or noradrenaline (NA), and are based on serendipitous
discoveries made in the 1950s.
• Safe and effective, but delayed onset of clinical benefit.
• Despite several decades of research, drug-induced changes in the brain that
underlie their therapeutic actions remain unclear.
• <50% of all patients show full remission, highlighting need for faster acting,
safer and more effective treatments.
• Non-monoamine-based anti-depressants are being investigated as novel
strategies.
• Electroconvulsive therapy (ECT / shock treatment) is one of the most
effective treatments for depression, but is reserved for the most severely ill due
to the availability of numerous pharmacotherapies.
 Anti-Depressants:
From Serendipity to Prozac Nation
• 1950’s: The anti-tuberculosis drug iproniazid improved patients mood

• Later discovered that iproniazid is a monoamine oxidase inhibitor

(MAOI) → Prevents the breakdown of noradrenaline (NA) and
serotonin (5-HT).

• 1950’s: Imipramine, a tricyclic compound developed as an anti-

histamine was also found to improve mood.

• Later discovered that imipramine is a NA and 5-HT reuptake

inhibitor - it also acts at histaminergic, adrenergic and
cholinergic receptors → Side-Effects

• 1980’s: Selective serotonin reuptake inhibitors (SSRIs) e.g.

Fluoxetine (Prozac); Paroxetine (Seroxat)
Drug Treatment of Affective Disorders
 Classes of Anti-Depressant Drugs
1. Monoamine Oxidase Inhibitors (MAOIs)
• MAOA metabolises 5-HT, NA, DA and Tyramine
• MAOB mainly metabolises DA
• MAOIs inhibit MAOs, which increases monoamine levels

Examples:

•Iproniazid (discontinued)
• Tranylcypromine
• Phenelzine
• Clorgyline
• Moclobemide
 Monoamine Oxidase Inhibitors (MAOIs)
Mechanism of Action
Two MAO isoforms, MAO-A and MAO-B
Drug MAO Selectivity
Tranylcypromine, phenelzine Non-Selective
Clorgyline, moclobemide MAO-A Selective
Selegiline MAO-B selective (DA mainly)
• Selective inhibitors of MAO-A are more effective antidepressants
• Most MAOIs cause irreversible inhibition of MAO except moclobemide (RIMA:
Reversible inhibitor of MAO-A)
Serious Adverse Effect: Tyramine-rich foods e.g. aged cheese (Stilton), can cause
“cheese effect”. Tyramine is normally metabolised by MAO-A. MAOIs increase
plasma concentrations of tyramine which increase NA release from sympathetic
nerve endings è Hypertension
 Classes of Anti-Depressant Drugs
2. Tricyclic Antidepressants (TCAs):

• Prevent re-uptake of NA and 5-HT into

neuronal stores by blocking NA or 5-HT
transporter.
• Selectivity ratio for NA or 5-HT
transporter varies widely:
Desipramine relatively NA-selective,
Clomipramine relatively 5-HT selective
• Onset of action is delayed possibly due to
downregulation of presynaptic 5-HT1A
and/or a2-adrenergic receptors.

• Examples:
• Imipramine
• Amitriptyline
• Desipramine
• Nortriptyline
 Classes of Anti-Depressant Drugs

3. Selective Serotonin Reuptake Inhibitors (SSRIs):

SSRIs restore/increase levels of

5-HT in the synaptic cleft by
binding at the serotonin transporter
(SERT), preventing 5-HT re-uptake
and subsequent degradation.

Examples:
• Fluoxetine (Prozac™)
• Citalopram
• Fluvoxamine
• Paroxetine
• Sertraline
 Classes of Anti-Depressant Drugs

4. Noradrenaline-selective reuptake inhibitors (NRIs):

• Reboxetine
5. Serotonin and Noradrenaline reuptake inhibitors (SNRIs):
• Venlafaxine

6. Noradrenaline and Dopamine reuptake inhibitors (NDRIs):

• Bupropion

General observation with all anti-depressant drugs:

• Several weeks or months of anti-depressant treatment is required
before clinical improvement is reported.
• This is thought to be due to adaptive synaptic changes
• Role for brain derived neurotrophic factor (BDNF)
 SSRIs vs. Other Anti-Depressant Drugs
Benefits:
• Better side-effect profile than TCAs and MAOIs but not more
effective.
• Absence of anti-cholinergic side-effects improves compliance.
• Safer in overdose and in cardiovascular disease.
• Less likely to cause weight gain.

Adverse Effects:
• Nausea by potentiating 5-HT action in the CTZ (Chemoreceptor
trigger zone) “vomiting centre” of the brain
• Sexual side-effects (30-50% of patients, cognitive and physical)
• Increased suicidal thinking and behaviour: “Blackbox warning”
- Issued by FDA in 2004, based on epidemiology
- 4% on drug, vs 2% not on drug
 SSRIs vs. Other Anti-Depressant Drugs
• SSRI’s: Less “off-target” effects than TCAs
• TCA’s also inhibit Histamine Receptors → Drowsiness
• TCA’s also inhibit Muscarinic Acetylcholine Receptors → Anticholinergic Effects
 Evolution of Major Classes of Antidepressants

Antidepressant drugs are classified by chemical structure and mechanism of action:

TCA = Tricyclic Antidepressant NARI = Noradrenaline Reuptake Inhibitor
SSRI = Selective Serotonin Reuptake Inhibitor RIMA = Reversible Inhibitor of Monoamine Oxidase
SNRI = Serotonin Noradrenergic Reuptake Inhibitor
 Summary:
Mechanisms of Action of Anti-Depressants
Anti-Depressants: Other Mechanisms of Action
 Acute SSRI Effects on Serotonergic Transmission

• Acute admin of anti-depressants

produce a large increase of synaptic
5HT, which activates autoreceptors and
reduces 5HT release.

•Activation of presynaptic serotonin

autoreceptors (5HT1B (rodent), 5HT1D
(humans); 5HT1A) act as negative
feedback system to control neuron
firing and reduce 5HT release.
• Autoreceptors act as a regulatory
safety-valve for neurotransmission.
• Early / acute negative feedback system
diminishes antidepressant effects.
 Chronic Effects of Anti-Depressants on
Serotonergic Transmission
Chronic administration of antidepressants
can cause a number of changes in the brain,
depending on drug type:

1. SSRIs and MAOIs desensitize inhibitory

autoreceptors: 5-HT1A (somatodendritic)
5-HT1D (pre-synaptic)

2. TCAs, electroconvulsive therapy (ECT) and

other non-SSRI antidepressants can:
(i) Sensitize (↑) inhibitory post-synaptic 5-HT1A
receptors.
(ii) ↓ Expression of stimulatory 5-HT2A receptors.

3. Chronic antidepressant treatment can also affect

post-receptor signaling mechanisms, such as
G-protein coupled receptors (GPCRs)
Chronic Anti-Depressant Treatment: Gene Expression
 Chronic Anti-Depressant Treatment:
Neurotrophic Effects: Role of BDNF?

Neurogenesis: Birth of new

neurons may occur throughout
adulthood in the hippocampus.

Rediscovered in late 1990’s in

animal models, chronic stress
has been shown to decrease adult
hippocampal neurogenesis

Berton and Nestler, 2006

In Search of New Anti-Depressants
 Ketamine’s Inhibition of Pre-Synaptic NMDA receptors

Note: While ketamine inhibits NMDA receptors, it may indirectly potentiate AMPA receptor activation
 New / Alternative Treatment Strategies

• Electrical Stimulation of Neurons:

Invasive: Vagus Nerve Stimulation (VNS)
Deep Brain Stimulation
Non-Invasive: Trans Cranial Stimulation (TCS)

• Vassopressin receptor antagonists:

• Stress-induced vasopressin release potentiates effects of CRF on
ACTH release.
• V1b antagonists show antidepressant-like effects in rodents.

• Glucocorticoid Receptor Antagonists: Mifepristone

 Bipolar Disorder (Manic Depression)

Bipolar I Disorder: Recurrent episodes of

mania and depression.
Bipolar II Disorder: People who experience
milder episodes of hypomania and depression.

• Has a stronger genetic component (heritability) than unipolar depression

• Episodes of mania and depression that typically recur across the lifespan.
• Between episodes, most people with bipolar disorder are symptom free.
• Rapid mood cycling tends to develop later in the course of illness and more common in
women than men.
Treatments:
Mood stabilisers: Lithium (Li+), Antiepileptic drugs
Acute treatment of mania: Atypical antipsychotic drugs
• Mood stabilisers such as lithium are used for extended periods of time (years).
• Other medications e.g. atypical antipsychotics are added when necessary to treat episodes
of mania or depression as they arise.
 Mood Stabilisers: Lithium

• Lithium carbonate was first used as an anti-manic agent in 1949 by John Cade
• First mood-stabilizing medication approved by the U.S. Food and Drug Administration
(FDA) for treatment of mania, is often very effective in controlling mania and is also
used as a prophylactic treatment to prevent the recurrence of both manic and
depressive episodes.
• Chronic treatment required for therapeutic effect
• Effective, but many side-effects affect patient compliance
• Narrow therapeutic index: Therapeutic: 0.5 – 1mM/L; Toxic effects: > 1.5mM/L, thus
monitoring of plasma conc. is required.

Toxicity:
• Kidney damage: Nephrogenic diabetes insipidus, Renal failure
• Hypothyroidism, weight gain and cognitive effects (chronic use)
• Acute toxicity > 3-5 mM/L: convulsions, coma, death. Dose must be adjusted
according to [plasma].
• Diuretics can increase toxicity by increasing the reabsorption of Li+.
 Lithium: Multiple Mechanisms of Action

Li+ modulates neurotransmitter balance between excitatory and inhibitory neurons,

which may contribute protection:

1. Thought to mimic Na+ and permeate voltage-gated Na+ channels thus accumulating in
the cell and causing depolarization, particularly serotoninergic neurons.

2. Blocks the phosphatidylinositol (PI) pathway at the point where inositol-1-phosphate

is hydrolysed to inositol. This causes a depletion of membrane phosphatidyl inositol
bisphosphate (PIP2) which reduces the action of transmitters acting at receptors that use
inositol-1,4,5-trisphosphate/diacylglycerol (InsP3/DAG) as their second messengers.

3. Lithium modulates signals that regulate neuronal plasticity (the ability of neurons to change
their structure or function). It has been suggested that neuronal plasticity is critical for mood
recovery and stabilization:
• Inhibits glycogen synthase kinase-3 (most convincing evidence)
• Inhibits protein kinase C
• Activates ERK/MAPK kinases
Lithium: Multiple Sites of Action
 Bipolar Treatment: Other Mood Stabilisers

Anticonvulsants / Anti-Epileptic Drugs:

Na+ channels blockers: Carbamazepine, lamotrigine, valproate
Can be used prophylactically to prevent manic episodes
Anti-Epileptic drugs may be combined with Li+ for maximum effect.

Atypical Anti-Psychotic Drugs:

Examples: Clozapine, olanzapine, risperidone, quetiapine and aripiprazole.

Anti-Depressants + Mood Stabilisers:

• People with bipolar disorder who take anti-depressants for low mood are at
risk of cycling between states of depression and hypomania/mania.
• Therefore, a combination of anti-depressants and mood stabilisers is used
to limit the switch in mood.