Depression and anxiety disorders

Question 1

Current theory

Answer 1

Cortisol is usually elevated in depressed patients; glutamate levels are increase in depression, which can lead to excitotoxicity and apoptosis.

For our purposes, the monoamine theory is the most important relating to medications.

The traditional theory: “Monoamine Hypothesis” – with a deficiency of monoamine neurotransmitters (NA and 5-HT)

Question 2

What strategies might address a monoamine deficiency?

Answer 2

Theoretically, we must increase or supplement the concentration of neurotransmitter in some way to “fix” or compensate for the shortage;
Strategies used in depression treatment:
• Prevent neurotransmitter from being taken up back into the neuron;
• Prevent neurotransmitter from being enzymatically broken down.

Question 3

Tricyclic Antidepressants: Imipramine

Answer 3

Imipramine was the first TCA to be developed (late 1950s), and due to their adverse effects they are not now used in first line treatment.
Imipramine is considered for treatment of resistant depression as well as for generalised anxiety disorder.

Question 4

How do TCAs work

Answer 4

TCAs inhibit the reuptake of both noradrenaline (NET) and serotonin (SERT) into the presynaptic neuron. Sounds great, as we target the two neurotransmitters that have
decreased activity in depressed patients.
TCAs also bind and antagonise histamine H1 receptors (sedation); α-adrenoreceptors (postural hypotension); muscarinic acetylcholine receptors (blurred vision, dry mouth and constipation)

Question 5

TCA side effects

Answer 5

TCA side effects can be serious and may discourage patients from taking their medication.

Blockade of muscarinic cholinergic receptors may lead to tachycardia due to prolonged QT of the ECG.
• Therefore, overdose of TCAs can be FATAL due to their cardiac effects. TCAs should never by used by someone taking additional drugs which affect the cholinergic system.
• Nevertheless, the good effects outweigh the bad side effects in most cases, and TCAs have helped many patients.

Question 6

Selective Serotonin Reuptake Inhibitors

SSRIs

Answer 6

SSRIs bind and block SERT proteins, preventing re-uptake and slowing degradation of 5-HT in the presynaptic neuron.

Long term use increases cAMP signalling and phosphorylation of nuclear transcription factor CREB, increases in neurogenesis from progenitor cells of hippocampus as well as downregulation of SERT – leading to elevated 5-HT levels.

• For most patients,, SSRIs are more effective than TCAs in relief of depression, and these are usually the first-line agents used in treatment..

Question 7

Serotonin and Noradrenaline Reuptake Inhibitors: SNRIs

Answer 7

Both NA and 5-HT synapses are affected simultaneously, but with greater specificity than the TCAs.

• Minimal affinity and thus minimal antagonism of histamine H1 or muscarinic ACh receptors, so reduced sedation or cardiovascular effects.

Question 8

SNRIs: compare to TCAs and SSRIs?

Answer 8

• Has pharmacological actions similar to both, but fewer of the side effects than TCAs due to lesser affinity for and antagonism of cholinergic and adrenergic receptors.
• SNRIs inhibit SERT, which leads to activation of autoreceptors and then desensitization.

Question 9

Serotonin Syndrome

Answer 9

Combinations with the following drugs are contraindicated while taking a MAOI (Monoamine oxidase inhibitors) and for 14 days after stopping it because of the possibility of either severe hypertension (resulting from the accumulation of endogenous catecholamines) or the development of serotonin toxicity during this period:

atomoxetine, cocaine, desvenlafaxine, dexamphetamine, dextromethorphan, duloxetine, entacapone, ephedrine, fentanyl, linezolid, methylphenidate, mianserin, pethidine, phentermine, phenylephrine, pseudoephedrine, reboxetine, SSRIs, TCAs, tramadol and venlafaxine.

Be aware that toxicity may result from misuse of drugs, eg amphetamines, cocaine, pethidine, and that the nonselective MAOIs also interact with some illicit drugs, eg ‘ecstasy’, LSD.

Question 10

MAO (Monoamine oxidase)

Answer 10

These enzymes have major roles in metabolism of exogenous (dietary tyramine) and endogenous (monoamines) compounds.
We have two forms of MAO enzymes in the brain:
MAO-A – located throughout tissues, in gut and CNS; metabolises tyramine in the intestine and preferentailly NA, 5-HT in the CNS.
MAO-B: located in CNS dopaminergic neurons where it preferentially metabolises DA.
MAO-A-inhibitors are used to treat depression, while MAO-B-inhibitors are utilised in Parkinson’s Disease to increase dopamine concentrations.

Some strategies which work across various diseases:
either add neurotransmitter or its precursor
Prevent neurotransmitter from being taken up back into the neuron
Prevent neurotransmitter from being enzymatically broken down.

Question 11

MAOI mechanisms of action

Answer 11

In some cases, the MAOI covalently binds to MAO-A. This requires the neurons to synthesize new MAO-A enzyme every time antagonism occurs to replenish supply.

In the gut, irreversible inhibition of MAO-A means that tyramine is NOT broken down in the GI tract, and unaltered tyramine can readily enter the blood stream.
Tyramine crosses the BBB, enters neurons by NET, and displaces noradrenaline from synaptic termini, triggering a sudden and dangerous increase in blood pressure.

Patients are placed on tyramine- restricted diets while on MAOI medication: no cheese, yeast (Vegemite!), beer, Chianti wine, avocados, yogurt, soy sauce, bean pods, banana skins; as well as some medications, such as L- DOPA and SSRIs.

If patient ingests these things, they may have skin flushing and strong headaches… a “cheese reaction”

Question 12

(Monoamine oxidase inhibitors) MAOI - medications

Answer 12

Isocarboxazid, Phenelzine, Selegiline, Tranylcypromine.

Dietary requirements - no food containing tyramine

Adverse effects: HTN, palpitations, chest pain, muscle rigidity, nausea, sedation, confusion.

Selegiline was put on the market in the form of a transdermal patch, which bypasses the digestive tract, and reduces risk of hypertensive crisis.
Good news: more selective MAO-A inhibitors are being found, such as moclobemide, which is short- acting and safer than earlier forms in this class.
Toxicity and major interactions with food make these a less preferred choice for depression.

Question 13

Other antidepressants

Answer 13

NDRIs - noradrenaline-dopamine reuptake inhibitors
- bupropion IR, SR, XL
(contraindicated in patients with anorexia, bulimia, or seizure disorders)

Mixed action antidepressants - serotonin 5-HT2A receptor antagonists
- mirtazapine, nefazodone, trazodone

Question 14

Agomelatine (Valdoxan)

Answer 14

(2011): Used to treat anxiety in depressed patients.
• MOA: acts as agonist on melatonin receptors MT1 and MT2 as well as
antagonising 5-HT2C.
• It is thought that agomelatine thus resynchronises circadian rhythms that are disrupted in depressed patients.
• Agomelatine is also a non-monoadrenergic compound; used in depression and anxiety?

Question 15

Choosing antidepressant class

Answer 15

Approximately half of adults with moderate-to-severe major depression respond to antidepressant treatment, and relapse is relatively common.
• Most antidepressant drugs are approximately equal in efficacy, although individual patient response may vary markedly. Similarly, although the antidepressant classes have different adverse effects, no class is clearly superior in terms of tolerability.
• SSRIs can be regarded as first-line drugs in adults due to their generally favourable risk–benefit ratio.
• Nonselective MAOIs (phenelzine, tranylcypromine) are generally used for those who have previously responded well to them, or when other treatments are ineffective or not tolerated.

Question 16

What happens to the patient once they are in remission?

Answer 16

• The antidepressant is use should be continued for at least nine months at the dose which maintains normal mood.
• If the dose is reduced or stopped during this time, relapse may occur as well as withdrawal syndrome (dizziness, headache, nausea, nervousness and insomnia).
• When a medication is discontinued after nine months, the dose if often gradually reduced over a six week period to avoid symptoms such as anxiety, agitation, mood swings, and nausea.
• Some SSRIs have active metabolites while others don’t and this can impact on aspects of withdrawal.

Question 17

Electroconvulsive therapy (ECT)

Answer 17

Typically involves 6-8 generalised seizures under light anaesthesia over 2-3 weeks.

ECT is one of the MOST effective treatments for depression, but effects are short-lived; thus combined with anti- depressant.

Patient is treated with muscle paralysing agents but there must be evidence on EEG of seizure to be effective. Memory loss is commonly reported as a side effect.

Mechanism: may promote neurogenesis? In animals, 5-HT synthesis and uptake are unaltered, NA uptake is slightly increased.

Question 18

Benefits of psychotherapy + pharmacology

Answer 18

Combining psychotherapy with medication:

• reduces aspects of stress as patient develops strategies to cope
• renews perspectives on problems
• supports use of medications
• strategies about dealing with side effects
• support in how to inform others about condition.
• catching early signs that depression is worsening.

That said, it is estimated that only about 30% of patients are effectively managed long-term for depression.

• Combining medications with cognitive strategies may improve responses and promote remission..
• Depression is a disorder of prolonged time course, in which patient education and collaboration with health professionals is a must..
• About 15% of depression patients will commit suicide, making depression a life-threatening illness.

Question 19

Anxiety

Answer 19

• Term used to describe both symptoms and disorders
• Occurs normally as signal of impending danger or threat
• Very common, occurs in many disorders in addition to the anxiety disorders

Adaptive value of anxiety :
• helps to plan and prepare for threat
• moderate levels enhance learning and performance
• Maladaptive when chronic / severe; pathological anxiety is excessive and impairs function.

Historically,
many drugs have been used for relief from anxiety,
including alcohol, barbiturates and opium.
These drugs are generally depressants, which slow down nervous system, leading to drowsiness, impaired memory, and physical dependence.

Question 20

Classifications of anxiety disorders

Answer 20

In anxiety disorders, we have a shift in the balance of CNS neurotransmitters…possibly leading to aspects of “overexcitation”, perhaps due to the systemic effects experienced..
To counter this effect, traditionally we have used means and methods to decrease the neuronal and synaptic activity of the nervous system.

Anxiety disorders: phobias, OCD, panic disorder, generalised anxiety disorder, PTSD

Question 21

GABA A receptors: “inhibitory modulation”

Answer 21

Binding of GABA alters the shape of the central pore through the middle of the GABAA receptor complex, allowing Cl- ions to pass through down their concentration gradient, from outside the neuron to inside the neuronal cytoplasm.

This influx of Cl- ions increases the negative membrane potential of the postsynaptic neuron, and essentially makes it less likely that it will fire a subsequent action potential.

Benzodiazepines do not have ANY effect on the GABAA receptor themselves, but they are positive allosteric modulators which enhance the affinity of the receptors for GABA and cause the chloride channel to open more frequently and for longer periods of time.

Question 22

Benzodiazepines - Properties

Answer 22

Pharmacological Effects:
• Reduction of anxiety.
• Induction of sleep.
• Potential anaesthesia – some benzodiazepines.
• Respiratory depression not as great as observed with barbiturates.

Adverse Effects:
Expected side effects: sedation, ataxia, dependence.
• Impaired cognition and motor function.
• Confusion.
• Amnesia.
• Fatal overdose is uncommon, except when taken with alcohol.

Question 23

Benzodiazepines – Concentration, Tolerance and Discontinuing Use

Answer 23

[Nanomolar] Anxiolytic sedation
Action effectively blocked by flumazenil.
[Micromolar]
Anesthesia – diazepam, midazolam, lorazepam.
Flumazenil may precipitate withdrawal symptoms in patients dependent on

Benzodiazepines may induce tolerance in some individuals.
Discontinuation of benzodiazepine therapy in tolerant patients MUST be gradual.
Lowest effective dose for the shortest possible time.
Most common complaint: feeling sedated or mentally “fuzzy” in the morning…check half-life!
The longer the drug’s half-life, the more common this complaint by patients.
As before, do not mix these with alcohol!

Question 24

Benzodiazepines

Answer 24

Neural circuitry involving the amygdala and hippocampus is thought to underlie anxiety, so activation of GABAergic neurons may create a sense of relaxation.

However, benzodiazepine action is not region specific, so binding to GABAA receptors in the respiratory centres in the brain stem slows down breathing.

This makes them useful for insomniacs.

Question 25

Buspirone (BuSpar)

Answer 25

Partial agonist at the serotonin 1a receptor; non BZD and no interaction on GABAA receptor, no issues with alcohol consumption
• Relieves anxiety without producing sedation, impairment of motor skills, or memory loss.
• Does not induce withdrawal symptoms upon discontinuation.

Does not act immediately.
• Can take up to 1 week to become
effective.
• Used for chronic GAD states.

Pharmacokinetics:
• Rapidly absorbed orally.
• Rapid first-pass effect.
• Elimination half-life = 2-4 hrs.
• Metabolism is primarily hepatic.

Question 26

Anxiety and antidepressants

Answer 26

• Recall that treatment of depression has traditionally involved SSRIs, SNRIs, TCAs, and MAOIS, which increase concentrations of 5-HT and NA within CNS.
• SSRIs and SNRIs can be effective treatments for GAD (generalized anxiety disorder), phobias, social anxiety disorder, OCD and PTSD. They also reduce depression associated with anxiety.
— Imipramine (TCA) has positive effects in 60- 70% of panic disorder patients, although at a higher dose than used in treating depression.
— MAOIs can be used to treat PTSD, agoraphobia, panic disorder, and social phobia.

This suggests that serotonin and/or noradrenaline are involved in stress effects as well as depression in the brain

Question 27

Cognitive-Behavioural Therapy (CBT)

Answer 27

Very useful in treating anxiety disorders.

— The cognitive part helps people change the thinking patterns that support their fears.
— The behavioural part helps people change the way they react to anxiety-provoking situations.
—
The benefits of CBT may last longer than those of medication for people with PD, and the same may be true for OCD, PTSD, and social phobia.
—
Medication should be combined with psychotherapy for specific anxiety disorders, and this is the best treatment approach for many people.