D,B+A

Question 1

Why is there a limited range of antidepressants?

Answer 1

Limited understanding of the precise mechanisms associated with depression

Most development of therapeutic drugs is based on the “monoamine hypothesis” but it is complex in nature, heterogeneous and associated with other comorbid psychiatric disorders

Biological testing of an individual is difficult

Can be a difficult regulatory environment. E.g. difficult to get approval to study psychedelics
New drug discovery for depression is very reliant on animal models

No single behavioural test can ‘model’ depression

Question 2

What is studied when a new antidepressant is tested?

Answer 2

• Cognition and Emotion,
• Behavioural Despair,
• Social models,
• Hopelessness,
• Anxiety-like symptoms,
• Locomotor activity,
• Anhedonia

Question 3

What are the 7 effects of Salvia divinorum (kappa opioid receptor agonist)?

Answer 3

1) Uncontrollable hysterical laughter
2) Becoming objects
3) Overlapping realities
4) Loss of the body or identity
5) Entering a 2-dimensional world
6) Revisiting places from the past
7) Weird physical sensations, being pulled or twisted

Question 4

What is the role of the kappa-opioid system in antidepression?

Answer 4

Activation of CREB (cAMP-responsive-element-binding protein) by stress, mediates the induction of dynorphin (a kappa agonist), which then contributes to anhedonia-like symptoms.

CREB is activated by D1 dopamine receptors leading to increased expression of dynorphin. Dynorphin feeds back onto opioid receptors located in the ventral tegmental area (VTA).

Stimulation of these receptors inhibits the VTA neurons, which leads to anhedonia-related symptoms. Therefore, antagonists of kappa receptors might block the consequences of CREB-induced increases in dynorphin activity, and exert antidepressant effects in some individuals.

Question 5

How were receptor selective opioid antagonists developed?

Answer 5

The message-address concept: The ‘message’ component of a ligand defines the primary receptor recognition (e.g. to a receptor family) while the ‘address’ portion confers selectivity to a particular receptor subtype.

Question 6

What are pharmacophores?

Answer 6

A pharmacophore is a set of structural and electronic features that are required for a compound to bind to a biological target. Pharmacophores are used in drug discovery to identify potential lead compounds.

Question 7

What are the three aims of treatment for depression?

Answer 7

• Remission
• Relapse prevention
• Function restoration

Question 8

What are NICEs reccommendations for treating depression?

Answer 8

• Match the level of care to the severity
• Match closely the patients preference

Question 9

What are the different types of therapy offered by nice?

Answer 9

• psychodynamic psychotherapy
• Counselling
• Interpersonal psychotherapy
• Individual behavioural activation
• Individual CBT
• Group behavioural activation

Question 10

What are the four more common antidepressant treatment escalations?

Answer 10

• SSRIs
• Alternative SSRI
• Recognised combo
• Addition of mood stabiliser/antipsychotic

Question 11

What are the three less common antidepressant treatments?

Answer 11

• MAOIs
• Tricyclics
• Vortioxetine

Question 12

How is antidepressant therapy monitored?

Answer 12

Duration
Efficacy
Side-effects
When to consider changing to another agent
When to stop treatment and importance of slow withdrawal

Question 13

What are serotonergic side effects?

Answer 13

Gastrointestinal
Nausea, diarrhoea, decreased/increased appetite
Sexual dysfunction
E.g. delayed ejaculation
Insomnia & agitation
More rarely bruising and bleeding
Antiplatelet effect - beware those also on aspirin
More rarely hyponatraemia
Withdrawal syndrome

Question 14

What is serotonin syndrome?

Answer 14

A predictable reaction when two or more agents increasing levels of serotonin are co-prescribed
Onset is usually rapid, often occurring within minutes to hours of elevated serotonin levels
Serotonin syndrome encompasses a wide range of clinical findings
Current thinking favours the spectrum concept of ‘serotonin toxicity’ as a continuum of serotonergic effects ranging from mild adverse effects through to a life-threatening syndrome

Question 15

What are the cognitive effects of serotonin syndrome?

Answer 15

headache, agitation, hypomania, mental confusion, hallucinations, coma

Question 16

What are the autonomic effects of serotonin syndrome?

Answer 16

shivering, sweating, hyperthermia, vasoconstriction, tachycardia

Question 17

What are the somatic effects of serotonin syndrome?

Answer 17

myoclonus (muscle twitching), hyperreflexia, tremor

Question 18

How is serotonin syndrome managed?

Answer 18

Stop interacting agents
Support organ function
Managing temperature
Agitation and muscle twitching use benzodiazepines
Serotonin antagonist cyproheptadine can be used

Question 19

What do patients need to know before starting antidepressant therapy?

Answer 19

Symptoms may get worse in first week to 10 days, including increased anxiety & suicide ideation (SSRIs)
Once well treatment continued for at least 6 months to prevent relapse as depression often reoccurs
The chances of staying well are improved by antidepressants (prophylaxis)
Greater than 2 major depressive episodes consider long-term prophylaxis at full therapeutic dose
Some people may need treatment for several years
Antidepressants are not addictive but can cause withdrawal
Antidepressants should not be stopped or changed suddenly: taper down
Relevant interactions with other medicines including OTC

Question 20

What do patients need to know about stopping antidepressants?

Answer 20

When stopping antidepressants, some patients experience uncomfortable and distressing withdrawal effects
This has not been well recognised or acknowledged by many healthcare professionals in the past
Not all patients experience these symptoms, For others withdrawal symptoms can be mild and go away relatively quickly. Other people can have more severe symptoms which last much longer (sometimes months or more)

Question 21

What is treatment resistant depression?

Answer 21

One third of people will not respond to their first antidepressant
About 20% of people never respond to antidepressants and may seek ECT or augmented combinations
Try switching to another agent, same class or different if adverse effects
Can augment with another medication e.g. lithium, sodium valproate or olanzapine
Don’t forget non-pharmacological options
Have a clear strategy and comprehensive medication history

Question 22

What is bipolar?

Answer 22

Bipolar disorder is a recurrent and often chronic mental illness marked by alternating periods of abnormal mood elevation and depression associated with a change or impairment in functioning.
The long-term course of illness is characterised by a predominance of depression, although a history of at least one manic, hypomanic, or mixed episode is required to make the diagnosis of a bipolar disorder.
Misdiagnosis of bipolar disorder is common, with unipolar major depressive disorder the most frequent diagnostic error made.
The management of acute mania requires mood stabilisers or atypical antipsychotics, as monotherapy or in combination. There are fewer approved treatment options for acute bipolar depression; traditional antidepressants are not indicated.
Bipolar disorder requires an individualised long-term management plan that includes maintenance medication(s), adjunctive psychosocial therapies, careful monitoring for any treatment-emergent complications, and promotion of a healthy lifestyle including sleep hygiene, exercise, and stress management.

Question 23

How is bipolar treated pharmacologically?

Answer 23

Mood stabilisers
Lithium
Anti-convulsant medications such as valproate or lamotrigine
Antipsychotics
Benzodiazepines
Beware dependence
Antidepressants
A controversial treatment o

Question 24

How is lithium used therapeutically?

Answer 24

Offer lithium as a first‑line, long‑term pharmacological treatment for bipolar disorder (NICE CG 185 recommendation 1.7.6)
But taking lithium erratically is probably worse than not taking it at all
Ideally the decision to take lithium should be a joint one so the patient has the chance to consider the issues around side-effects and monitoring
Therefore acute treatment of either pole of the illness is likely to focus on other treatments, despite the fact that lithium can have acute efficacy in both depression and mania
Mainly used prophylactically:
Only reduce mania in acute episodes
Reduce both depressive and manic phases
Long term treatment to prevent relapse
Effects seen after 3-4 weeks of treatment

Narrow therapeutic window
Therapeutic range; 0.4 mmol/L – 1.0 mmol/L
Potentially fatal > 1.5mmol/L
Plasma concentration monitoring required

Question 25

How can lithium be used effectively?

Answer 25

Dose adjusted according to serum-lithium concentration and once daily administration is preferred when treatment is stabilised
A narrow therapeutic window – therapeutic drug monitoring and careful management of salt and fluid intake is very important
There are several key drug interactions including ACEI, diuretics and NSAIDs (including OTC preparations)
Monitoring of adverse effects including renal and thyroid function are key
A single daily dose regimen is associated with less polyuria, a reduction in permanent renal damage and better compliance
Solid dose forms (lithium carbonate) and liquids (lithium citrate) need careful dose conversion if swapping between them
Preparations vary in bioavailability by brand, stick to the same whenever possible
Abrupt withdrawal is necessary in severe toxicity but if possible should otherwise be avoided – rebound mania can be severe and difficult to treat

Question 26

How is lithium monitored?

Answer 26

Therapeutic serum-lithium concentrations should be taken 12hrs post-dose and the target range is usually 0.4–0.8 mmol/litre (may be as high as 1mmol/litre in specific cases)
concentrations in excess of 2 mmol/litre are usually associated with serious toxicity
Weekly monitoring is required while treatment is established or re-started
Monitoring of lithium levels and other key parameters including renal function should be undertake at least every 6-months for patients on a stable dose, more frequently (3-monthly) in higher risk groups
several variability factors for PK profile including age, body weight, renal function and pregnancy
The pharmacokinetic profile of lithium is linear within the dose regimen used in clinical practice

Question 27

Side fx of lithium

Answer 27

Acute
Polyuria and polydipsia (renal problems)
Weight gain
Aggravation/precipitation of skin disorders
Tremor, Muscle twitching, Dysarthria
Nausea, Vomiting, Appetite loss, Diarrhoea
Sluggishness, Languidness, Drowsiness
Coma, Hyper-reflexia, Fasiculations
Choreiform and Parkinsonian motor symptoms
Limb Hyperextension, Seizure and Convulsions
Chronic
Thyroid goitre
Nephrotoxicity
Hair loss

Question 28

MoA of lithium

Answer 28

We don’t really know!
Monovalent cation that permeates voltage-gated sodium channels
Not removed by Na/K ATPase
Depolarization of excitable cells

Inhibition of phosphatidyl inositol pathway
Prevents agonist stimulated IP3 formation

Inhibition of glycogen synthase kinase 3 (GSK3)
Involved in apoptosis and amyloid formation
Lithium beneficial in neurodegeneration?

Question 29

What are the symptoms of lithium toxicity?

Answer 29

Gastro-intestinal disturbances (vomiting, diarrhoea),
Visual disturbances
Polyuria
Muscle weakness
Fine tremor increasing to coarse tremor,
CNS disturbances which can be confused with symptoms of bipolar (confusion and drowsiness increasing to lack of coordination, restlessness, stupor)
Abnormal reflexes, myoclonus

Question 30

When is CBT recommended?

Answer 30

Recommended for depression, anxiety, OCD, panic, social anxiety, phobias, and adapting to long-term health conditions.

Question 31

Family intervention therapy?

Answer 31

Recommended to help families work together to support a loved one who has a severe mental health disorder

Question 32

Behavioural activation therapy?

Answer 32

Recommended for subthreshold depressive symptoms, mild to moderate depression, and severe depression.

Question 33

Trauma focused CBT/EMDR?

Answer 33

Recommended for PTSD

Question 34

DBT?

Answer 34

Recommended for borderline personality disorder.

Question 35

Initiating a conversation around deprescribing?

Answer 35

Initiated by the patient
Respect the patient’s request – don’t be dismissive
Exploring reasons for the request
Initiated by a healthcare professional
Don’t rush a patient into a decision to stop/reduce
Explain reasons
Be prepared for queries about prescribing decisions made previously. Explain that our understanding of the balance of risks and benefits of a medicine can change over time.

Question 36

Factors to consider when deprescribing

Answer 36

Is the patient symptom-free, and if so, for how long?
Long-standing, non-distressing symptoms which have not previously been responsive to medication may be excluded.
What is the severity of adverse-effects (EPS, TD, sedation, obesity, etc.)?
What was the previous pattern of illness?
Consider the speed of onset, duration and severity of episodes and any danger posed to self and others.
Has dosage reduction been attempted before, and, if so, what was the outcome?
What are the patient’s current social circumstances?
Is it a period of relative stability, or are stressful life events anticipated?
What is the social cost of relapse
e.g. is the patient the sole breadwinner for a family?
Is the patient/carer able to monitor symptoms, and, if so, will they seek help?

Question 37

Withdrawal or discontinuation reactions

Answer 37

Not well recognised previously, patients have worked hard to have this phenomenon accepted.
Approximately half of patients will experience withdrawal symptoms on reducing or stopping their antidepressant. For some of these patients the symptoms will be severe (possibly up to half) and can be long-lasting (for months, or years). For others they may be mild and self-limiting.
There is some evidence that tapering slowly can reduce the chance of intolerable withdrawal symptoms.
Clinical experience suggests that most patients take between 3 months and 2 years to withdraw in a tolerable manner from long-term antidepressant treatment.

Question 38

Withdrawal symptoms

Answer 38

Paresthesia
Numbness
Shock-like sensations
Rushing noises
Palinopsia
Confusion
Decreased concentration
Amnesia
Hypersensitivity

Question 39

NICE guidelines on withdrawal

Answer 39

Explain to people taking antidepressant medication that:
withdrawal symptoms can be mild, may appear within a few days of reducing or stopping antidepressant medication, and usually go away within 1 to 2 weeks
withdrawal can sometimes be more difficult, with symptoms lasting longer (in some cases several weeks, and occasionally several months)
withdrawal symptoms can sometimes be severe, particularly if the antidepressant medication is stopped suddenly.
Recognise that people may have fears and concerns about stopping their antidepressant medication (for example, the withdrawal effects they may experience, or that their depression will return) and may need support to withdraw successfully, particularly if previous attempts have led to withdrawal symptoms or have not been successful. This could include:
details of online or written resources that may be helpful
increased support from a clinician or therapist (for example, regular check-in phone calls, seeing them more frequently, providing advice about sleep hygiene).
When stopping a person’s antidepressant medication:
take into account the pharmacokinetic profile (for example, the half-life of the medication as antidepressants with a short half-life will need to be tapered more slowly) and the duration of treatment
slowly reduce the dose to zero in a step-wise fashion, at each step prescribing a proportion of the previous dose (for example, 50% of previous dose)
consider using smaller reductions (for example, 25%) as the dose becomes lower
if, once very small doses have been reached, slow tapering cannot be achieved using tablets or capsules, consider using liquid preparations if available
ensure the speed and duration of withdrawal is led by and agreed with the person taking the prescribed medication, ensuring that any withdrawal symptoms have resolved or are tolerable before making the next dose reduction
take into account the broader clinical context such as the potential benefit of more rapid withdrawal if there are serious or intolerable side effects (for example, hyponatraemia or upper gastrointestinal tract bleeding)
take into account that more rapid withdrawal may be appropriate when switching antidepressants
recognise that withdrawal may take weeks or months to complete successfully
Do not stop a medicine abruptly (complete cessation with immediate effect) unless there are exceptional medical circumstances such as the occurrence of serious side effects (for example, upper gastrointestinal bleeding from an antidepressant, respiratory depression from an opioid or severe ataxia from a gabapentinoid)
Suggest a slow, stepwise rate of reduction proportionate to the existing dose, so that decrements become smaller as the dose is lowered, unless clinical risk is such that rapid withdrawal is needed
If using a published withdrawal schedule, apply it flexibly to accommodate the person’s preferences, changes to their circumstances and the response to dose reductions.
Ensure the plan for dose reduction or withdrawal is clearly recorded in the overall management plan.
During withdrawal, offer continued management of the underlying condition for which the medicine was prescribed, if needed.
Explain that the reduction schedule can be modified to allow intolerable withdrawal symptoms to improve before making the next reduction
Consider giving the person additional control over the process of dose reduction (e.g. issuing their usual daily dose in a form that allows them to reduce the amount in small decrements at a pace of their choosing, rather than issuing successive prescriptions for reduced daily doses)

Question 40

Practicalities of withdrawal

Answer 40

Inform patients of potential withdrawal symptoms, but don’t sensationalise (be aware that those with previous negative experiences will need more reassurance)
Be realistic about timescales
Discuss differences between relapse and withdrawal symptoms
Be prepared for the plan to be flexible and responsive to the patient
If symptoms become intolerable, either hold the current dose for longer or return to the last tolerated dose and then make the next reduction smaller
Currently available pharmaceutical preparations make very slow downward titrations difficult
Use liquid preparations where possible
! If at all possible, avoid a blanket refusal of liquid preparations
! Careful prescribing and dispensing needed – risk of errors
Some patients gain access to tapering strips but these are not widely available
Final reductions may need to be very small
In almost all cases, alternate day dosing is to be avoided

Question 41

What are mood disorders?

Answer 41

Complex and heterogeneous - includes depression and mania
Leading cause of illness worldwide
Globally, more than 300 million people of all ages suffer from depression (WHO)
Suicide is the second leading cause of death in 15-29-year-olds.(WHO)
Can occur with anxiety, psychosis and other psychiatric symptoms
Commonly involves somatic symptoms and disorders
Difficult to categorize, diagnose and treat

Question 42

prevalence of depression

Answer 42

Depression is common
Lifetime prevalence of unipolar depression 5% - ~1 in 38 adults in the UK at any one time
Globally > 300 million patients with depression (WHO estimates)
Co-morbidity is common
2/3 of those with MDD will also meet criteria for anxiety disorder at some point (Mineka, et al., 1998)
MDD twice as common in women than men
Similar discrepancy occurs in many countries
Differences emerge in adolescence (age of onset?)
Symptom variation
across cultures
across life span
Episodic, recurrent can lead to suicide (0.04-0.08%)

Question 43

diagnosing depression

Answer 43

EITHER Depressed mood most of the day, nearly every day
OR Diminished interest/pleasure in everyday activities (anhedonia), nearly every day

PLUS 4 or more of the following
Significant weight loss/gain (>5% in a month) or change in appetite
Insomnia/ hypersomnia
Slowing down of thought and reduction of physical movement
Fatigue or loss of energy nearly every day
Feelings of worthlessness or excessive or inappropriate guilt
Diminished concentration, or indecisiveness, nearly every day
Recurrent thoughts of death or suicide

Question 44

assessment of depression

Answer 44

Clinician administered assessment scales
Hamilton Depression Rating Scale (HAM-D or HDRS)
Montgomery-Asberg Depression Rating Scale (MADRS)

Self-rating assessment scales
Beck Depression Inventory (BDI)

Why?
Assess severity of symptoms
Evaluate response to treatment
Promote self-management strategies

Question 45

Major depressive disorder

Answer 45

Episodic
Symptoms tend to dissipate over time
Recurrent
Once depression occurs, future episodes likely
Average number of episodes is 4 (Judd, 1997)
Subclinical depression
Sadness plus 3 other symptoms for 10 days
Significant impairments in functioning even though full diagnostic criteria are not met

Question 46

Persistent Depressive Disorder (Dysthymia)

Answer 46

Chronic depression
Depressed mood for at least 2 years (not severe enough for a MD episode)
PLUS 2 other symptoms:
Poor appetite or overeating
Sleeping too much or too little
Psychomotor agitation or retardation
Loss of energy
Feelings of worthlessness
Difficulty concentrating or indecisiveness
Recurrent thoughts of death or suicide

Question 47

bipolar disorders

Answer 47

Usually involve episodes of depression
alternating with mania – difficult to recognize
Mania
States of intense elation or irritability
Mixed episode
Symptoms of both mania and depression in the same week
Hypomania
Symptoms of mania but less intense
Four or more days of elevated mood
Doesn’t interfere with functioning
Hypomania alone is not a DSM diagnostic category

Question 48

criteria for manic and hypomanic episodes

Answer 48

Elevated, expansive, or irritable mood
PLUS 3 of the following (4 if mood is irritable):
Psychomotor agitation or increase in goal-directed behavior
Excessive talking or pressured speech
Flights of ideas; racing thoughts
Reduced need for sleep
Grandiosity or inflated self esteem
Easily distractible
Excessive involvement in pleasurable activities with negative consequences e.g. spending sprees
For manic episode:
Symptoms last for 1 week OR require hospitalization
Symptoms cause significant distress or functional impairment
For hypomanic episode:
Symptoms last at least 4 days
Clear changes in functioning but impairment is not marked

Question 49

3 forms of bipolar

Answer 49

Bipolar I
At least one episode or mania or mixed episode

Bipolar II
At least one major depressive episode with at least one episode of hypomania

Cyclothymic disorder (Cyclothymia)
Milder, chronic form of bipolar disorder
Lasts at least 2 years
Numerous periods with hypomanic and depressive symptoms

Question 50

bipolar prevalence

Answer 50

Prevalence rates for bipolar disorder lower than MDD
1% for Bipolar I (Weissman et al., 1996)
Average age of onset in 20s
No gender differences
Tends to be recurrent
Severe mental illness
A third unemployed a year after hospitalization (Harrow et al., 1990)
Suicide rates high (Angst et al., 2002)

Question 51

subtypes of depressive disorders

Answer 51

Seasonal (SAD)
Episodes happen regularly at a particular time of year
Rapid cycling (Bipolar I and II)
At least 4 episodes within past year
Postpartum onset
Within 4 weeks of giving birth
Catatonic features
Extreme physical immobility or excessive peculiar physical movement
Psychotic features
Delusions or hallucinations
Melancholic
Inability to experience pleasure (anhedonia)

Question 52

medical conditions associated with mood disorders

Answer 52

Pulmonary disease (COPD, asthma)
Endocrine disorders (Hypo/hyperthyroidism, diabetes)
Cancer
Cardiovascular disease, especially MI
CNS (migraine, infection, tumour, stroke, head injury, hypoxia)
Neurological disorders (Alzheimer’s, Epilepsy, Parkinson’s, Huntington’s, Multiple Sclerosis)
B12, folate deficiency
Chronic pain, back problems
Sleep apnea

Question 53

What causes mood disorders

Answer 53

Genetic factors - Heritability estimates
93% Bipolar Disorder
37% Major depression
Neurotransmitter dysfunction
Monoamines – 5HT, noradrenaline, dopamine
Neuroendocrine – disruption of the hypothalamic-pituitary-adrenal axis
Neurogenesis – Decreased rate of newborn neurones in the adult hippocampus
Neuroinflammation – any chronic inflammatory condition could produce cytokines/inflammatory markers that are able to cross blood-brain barrier and activate microglia
Glutamate – glutamate antagonists e.g. ketamine (NMDAR antagonist) antidepressant
Psychosocial/environmental factors
Stressful life events e.g. marriage breakdown, loss of job
Co-morbidity e.g. chronic pain, substance abuse
Medication e.g. corticosteroids, oral contraceptives, interferon

Question 54

neurotransmitters that cause mood disorders

Answer 54

Neurotransmitters most implicated in mood disorders are the monoamines:
MDD
Low levels of 5-hydroxytryptamine and/or noradrenaline (and/or dopamine)

Mania
High levels of noradrenaline and dopamine, low levels of 5-hydroxytryptamine

Based largely on the ability of known antidepressant drugs to facilitate monoaminergic transmission = ‘the monoamine hypothesis of depression”

Reserpine – inhibits 5-HT and NA storage – lowers mood
Tryptophan depletion – lowers brain 5-HT synthesis – induces relapse in recovered patients

Question 55

what is the monoamine theory of depression

Answer 55

depression is a functional deficit of 5HT and/or noradrenaline in the brain

Question 56

psychological treatment of mood disorders

Answer 56

Interpersonal psychotherapy (IPT)
Short term psychodynamic therapy
Focus on current relationships
Cognitive therapy
Monitor and identify automatic thoughts
Replace negative thoughts with more neutral or positive thoughts
Behavioral activation
Mindfulness based cognitive therapy (MBCT)
Strategies, including meditation, to prevent relapse

Question 57

electroconvulsive therapy

Answer 57

Reserved for
Severe depression with high risk of suicide
Depression with psychotic features
Treatment non-responders

Induce brain seizure and momentary unconsciousness
Unilateral ECT
Side effects
Memory loss

Question 58

monoamine oxidase inhibitors

Answer 58

e.g. phenelzine, tranylcypromine, iproniazid

Irreversible inhibitors of monoamine oxidase
MAO is widely expressed
Within nerve terminals regulates intraneuronal concentration of NA/5HT
In the gut wall inactivates endogenous/ingested
amines
Enzyme exists in two forms MAOA and MAOB
MAOA – substrate preference = 5HT
MAOB – substrate preference = DA

Question 59

‘Cheese reaction’ with irreversible MAOIs

Answer 59

Tyramine (diet) normally metabolised by MAO in the gut/ liver.

During non-selective MAOI:
Tyramine not metabolised but absorbed
Tyramine has sympathomimetic effects
Can result in acute hypertension, headache, angina, cardiac arrest, pulmonary oedema, intracranial haemorrhage.

Question 60

major side effects of MAIOs

Answer 60

Major side effects of MAOIs:
Hypotension (sympathetic block)
Atropine-like effects
Hepatocellular jaundice

Question 61

Reversible Inhibitors of MAOA (RIMA)

Answer 61

e.g. moclobemide

Reversible action allows MAOA inhibition to be partially overcome by high concentrations of substrate, e.g. tyramine

Unlikely to result in ‘cheese reaction’ if tyramine or sympathetic amines ingested

Question 62

Tricyclic antidepressants (TCAs)

Answer 62

e.g. imipramine, amitriptyline, clomipramine

Block the uptake of amines by nerve terminals
5-HT=NA&raquo_space; DA
Competitive with endogenous substrate
Relatively non-selective

Receptor blockade e.g. mAChRs, HA, 5-HT
Contributes to side effect profile

Major metabolites also active

Question 63

Major side effects of TCAs

Answer 63

Sedation
Atropine-like (muscarinic blockade)
Postural hypotension
Mania and convulsions (rare)
Dysrhythmia and heart block

Question 64

acute overdose of TCAs

Answer 64

Prominent antimuscarinic
Confusion, mania
Cardiac arrhythmias
Coma
Respiratory depression
hypoxia

Question 65

SSRIs

Answer 65

e.g. fluoxetine (Prozac), paroxetine citalopram
Developed by Eli Lilly in 1980s on the concept that
‘biological’ components of depressive illness are sensitive to antidepressant effects on NA systems
‘emotional’ components of depressive illness are sensitive to antidepressant effects on 5-HT systems
The most commonly prescribed class of antidepressants = 1st line
Also used to treat anxiety disorders

Question 66

SSRIs vs TCAs

Answer 66

Better side-effect profile?
Safer in overdose
No evidence of greater efficacy
No evidence of more rapid onset
Newer drugs
Serotonin and noradrenaline uptake inhibitors (SNRIs) e.g. venlafaxine
Greater therapeutic efficacy?
Lower side effect profile?
More rapid onset
Noradrenaline and dopamine uptake inhibitor e.g. bupropion
Depression with anxiety
Nicotine dependence, ADHD

Question 67

Monoamine receptor blockers

Answer 67

Mirtazapine – blocks a2 adrenoceptors/5HT2C receptors
Enhanced NA/5HT release
?More rapid acting, less side effects?

Trazodone - blocks 5HT2A/2C and 5HT reuptake

Mianserin – blocks multiple 5HT receptors, a1/2 adrenoceptors

*Agomelatine – blocks melatonin receptors
Useful for depression associated with sleep disturbance

Question 68

Limitations of antidepressants

Answer 68

Efficacy of antidepressants
<40% achieve remission from symptoms
Robust effect in preventing relapse in recurrent MDD

Tolerability
side effect profile deters use e.g. emotional blunting/detachment with SSRIs

Time to onset/discontinuation effects
Typically 4-6 weeks to onset of therapeutic benefit

Safety of antidepressants
Risk of suicide
Older drugs are cardiotoxic, dangerous in overdose

Question 69

Issues with the monoamine theory

Answer 69

Immediate short-term pharmacological effects
MAOIs increase 5-HT, NA by inhibiting metabolism
TCAs increase 5-HT, NA by blocking reuptake
SSRIs increase 5-HT by blocking reuptake

Clinical effects appear to take weeks to onset
Suggests chronic adaptive changes in response to antidepressants rather than acute

Question 70

Medication for bipolar

Answer 70

Aka “mood stabilizing drugs”
Lithium
Up to 80% receive at least some relief with this mood stabilizer
Potentially serious side effect = Lithium toxicity
Anticonvulsants (prevent relapse to depression?)
e.g. valproate, lamotrigine
Antipsychotics (co-prescribed, where mania predominates?)
e.g. olanzapine, risperidone, quetiapine, aripiprazole

Question 71

What is anxiety?

Answer 71

Anxiety is a normal, physiological response to threatening situations that serves a protective function

Anxiety is pathological when there is a bias to interpret non-threatening situations as threatening

The concern about the stressor is out of proportion to the realistic threat and can occur without exposure to an external stressor = pathological anxiety
Negative cognition:
Bias to interpret unthreatening situations as threatening
Context/memory/ reinforcement

Physiological symptoms: autonomic activation
Racing heart
Palpitations
Restlessness
Sweating
increased blood pressure

Defence/ Avoidance behaviours:
Activation of aminergic pathways

Question 72

anxiety disorders

Answer 72

Simple/Specific phobias
Social phobia/ Social anxiety disorder (SAD)
Panic disorder (PD)
Posttraumatic stress disorder (PTSD)
Generalized anxiety disorder (GAD)
Obsessive compulsive disorder (OCD)
(Premenstrual dysphoric disorder (PMDD))

Question 73

diagnosis of GAD

Answer 73

DSM criteria for generalized anxiety disorder include:
Excessive anxiety and worry about several events or activities most days of the week for at least six months
Difficulty controlling feelings of worry
At least three of the following symptoms in adults: restlessness, fatigue, trouble concentrating, irritability, muscle tension or sleep problems
Anxiety or worry that causes significant distress or interferes with daily life

Some disorders that commonly occur with generalized anxiety disorder include:
Phobias
Panic disorder
Depression
Substance abuse
PTSD

Question 74

causes of anxiety disorders

Answer 74

Largely unknown
Abnormal regulation of brain areas involved in stress/fear

Several neurotransmitter systems implicated:
Underactivity of 5HT system?
Overactivity of NA system?
Disruption in level of GABA inhibition?
reduced expression of GABAA-receptors
reduced function/regulation of GABAA-receptors by benzodiazepines
reduced function/regulation of GABAA-receptors by neurosteroids
Genetic and environmental factors play a role

Question 75

treatment of anxiety disorders

Answer 75

Pharmacotherapy
b-blockers – target autonomic symptoms
Benzodiazepines*
Antidepressants (SSRIs)
Buspirone (partial agonist at 5-HT1A receptors)
Specific NICE guidance for different anxiety disorders

Evidence-based psychological interventions
Low intensity interventions e.g. self-help approaches
High intensity interventions e.g. CBT for social anxiety disorder
Stepped-care approach (NICE guidance)

Question 76

beta blockers eg propranolol

Answer 76

Treat the physiological symptoms of anxiety
Reduce the sympathetic manifestations of stress/fear response
No effect on affective components
Useful in treating phobias
Evidence for use in curing phobias
Useful in treating PTSD
Effects on memory consolidation

Question 77

Benzodiazepines bind to an allosteric site on the GABAA receptor

Answer 77

Functional GABAA receptors are pentameric combinations of different subunits arranged to form the integral chloride ion channel
Most prevalent receptor in mammalian brain consists of two α, two β and one γ-subunit
GABA binds between α and β-subunits – so 2 molecules to activate receptor
Benzodiazepines bind at the interface between α/γ-subunits and affect chloride ion conductance to regulate GABAergic inhibition

Question 78

Development of benzodiazepines (BZs)

Answer 78

Developed in the 1950’s for their tranquilizing properties
First trials in monkeys noted “loss of fear, hostility, and aggressiveness; increased friendliness; still fully in touch with environment”
In the early 1970s more potent BZs such as chlordiazepoxide (Librium) and diazepam (Valium) accounted for 50% of all US psychoactive drug prescriptions
Fast acting and effective relief of anxiety and safer than barbiturates e.g. pentobarbital

Question 79

structure of benzodiazepines

Answer 79

The core of all BZ ligands is a benzene ring joined to a 7-membered 1,4-diazepine ring

R side groups influence the
AFFINITY of the BZ to bind the receptor
INTRINSIC EFFICACY of BZ to produce a functional effect
BZ AGONISTS have 100% intrinsic efficacy
BZ INVERSE AGONISTS bind to the site but produce the opposite effect and are said to have negative intrinsic efficacy.
BZ ANTAGONISTS bind to the BZ site but are unable to activate the receptor (intrinsic efficacy = 0)
other properties such as lipophilicity, water solubility etc.

Question 80

downsides of benzos

Answer 80

Memory loss
Sedation
Abuse potential (?)
Addictive (?)
Withdrawal syndrome

Question 81

What is sleep?

Answer 81

A readily reversible state of reduced responsiveness to, and interaction with, the environment

What is it for?
Cortical recovery
Organizing/storing memories
Metabolism/weight homeostasis
Sleep deprivation may provide clues

Question 82

What is REM sleep?

Answer 82

EEG like that of an active waking brain (“paradoxical sleep”)
Oxygen consumption of brain is high
Vivid dreaming
Loss of skeletal muscle tone (atonia)
Bursts of rapid eye movements
Sympathetic activity predominates

Question 83

What is non-REM sleep?

Answer 83

Non-REM sleep is a rest period
Muscle tension reduced
Body temperature lowered
Energy consumption lowered
Increase in parasympathetic activity
Brain rhythms slow (“slow wave sleep”)

Question 84

Brain mechanisms of sleep

Answer 84

Ascending reticular activating system (RAS)
Locus coeruleus – noradenaline
Raphe nuclei – serotonin
Brainstem/forebrain – acetylcholine
Midbrain – histamine

Firing of these neurons = awakening
Firing of these neurons = falling asleep

Question 85

Sleep regulating substances

Answer 85

Interleukins
immune mediators

Melatonin
derived from 5-HT in endocrine pineal gland
cure for jet lag?

Hypocretin-orexin
Hypothalamic neuropeptide regulates appetite, metabolism

Stimulants
e.g. caffeine, cocaine, amphetamine

Question 86

Sleep disorders - insomnia

Answer 86

Transient insomnia
e.g. noise, shift work, jet lag

Short-term insomnia (“primary insomnia”)
e.g. emotional problems, stress, anxiety

Chronic insomnia (“secondary insomnia”)
e.g. pain, depression, anxiety, alcohol abuse, dyspnoea

Fatal familial insomnia – very rare

Question 87

tips for sleeping better

Answer 87

• regular sleep hours
• restful environment
• move more
• be awake if awake
• write worries
• less caffeine

Question 88

Hypnotics

Answer 88

Good sleep hygiene = behavioural, environmental & temporal factors?
Hypnotic = a drug used to induce and maintain sleep

Use should be
intermittent
short term (< 2 weeks) if daytime impairment is severe
tolerance may develop
withdrawal syndromes can occur

Treatment aims to shorten time to sleep, increase total duration of sleep, without suppressing sleep cycle and REM sleep

Question 89

Benzodiazepine hypnotics

Answer 89

Long acting e.g. flurazepam/ Dalmane (2-keto)
May give rise to “hangover” effect

Short acting e.g. temazepam/ Restoril (3-OH), triazolam/ Halcion
little or no “hangover” effect
Rohypnol (flunitrazepam) – “date rape”

Little to distinguish between BZs in terms of efficacy, adverse effects or risk of dependency

Next-day residual effects common with diazepam, nitrazepam and flurazepam

Question 90

Non-benzodiazepine hypnotics

Answer 90

Zaleplon, zolpidem, zopiclone (“Z drugs”)
Non-benzodiazepines that bind to GABAA receptor
Short duration of action
Less likely to cause rebound insomnia than BZs
Dependence may be a problem

Question 91

OTC sleep aids

Answer 91

Antihistamines
Promethazine (Phenergan)
Diphenhydramine (Nytol)

‘Natural remedies’
Melatonin (Circadin)
Chamomile tea ?
Lavender?
Evening primrose oil?
Valerian?