Anxiety & Depression

Question 1

What is anxiety

Answer 1

Both depression and anxiety are mental health states that are associated with imbalances
of excitatory and inhibitory neural pathways within the CNS.

Anxiety-related disorders are generally the reverse of this, due primarily to the overactivity of monoamine pathways (dopamine and noradrenaline).

Question 2

What is depression

Answer 2

Both depression and anxiety are mental health states that are associated with imbalances
of excitatory and inhibitory neural pathways within the CNS.

Depression is
due to underactivity of monoamine neurotransmitter pathways, principally noradrenaline and
serotonin (5HT).

Question 3

What do SSRIs do?

Answer 3

The SSRIs inhibit the reuptake of serotonin (5HT) into the presynaptic neuron, thus increasing the amount of serotonin in the synapse and prolonging serotonin signalling.

They have a much greater affinity for the serotonin transporter than the noradrenaline or dopamine transporters

Question 4

Explain SSRIs interactions

Answer 4

Selective serotonin reuptake inhibitors can, however, interact with other receptors, such
as the muscarinic acetylcholine receptor, to a limited degree and affect liver enzyme systems.

The degree of interaction depends on the specific SSRI and as such, you cannot assume that they all have the same level of effect.

All drugs of this class are considered to have an increased suicide risk in adolescents

Question 5

What are SSRI side effects

Answer 5

Side effects related to the increase in serotonin in the brain include agitation, amnesia,
confusion, emotional lability and sleep disorder.

Fluoxetine has a neurostimulant action and hence is taken in the morning rather than in the evening.

There is an emerging view that there is increased risk of upper gastrointestinal bleeding with SSRI antidepressants, probably via an effect on systemic serotonin levels

Selective serotonin reuptake inhibitors may also cause hyponatremia.

Question 6

What are TCA’s

Answer 6

Tricyclic antidepressants are used primarily to produce non-selective inhibition of noradrenaline and serotonin reuptake systems in the CNS.

These drugs have the effect of raising noradrenaline and serotonin levels throughout the body, including the CNS

Question 7

What are TCS interactions

Answer 7

TCAs exhibit substantially more side effects than SSRIs; related to their antagonist action at other receptors in the body, including the muscarinic acetylcholine and histamine H1 receptors.

Patients may notice side effects of these drugs within a very short space of time, long before the therapeutic effects are apparent.

Many TCAs have pharmacologically active metabolites. For example, nortriptyline, which is a drug in its own right, is actually a metabolite of amitriptyline.

The presence of active metabolites may increase the severity of side effects.

Question 8

What are TCAs side effects

Answer 8

TCAs have a higher rate of Q-T interval prolongation than SSRIs, especially at higher doses and in overdose.

They also have a narrow therapeutic index which means that when used together with drugs which inhibit cytochrome P450 activity (e.g. cimetidine), the severity of side effects may be increased, possibly leading to increased toxicity. On the other hand, when used with drugs which induce cytochrome P450 activity (e.g. rifampicin), therapeutic effect may be diminished.

Question 9

Give examples of TCAs

Answer 9

Amitriptyline
Imipramine
Nortriptyline

Question 10

Give examples of SSRIs

Answer 10

Sertraline
Citalopram
Fluoxetine
Paroxetine

Question 11

What are SNRI’s

Answer 11

Serotonin and noradrenaline reuptake inhibitors (SNRIs)
work by selectively inhibiting the reuptake of serotonin and noradrenaline in much the same way that TCAs do. However, they do not show antagonist activity at other receptors so their side
effect profile is reduced.

Question 12

What side-effects do SNRI’s have?

Answer 12

Serotonin and noradrenaline reuptake inhibitors are sympathomimetic and in high dose has been associated with hypertensive crisis.

Question 13

What are MAOI’s?

Answer 13

Monoamine oxidase inhibitors produce a non-selective
irreversible inhibition of the mitochondrial enzyme monoamine oxidase.

By inhibiting the enzyme responsible for monoamine metabolism, they inhibit the breakdown of monoamines
(e.g. serotonin and noradrenaline), resulting in enhanced levels of available monoamines in the
presynaptic neuron.

Question 14

Give examples of SNRIs

Answer 14

Venlafaxine, duloxetine

Question 15

Give examples of MAOI’s

Answer 15

Phenelzine

Question 16

What is the issue of taking MAOIs with foods rich in AA tyramine?

Answer 16

Foods rich in the essential amino acid tyramine, such as mature cheese, pickled herring, broad
bean pods, meat or yeast extract products (Bovril , Marmite & Oxo), may cause a
potentially fatal rise in blood pressure if taken together with an MAOI

Question 17

How do benzodiazopines works?

Answer 17

All benzodiazepines act via the GABAA receptor by producing changes that increase the effectiveness of the naturally produced GABA.

Increased GABA interaction leads to an increase in chloride influx and thus prolonged hyperpolarisation (brain
suppression).

Benzodiazepines only work in the presence of endogenous GABA.

Question 18

Describe the pharmacokinetics of BZDs

Answer 18

The speed of action and elimination of individual benzodiazepines varies. These differences are primarily due to variations in pharmacokinetic properties such as absorption, lipid solubility (if high then rapid onset of action), presence or absence of active metabolites, hepatic metabolism and elimination half-life.

Some benzodiazepines have many active metabolites
which complicates an understanding of their pharmacokinetic profile.

Fast-acting benzodiazepines
have higher lipid solubility and as a consequence cross cell membranes, including the
blood–brain barrier, more easily than more water-soluble (hydrophilic) drugs.

They are also
much more addictive.

Question 19

What are the side effects of BZDs

Answer 19

• disinhibition (especially in children and the elderly)
• CNS depression
• rebound insomnia,
• anxiety (especially for short-acting benzodiazepines such as midazolam)
• respiratory depression.

As well as onset adverse reactions, benzodiazepines have a complex series of withdrawal signs and symptoms that can mimic the conditions for which the drug was initially prescribed, such as ‘rebound anxiety’ or panic attacks.

Discontinuation of benzodiazepines therefore requires tapering of the dose which allows the body to adjust to a reduction in GABAergic output in a way that does not precipitate rebound sympathomimetic effects, such as anxiety

Question 20

Explain the BZDs interactions

Answer 20

Some benzodiazepines alter the activity of cytochrome P450 enzymes in the liver and this
may alter the pharmacokinetics and effects of the benzodiazepine or other drugs prescribed concomitantly.

If given with other drugs that are CNS depressants, such as tricyclic antidepressants,
anticonvulsants or antipsychotic drugs, there will be enhanced sedation.

Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the hepatic CYP3A4 enzyme system (e.g. cimetidine, erythromycin and verapamil) as these drug interactions may result in prolonged sedation due to a decrease in plasma clearance
of midazolam

Question 21

What other areas are BZDs used?

Answer 21

sedation/insomnia
agitation
anaesthesia induction
akathisia (motor restlessness due to antipsychotics)
seizures including status epilepticus

Question 22

Learning outcome: Describe the stepwise approach promoted by NICE to manage generalised anxiety and depression

Question 23

Learning outcome: Utilise the BNF to identify interactions involving antidepressants
and suggest appropriate strategies to avoid or minimise them

Question 24

Learning outcome: Explain how co-morbidities, concurrent medication and cost
can influence the selection of a selective serotonin reuptake
inhibitor (SSRI)

Question 25

Learning outcome: Outline the importance of counselling when starting, stopping or
switching an antidepressant