W19 CNS conditions: Depression and Bipolar

Question 1

Depression – What is it referred to as? (2)

Answer 1

Depression may refer to a:
▪ Mood state, as indicated by feelings of sadness, despair, anxiety, emptiness, discouragement, or hopelessness; having no feelings; or appearing tearful.
▪ Mental disorder, the syndrome of major depression can occur in several disorders, such as bipolar disorder and schizophrenia

Question 2

Depression - Assessment
What is is the assessment called?
conditions to diagnose depression?

Answer 2

▪ Assessment of depression is based on the criteria in DSM-IV (Diagnostic and Statistical Manual of Mental Disorders)
▪ The DSM-IV system requires at least 5 out of 9 for a diagnosis of major depression.
▪ Symptoms should be present for at least 2 weeks and each symptom should be present at sufficient severity for most of every day.
▪ The DSM-IV system requires at least one key symptom (low mood, loss of interest and pleasure or loss of energy to be present.

Question 3

What are the Symptoms of Depression?

Answer 3

Key symptoms:
▪ Persistent sadness or low mood, and/or
▪ Marked loss of interest or pleasure.
At least one of these, most days, most of the time for at least 2 weeks.

If any of above present, ask about associated symptoms:
▪ Disturbed sleep
▪ Decreased or increased appetite and/or weight
▪ Fatigue or loss of energy
▪ Agitation or slowing of movements
▪ Poor concentration or indecisiveness
▪ Feelings of worthlessness or excessive or inappropriate guilt
▪ Suicidal thoughts or acts.

Question 4

Management using anti-depressants:
What are the 5 considerations?

Answer 4

▪ Starting treatment
▪ Switching treatment
▪ Response to treatment
▪ Remission
▪ Maintenance

Question 5

What are the 5 classes of pharmacological treatment for depression? (5)

Answer 5

▪ Selective serotonin reuptake inhibitors (SSRIs)
▪ Serotonin - noradrenaline reuptake inhibitors (SNRIs)
▪ Tricyclic antidepressants (TCAs)
▪ Monoamine oxidase inhibitors (MAOIs)
▪ Atypical anti-depressants

Question 6

Definition of Depression?

Answer 6

Depression symptoms range from lasting feelings of unhappiness and hopelessness to losing interest in the things you used to enjoy and feeling very tearful. Also physically feeling constantly tired, sleeping badly, having no appetite or sex drive, and various aches and pains.

Question 7

Management of depression?

Answer 7

Lifestyle changes such as regular physical activity, eating a healthy diet, not over-using alcohol, and getting enough sleep should be encouraged, as these may help to improve the patient’s sense of well-being.

Question 8

What should choice of treatment be based on? (5)
What are the first-line treatment options?

Answer 8

▪ The patient’s clinical needs
▪ Their preference
▪ Response to any previous treatment
▪ Co-morbid diseases
▪ Existing therapy
▪ suicide risk

▪ The use of an antidepressant
and/or
▪ Psychological and psychosocial treatment
(guided self-help, CBT, behavioural activation (BA), group physical activity provided by a trained healthcare professional, group mindfulness and meditation, interpersonal psychotherapy (IPT), counselling, or short-term psychodynamic psychotherapy (STPP)

Question 9

Mild depression is ideally treated with? (3)

Answer 9

1. NOTHING
2. Psychological and psychosocial therapy (such as guided self-help, CBT, or BA)
3. Pharmacotherapy – SSRIs: Citalopram, Escitalopram, Sertraline, Fluoxetine
4. Herbal remedies such as St John’s Wort? NO- many interactions

Question 10

Moderate to severe depression ideally treated with? (3)

Answer 10

1. Psychological therapy AND drug therapy
2. Psychological therapy OR drug therapy
   Pharmacotherapy – 1) SSRIs; or 2) SNRIs; or 3) TCA
3. Electroconvulsive therapy (ECT)

Question 11

Treatment duration of antidepressants:

Answer 11

During the first few weeks of treatment, there is an increased potential for agitation, anxiety, and suicidal ideation

▪ Patients reviewed every 1-2 weeks at the start
▪ Response to treatment should be assessed within 2-4 weeks
▪ Effects of treatment usually seen within 4 weeks
▪ Treatment should be continued for at least 6 months
▪ Following remission - treatment continued at the same dose for at least 6 months

Question 12

Treatment options – General comments

Answer 12

▪ SSRIs - better tolerated and safer in overdose
▪ Sertraline is safer in patients with unstable
angina, or who have had a recent myocardial
infarction
▪ TCAs - similar efficacy - more side effects and toxicity in overdose.
▪ MAOIs have dangerous interactions with some foods and drugs - should be reserved for specialist use

Question 13

SSRIs - Pharmacology?

mechanism of action?

Answer 13

▪ Should be considered first-line for treating depression.
▪ Indicated for depression and panic disorder
▪ SSRIs are better tolerated and are safer in overdose than other classes of antidepressants
▪ SSRIs are less sedating and have fewer antimuscarinic and cardiotoxic effects than TCAs

Question 14

SSRI’s mechanism of action?

Answer 14

▪ Selectively inhibit the re-uptake of serotonin (5-hydroxytryptamine (5-HT))

1. Tryptophan (a.a.) synthesises serotonin (5-HT) 2. This is packaged into vesicles.
2. Monoamine oxidase enzymes breakdown and serotonin released into synaptic cleft and
3. Binds to 5-HT receptors on post-synaptic neuron. 5. Reuptake of serotonin by SERT (serotonin transporters)

Question 15

SSRIs:
MHRA/CHM Guidance?
C/I?
Overdose symptoms?
Withdrawal symptoms?

Answer 15

▪ SSRIs are less cardiotoxic, less sedating and less antimuscarinic than TCAs
▪ They are also safer in unstable angina and myocardial infarction and in overdose

MHRA/CHM advice:
▪ SSRIs/SNRI - small increased risk of postpartum haemorrhage when used in the month before delivery
▪ Increases risk of bleeding and postpartum haemorrhage due to effect on platelet function

Contraindications
▪ Poorly controlled epilepsy
▪ Should not be used if patient enters a manic phase
▪ QT-interval prolongation

Overdose: nausea, vomiting, agitation, tremor, nystagmus, drowsiness, tachycardia, convulsions.

Treatment cessation

Withdrawal symptoms: GI disturbances, headache, anxiety, dizziness, electric shock sensation in the head, neck and spine, tinnitus, sleep disturbances, fatigue, sweating
Withdraw gradually over a few weeks or longer

Question 16

Examples of SSRIs?

Answer 16

Citalopram (10,20,40mg)
Fluoxetine (20,60mg)
Paroxetine (10mg)
Escitalopram (5,10,20mg)
Sertraline (50,100mg)
Fluvoxamine (maleate) 25, 50mg

Question 17

What are SNRIs?
Examples?

Answer 17

Serotonin-noradrenaline reuptake inhibitors
Venlafaxine, Duloxetine, Desvenlafaxine

Question 18

SNRIs - Pharmacology- What conditions are they indicated for?

Answer 18

▪ Indicated for:
➢major depression
➢generalised anxiety disorder
➢social anxiety disorder
➢panic disorder
➢menopausal symptoms, particularly hot flushes in women with breast cancer
▪ Known to be associated with severe withdrawal symptoms

Question 19

Mechanism of action SNRIs?

Answer 19

▪ Selectively inhibit the re-uptake of serotonin 5-HT and norepinephrine (NE)

1. Tyrosine (a.a) synthesises NE and this is packaged into vesicles
2. MAO enzymes breakdown
3. Transported into synaptic cleft and binds to Beta and Alpha 1 receptors of post-synaptic neuron
4. Reuptake via NE transporters.

Question 20

Examples of SNRIs?

Answer 20

Duloxetine, Desvenlafaxine, Venlafaxine

Question 21

TCAs - Pharmacology and mechanism of action

Answer 21

▪ TCAs have similar efficacy to SSRIs but are more likely to be discontinued because of side effects.
▪ Toxicity in overdosage is also a problem (Lofepramine safest; both amitriptyline and dosulepin dangerous).
▪ Indicated for:
➢major depression
➢neuropathic pain
➢migraine prophylaxis
➢emotional liability in patients with multiple sclerosis
➢abdominal pain or discomfort (in patients who have not responded to laxatives, loperamide, or antispasmodics)

Question 22

TCAs – examples?

Answer 22

Tricyclic antidepressants
Amitriptyline, Nortriptyline, Clomipramine

Question 23

TCAs - Mechanism of action?

Answer 23

Inhibit the re-uptake of 5-HT and NE, Also inhibit the histamine and muscarinic
receptors and block the sodium channels in the heart.

(Same as both SSRI and SNRI examples)

Question 24

Tricyclic and related antidepressant drugs

Answer 24

Amitriptyline:
Side effects are reduced by titrating slowly to the minimum effective dose
(every 2-3 days)
Overdose: dry mouth, coma, hypotension, hypothermia, convulsions, respiratory failure, cardiac conduction defects and arrhythmias

Treatment cessation
▪ Withdrawal effects may occur within 5 days of stopping - usually mild and self-limiting.
▪ Risk of increased if stopped suddenly after 8 weeks or more. Preferably be reduced over 4 weeks

Question 25

Tricyclic and related antidepressant drugs
Which are more and less sedating?

Answer 25

More sedating
▪ Amitriptyline
▪ Clomipramine
▪ Dosulepin
▪ Doxepin
▪ Mianserin
▪ Trazodone
▪ Trimipramine

Less sedating
▪ Imipramine
▪ Lofepramine
▪ Nortriptyline

Question 26

MAOIs - Pharmacology and mechanism of action
Indicated for?
What can they interact with?
Examples?

Answer 26

▪ Mainly indicated for major depressive illness.
▪ MAOIs have dangerous interactions with some foods and drugs, and should be reserved for use by specialists.

▪ Foods rich in tyramine:
➢Cured, smoked, or processed meats include dried sausages like pepperoni and salami, hot dogs, bologna, bacon, and smoked fish.
➢Sauerkraut, kimchi, pickled beets, pickled cucumbers, and pickled peppers have high tyramine levels.
➢Also, fermented soy products like tofu, miso, and soy sauce contain tyramine

MoA= Inhibit MAO enzymes subtypes A and B.
Examples- Moclobemide, Isocarboxazid, Phenelzine

Question 27

Monoamine oxidase inhibitors (MAOI)
What patients respond best to MAOIs? (2)
Contraindications?

Answer 27

▪ Phobic patients and depressed patients with atypical, hypochondriacal, or hysterical features are said to respond best to MAOIs.
▪ Less suitable for prescribing due to dangers of dietary and drug interactions

C/I:
▪ Cerebrovascular disease
▪ Not indicated in manic phase
▪ Severe cardiovascular disease
▪ phaeochromocytoma

Question 28

MAOI Interactions:

Answer 28

Long duration of action
- gap between switching treatments

Other antidepressants should not be started for 2 weeks after treatment with MAOIs has been stopped (3 weeks if starting clomipramine or imipramine). Conversely, an MAOI should not be started until:
* at least 2 weeks after a previous MAOI has been stopped (then started at a reduced dose)
* at least 7–14 days after a tricyclic or related antidepressant (3 weeks for clomipramine or imipramine)
has been stopped
* at least a week after an SSRI or related antidepressant (at least 5 weeks in the case of fluoxetine) has been stopped

Question 29

MAOI Food and Lifestyle:
What are the food interactions with MAOIs?

Answer 29

Potentially life-threatening hypertensive crisis can develop in those taking MAOIs who eat tyramine-rich food (such as mature cheese, salami, pickled herring, Bovril®, Oxo®, Marmite® or any similar meat or yeast extract or fermented soya bean extract, and some beers, lagers or wines) or foods containing dopa (such as broad bean pods). Avoid tyramine-rich or dopa-rich food or drinks with, or for 2 to 3 weeks after stopping, the MAOI.

Question 30

Atypical Antidepressants
Examples?

Answer 30

▪ Bupropion – weak NE and DA reuptake inhibitor
▪ Mirtazapine – α-2 receptor antagonist, thus increasing 5-HT
and NE transmission. Also post-synaptic 5-HT blocker and antihistamine receptors.
▪ Trazodone – inhibits re-uptake of 5-HT receptors, and blocks post-synaptic 5-HT 2a receptors. Also, blocks histamine and α-1 post-synaptic receptors

Question 31

Antidepressants side effects - Hyponatraemia

Common in..?
Hyponatraemia should be considered in all patients who develop..? (3)

Answer 31

▪ Usually in the elderly
▪ Possibly due to inappropriate secretion of antidiuretic hormone)

▪ Drowsiness
▪ Confusion
▪ Convulsions

Question 32

Antidepressants side effects?
What are the symptoms? (SS and SRI- serotonin syndrome)

Answer 32

S= Suicide risk INC
S= Slow Onset & Slow Taper off
S= Sweat and Hot Fever
R= Rigid muscles + Restlessness & Agitation
I= Increased Heart Rate *Tachycardia
Weight Gain
Sexual Dysfunction

Question 33

Antidepressants side effects – Serotonin Syndrome
Onset of symptoms?
Symptoms? (3)

Answer 33

Onset of symptoms:
▪ Range from mild to life threatening
▪ Occur within hours or days following initiation, dose escalation, or overdose of a serotonergic drug, addition of a new serotonergic drug, or replacement of one serotonergic drug by another without allowing a long enough washout period in-between, particularly when the first drug is an irreversible MAOI or a drug with a long half-life.
▪ Severe toxicity, which is a medical emergency, usually occurs with a combination of serotonergic drugs, one of which is generally an MAOI

1. Neuromuscular hyperactivity (such as tremor, hyperreflexia, clonus, myoclonus, rigidity)
2. Autonomic dysfunction (tachycardia, blood pressure changes, hyperthermia, diaphoresis, shivering, diarrhoea)
3. Altered mental state (agitation, confusion, mania)

Question 34

Antidepressants side effects – Suicidal behaviour

Answer 34

▪ The use of antidepressants has been linked with suicidal thoughts and behaviour; children, young adults and patients with a history of suicidal behaviour are particularly at risk
▪ Patients should be monitored for suicidal behaviour, self-harm or hostility

Question 35

What is Discontinuation syndrome?

Answer 35

▪ Most common: GI disturbances, headache, anxiety, dizziness, paraesthesia, electric shock sensation in the head, neck, and spine, tinnitus, sleep disturbances, fatigue, influenza-like symptoms, and sweating.
▪ Less common: Palpitation and visual disturbances.
▪ Withdrawal effects may occur within 5 days of stopping treatment
▪ The risk of withdrawal symptoms is increased if the antidepressant is stopped
suddenly after regular administration for 8 weeks or more

Question 36

Failure to respond to treatment:

Answer 36

After 4 weeks of antidepressant treatment, or after 4 to 6 weeks of psychotherapy or combined antidepressant/psychological therapy

▪ Initially, may require an increase in the dose, or switching to a different SSRI
or mirtazapine.
▪ Second-line choices include lofepramine, moclobemide, and reboxetine.
▪ Other TCAs and venlafaxine should be considered for more severe forms of
depression.
▪ Irreversible MAOIs should only be prescribed by specialists.
▪ Failure to respond to a second. antidepressant:
➢Add another antidepressant of a different class.
➢or use of an augmenting agent (e.g. lithium, aripiprazole [unlicensed], olanzapine [unlicensed], quetiapine, or risperidone [unlicensed]).
▪ Electroconvulsive therapy may be initiated in severe refractory depression

Question 37

Complete the missing words/numbers:

▪The DSM-IV system requires a score of at least —– out of —— for a diagnosis of major
depression.
▪After initiating treatment, patients should be reviewed every —– weeks at the start
▪Treatment with SSRIs should be continued for at least —– (——-in elderly)
▪Following remission - treatment should be continued at the same dose for ——
▪Switching treatment to a different class of antidepressants can only happen after trialling the
initial drug for at least ——
▪With TCAs, withdrawal effects may occur within ——–of stopping - usually mild and self-limiting.
▪With TCAs, risk of withdrawal effects is increased if the TCA is stopped suddenly after ——– or
more. Preferably dose must be reduced over ——-.

Answer 37

▪The DSM-IV system requires a score of at least 5 out of 9 for a diagnosis of major
depression.
▪After initiating treatment, patients should be reviewed every —– weeks at the start
▪Treatment with SSRIs should be continued for at least —– (——-in elderly)
▪Following remission - treatment should be continued at the same dose for ——
▪Switching treatment to a different class of antidepressants can only happen after trialling the
initial drug for at least ——
▪With TCAs, withdrawal effects may occur within ——–of stopping - usually mild and self-limiting.
▪With TCAs, risk of withdrawal effects is increased if the TCA is stopped suddenly after ——– or
more. Preferably dose must be reduced over ——-.

Question 38

The DSM-IV system require at least ONE key symptom to be present. List FOUR of these key symptoms

Question 39

List the different classes of anti-depressants and examples of each:

Answer 39

SSRIs-sertraline, citalopram, fluoxetine
SNRIs- duloxetine
TCAs- amitriptyline, nortriptyline
Atypical- mirtazipine, buproprion

Question 40

List some of the withdrawal symptoms of SSRIs

Question 41

SAQ:
MAOIs are associated with serious interactions. List examples of these interactions AND their implications.

Question 42

SAQ: Discuss the steps that you need to undertake when a patient fails to respond to an antidepressant, listing suitable drugs in every step.

Answer 42

After 4 weeks of antidepressant treatment, or after 4 to 6 weeks of
psychotherapy or combined antidepressant/ psychological therapy

1. Initially, may require an inc in the dose or switch to. a different SSRI or mirtazapine
2. Second-line choices inc lofepramine, moclobemide and reboxetine
3. Other TCAs and Venlafaxine should be considered for more severe forms of depression
4. Irreversible MAOIs should only be prescribed by specialists
5. Failure to respond to a second antidepressant
   = Add another antidepressant of a different class
   OR use of an augmenting agent e.g. lithium, arpiprazole, olanzapine, quitiapine or risperidone
   Electroconvulsive therapy may be initiated in severe refractory depression

Question 43

What is Bipolar?
People with bipolar disorder have episodes of? (2)

Answer 43

Bipolar disorder is a mental health condition that affects your moods, which can swing from one extreme to another. It used to be known as manic depression

• depression – feeling very low and lethargic
• mania – feeling very high and overactive

Question 44

Bipolar Disorder:
Which antipsychotics are used as treatment?

Answer 44

• Haloperidol, olanzapine, quetiapine and risperidone
• If response is inadequate, then lithium or valproate may be added.
• Asenapine - moderate to severe manic episodes
• Olanzapine - long-term management

When discontinuing antipsychotics, dose should be reduced gradually over at least 4 weeks to minimise recurrence.

Benzodiazepines
* e.g lorazepam - used in initial stages of treatment for behavioural disturbance or agitation
* Should not be used for long periods due to dependence

Valproate
* Valproic acid and sodium valproate - can be used for manic episodes if lithium is not tolerated or contra-indicated.
* MHRA - high teratogenic risk in females of child-bearing potential.

Carbamazepine
* Long-term management, to prevent the recurrence of acute episodes in patients unresponsive to lithium therapy

Question 45

Lithium
What are the therapeutic levels?
Cautions?
Patient and carer advice?
Monitoring of patient parameters?

Answer 45

Therapeutic levels:
* 0.4-1 mmol/litre 12-hours post-dose
* 0.8-1 mmol/litre for patients who have previously relapsed or have sub-syndrome symptoms

Caution
Long-term use has been associated with
* Mild cognitive and memory impairment
* Lower seizure threshold
* Thyroid disorders (hypo/hyperthyroidism)
* QT prolongation
* Renal impairment (renally cleared and nephrotoxic)
* Teratogenicity in pregnancy - effective contraception in women of child-bearing age

Patient and carer advice
* Advise to report signs and symptoms of lithium toxicity, hypothyroidism, renal dysfunction, and benign intracranial hypertension (persistent headache and visual disturbances)
* Maintain adequate fluid intake and avoid dietary changes which reduce or increase sodium intake
* May cause drowsiness, avoid alcohol.
* Always carry lithium alert card

Monitoring of patient parameters
* Renal, cardiac and thyroid function
* ECG in patient with cardiovascular disease
* Body-weight or BMI
* Serum electrolytes (hyponatraemia= toxicity)
* Full blood count

Question 46

Lithium
Signs of toxicity & overdose:

Answer 46

Signs of toxicity & overdose
 GI disturbances: vomiting, diarrhoea
 Visual disturbances
 Renal: incontinence, hypernatraemia, polyuria
 Extrapyramidal symptoms: muscle weakness,
fine tremor, abnormal reflexes
 CNS disturbances: confusion, drowsiness, lack of coordination, restlessness, stupor
In higher doses
 Cardiac arrhythmias, blood pressure changes, circulatory failure, renal failure, coma, sudden death

Question 47

Lithium Interactions?

Answer 47

• Hyponatraemia increases risk to lithium toxicity especially when taken with diuretics and antidepressants
• Increased risk of nephrotoxicity when taken with ACE-inhibitors and NSAIDs
• Increased risk of seizures when taken with SSRis, quinolone antibiotics
• Advise patients to avoid OTC use of sodium-containing antacids, effervescent analgesics and NSAIDs

Question 48

Problems with Valproate?

Answer 48

 Highly teratogenic
 Potential for neurodevelopmental disorders
(approx. 30–40% risk) and congenital
malformations (approx. 10% risk).
 Must not be used in women and girls of
childbearing potential unless the conditions
of the Pregnancy Prevention Programme are
met and only if other treatments are
ineffective or not tolerated, as judged by an
experienced specialist

Starting from 31 January 2024, no-one under
the age of 55 – both men and women - should be started on valproate unless two specialists independently agree that there is no other safe and effective medication.

Question 49

Monitoring of Valproate?
What should be monitored?

Answer 49

Therapeutic drug monitoring:
Plasma-valproate concentrations are NOT a useful index of efficacy, therefore routine monitoring is unhelpful.

Monitoring of patient
* Monitor liver function before therapy and during first 6 months especially in patients most at risk.
* Measure full blood count and ensure no undue potential for bleeding before starting and before surgery.

Treatment cessation:
* Avoid abrupt withdrawal;
* If treatment with valproate is stopped, reduce the dose gradually over at least 4 weeks

Blood or hepatic disorders:
Patients or their carers should be told how to recognise signs and symptoms of blood or liver disorders e.g. bleeding, bruising, abdominal pain, mouth ulcers, sore throat.

Pancreatitis:
Patients or their carers should be told how to recognise signs and symptoms of pancreatitis e.g. abdominal pain, nausea, or vomiting develop.

Pregnancy Prevention Programme
Pharmacists must ensure that female patients have a patient card.

Question 50

List some important prescribing information that you need to be aware of when prescribing Valproate?

Answer 50

• Risk of suicidal thoughts
• Prescribe by brand as different products may not be bioequivalent
• Contraindicated in women and girls of childbearing potential unless conditions of the Pregnancy Prevention Programme (PPP) are met (NOW ALSO MEN)
• It should not be used in men or women < 55 years old unless there are no other alternatives