Drugs Used in Affective Disorders

Philip Sasi, July 2020

 Background
• Affective disorders are characterised by
disturbances in mood and the main types
are depression and mania
• Depression is the most common mental illness
– It may be unipolar(the mood is always low)
or bipolar (low mood alternates with mania –
manic-depressive illness)
 Background Continued
– It may be reactive (i.e. a response to traumatic life
events), or endogenous (i.e. with no obvious
cause)
• Severe endogenous depression may border on
the psychotic and can carry a high risk of
suicide.
 Pathophysiology
• The neurological basis of depression is poorly
understood
• The monoamine theory, which currently provides
the best explanation, states that
– in depression there is a functional deficit of the
transmitters noradrenaline (NA) and 5-
hydroxytryptamine (5-HT) in the forebrain and in
mania there is a functional excess.
– Evidence for this theory comes from the
antidepressant action of drugs acting at NA/5-HT
nerve endings:
 Pathophysiology Continued
• In support of this theory are the following
observations:
– inhibition of NA or 5-HT reuptake improves mood
– inhibition of monoamine oxidase (MAO: which
metabolises NA and 5-HT) has an antidepressant
effect
– reserpine, which depletes monoamine stores in the
nerve endings, causes depression.
 Pathophysiology Continued
• Against the monoamine theory are the following
observations:
– the sympathomimetic drugs cocaine and amphetamine lack an
antidepressant action
– some drugs (e.g. iprindole) have an antidepressant effect in the
absence of clear effects on NA/5-HT transmission
– there is a 2–4 week delay in the onset of the clinical action of
antidepressant drugs despite immediate effects on
neurotransmission
– there are inconsistent changes in NA and 5-HT receptor densities
and in the turnover of amine transmitters in depressed patients
 Drugs Used in Affective Disorders
• The main categories of drugs used in affective
disorders are:
– those used to treat unipolar depression, namely
the antidepressants
– those used to treat bipolar depression.
 Antidepressant Drugs
• The main classes of antidepressant are:
– inhibitors of the reuptake of monoamine
transmitters:
• tricyclic antidepressants (TCAs): e.g. imipramine,
amitriptyline, clomipramine
• selective serotonin reuptake inhibitors (SSRIs),
e.g. fluoxetine, paroxetine, citalopram
• miscellaneous reuptake inhibitors, e.g. maprotiline,
venlafaxine
 Antidepressant Drugs Continued
• Main classes of antidepressant continued
– MAO inhibitors (MAOIs), e.g. phenelzine,
isocarboxazid
– atypical antidepressants, e.g. trazodone,
bupropion.
 Mechanism of Action of
Antidepressants
• Monoamine reuptake inhibitors
– The explanation of how these drugs act is given by
their names
– Inhibition of reuptake raises the concentration of
transmitter in the synaptic cleft and increases
stimulation of postsynaptic receptors
– The selectivity for NA and 5-HT reuptake varies
between the three main groups and between
compounds in the same group
 Mechanism of Action of
Antidepressants Continued
• Monoamine Oxidase inhibitors (MAOIs)
– These inhibit MAO within nerve endings
– The cytosolic NA/5-HT concentration thus
increases and more leaks out into the synaptic
cleft
– There are two MAO isoenzymes (A and B)
– The selectivity of MAOIs for the isoenzymes is
shown in the table below
 Mechanism of Action of
Antidepressants Continued
• Monoamine Oxidase inhibitors (MAOIs)
continued
– Selective inhibitors of MAO-A are more effective
antidepressants with fewer side effects
– The older MAOIs bind covalently to the enzyme
and consequently have a long duration of action;
some newer drugs bind reversibly
(e.g. moclobemide) and are safer
TABLE 40.1 The selectivity of drugs for MAOIs
Selectivity Drugs
Iproniazid, isocarboxazid,
Non-selective
tranylcypromine, phenelzine
MAO-A selective Clorgyline, moclobemide
MAO-B selective Selegiline
 Mechanism of Action of
Antidepressants Continued
• Atypical antidepressants
– These have less well characterised mechanisms of
action; some combine actions on monoamine
transporters and on receptors For example (see
table below)
Mechanism of Action of Atypical Antidepressants
Drug Action
Trazodone has weak 5-HT uptake inhibition and
antagonism of 5-HT receptors
Bupropion has dopamine and NA reuptake
inhibition
Mianserin and Mirtazepine have α2-adrenoceptor antagonism (the
latter also has NA reuptake inhibition)
Iprindole has dopamine reuptake inhibition.
 Time Course of Action of
Antidepressants
• It is important to note that for both the reuptake
inhibitors and MAOIs, effects on
neurotransmission can be expected fairly rapidly.
• However, the antidepressant effect is not
apparent for 2–6 weeks
• This may be due to slower changes in receptor
density (β1, α2-adrenoceptors, 5-HT1A and 5-HT2-
receptors), desensitisation of monoamine
receptors or increased neurogenesis in the
hippocampus.
 Pharmacokinetic Aspects of
Antidepressants
• TCAs
– These are very lipid soluble and are well absorbed
by mouth.
– They bind strongly to plasma and tissue
components, which results in a large volume of
distribution.
– Many TCAs are tertiary amines with two methyl
groups attached to the side chain nitrogen.
 Pharmacokinetic Aspects of
Antidepressants Continued
• TCAs Continued
– Removal of one of these methyl groups (e.g.
imipramine to desmethylimipramine (desipramine)
or amitriptyline to nortriptyline) yields active drugs.
– The desmethyl metabolites show a greater ratio of
NA/5-HT reuptake inhibition.
– Many TCAs are subsequently conjugated with
glucuronic acid. TCAs have long half-lives and
dosage can often be once daily.
 Pharmacokinetic Aspects of
Antidepressants Coninued
• SSRIs
– These are given orally and are well absorbed. The
half-lives are: fluoxetine 24–96 h; citalopram
24–36 h and paroxetine 18–24 h.
 Unwanted effects of Antidepressant
Drugs
• TCAs
– Dangerous in overdose.
– They are chemically related to the antipsychotic
phenothiazines and many have a similar spectrum
of side effects due to receptor block:
• antimuscarinic actions: dry mouth, constipation, blurred
vision, urinary retention
• antihistamine effect: sedation
• α-adrenoceptor block: hypotension.
 Unwanted effects of Antidepressant
Drugs Continued
• SSRIs
– Generally safer and have fewer side effects than
TCAs; those that occur include:
• nausea and vomiting
• sexual dysfunction.
– Serious adverse effects can occur if SSRIs are given
concurrently with MAOIs
• Miscellaneous monoamine reuptake inhibitors
have fewer adverse actions than the TCAs
 Unwanted effects of Antidepressant
Drugs Continued
• Atypical antidepressants
– Fewer adverse effects than the TCAs
– Trazodone causes marked sedation, which leads to
low compliance
– Mirtazapine can cause weight gain
• All antidepressants can cause hyponatraemia,
especially in the elderly
 Unwanted effects of Antidepressant
Drugs Continued
• MAOIs
– These drugs potentiate amine transmitters and
indirectly acting amines, e.g. those used as
decongestants
– They can cause serious unwanted effects if given with
tyramine-containing foods (e.g. cheese, red wine)
– This is referred to as the ‘cheese reaction’. Because
tyramine is normally rapidly metabolised by MAO in
the gut and liver, therapy with MAOIs will lead to high
concentrations of this amine in the plasma
 Unwanted effects of Antidepressant
Drugs Continued
• MAOIs continued
– The tyramine will then release NA from
sympathetic nerve endings which can result in
dangerous hypertension
– Selective MAO-A inhibitors do not produce such a
strong ‘cheese-reaction
– MAOIs cause hypotension.
 Clinical Uses of Antidepressants
• SSRIs and TCAs are used primarily to treat
depression but are also used effectively in some
anxiety disorders:
– panic disorder (citalopram), obsessive compulsive
disorder, bulimia.
• The combination of an atypical agent with an SSRI
may be beneficial in antidepressant-resistant
patients.
 Clinical Uses of Antidepressants
continued
• TCAs produce varying degrees of sedation:
sedative agents being used for anxious
patients; less-sedative agents for withdrawn
patients.
• MAOIs are less effective and subject to more
drug interactions than the reuptake inhibitors
and are considered second line
 Drugs used for Bipolar Depression
• Lithium
– Lithium is an important drug for the prophylaxis of
bipolar disorder
– Its actions may be attributable to:
• inhibition of the formation of inositol trisphosphate (as a
result of protein kinase C activation),
• inhibition of kinases and/or by mimicking Na+
– thus modifying cell membrane potential and ionic
balance
•
Drugs used for Bipolar Depression
• Lithium continued
– It causes CNS toxicity and in large concentrations,
renal damage.
– Its low therapeutic index makes it essential to
monitor its plasma concentration.