[3] Depressive Disorder Flashcards
What is depressive disorder?
An affective mood disorder characterise dby persistent low mood, loss of plaeasure, and/or a lack of energy, accompanied by emotional, cognitive, and biological symptoms
What model is used when considering the development of depression?
Biopsychosocial model
What is the heritability of depression?
40-50%
It is likely that multiple genes are involved
What psychosocial factors increase the likelihood of developing depression?
- Personality type
- Stressful life events
- Failure of effective stress control mechanisms
What does the monoamine theory of depression state?
A deficiency of monoamines (noradrenaline, serotonin, and dopamine) cause depression
What evidence is there for the monoamine theory of depression?
Antidepressants which increase the concentration of the monoamines in the synaptic cleft improve the symptoms of depression
What can the risk factors in depression be categorised into?
Biological, psychological, and social, or predisposing, precipitating, or perpetuating
What are the biological predisposing risk factors for depression?
- Female gender
- Postnatal period
Family history - Physical co-morbidities
- Past history of depression
What are the biological precipitating risk factors for depression?
- Poor compliance with medication
- Corticosteroids
What are the biological perpetuating risk factors for depression?
Chronic health problems, e.g. diabetes, COPD, chronic pain syndromes
What are the psychological predisposing risk factors for depression?
- Personality type
- Failure of effective stres control mechanisms
- Poor coping strategies
- Other mental health conditions
What are the psychological precipitating risk factors for depression?
Acute stressful life events
What are the psychological perpetuating risk factors for depression?
- Poor insight
- Negative thoughts about self
What are the social predisposing risk factors of depression?
- Stressful life events
- Lack of social support
- Member of the asylum seeker/refugee population
What are the social precipitating risk factors for depression?
- Unemployment
- Poverty
- Divorce
What are the social perpetuating risk factors for depression?
- Alcohol or substance misuse
- Poor social support
- Low social status
What are the core symptoms of depression?
- Anhedonia
- Low mood, present for at least two weeks
- Lack of energy
What are the cognitive symptoms of depression?
- Lack of concentration
- Negative thoughts - negative views of oneself, negative views of the world, or negative views of the future
- Excessive guilt
- Suicidal ideation - recurrent thoughts of death or suicide without a specific plan
What are the biological symptoms of depression?
- Diurnal variation in mood
- Early morning wakening
- Loss of libido
- Psychomotor retardation
- Weight loss and loss of appetite
What is diurnal variation in mood?
When the patients low mood is more pronounced during certain times of day, usually morning
What is early morning wakening?
Waking up more than 2 hours earlier than they usually would
What is psychomotor retardation?
Slow speech and slow movement
What are the psychotic symptoms of depression?
- Hallucinations
- Delusions
What kind of hallucinations are usually present in depression?
Second person auditory hallucinations
What is the nature of the delusions in depession?
Usually hypochondriacal, guilt, nihilistic, or persectuory in nature
How is depression classifed according to the ICD-10?
- Mild = 2 core symptoms + 2 other symptoms
- Moderate = 2 core symptoms + 3-4 other symptoms
- Severe = 3 core symptoms + 4 or more other symptoms
- Severe depression with psychosis = 3 core symptoms + 4 or more other symptoms + psychosis
What investigations are done in depression?
- History
- MSE
- Investigations to exclude organic causes of depression
- Diagnostic questionnaires, e.g. PHQ-9, Beck’s depression inventory
What investigations can be done to exclude organic causes of depression?
- Blood tests
- Imaging
What blood tests are done to exlude organic causes of depression?
- FBC to check for anaemia
- TFTs to check for hypothyroidism
- U&Es, LFTs, and calcium levels, as biochemical abnormalities may cause physical symptoms which can mimic some depressive symptoms
- Glucose, as diabetes can cause anergia
When might a MRI or CT scan be required in depression?
Where presentation or examination is atypical, or where there are features suspicious of an intracranial lesion, e.g. unexplained headache or personality change
What are the differential diagnoses of depression?
- Other mood disorders, including bipolar affective disorder and other depressive disorders
- Physical conditions, e.g. hypothyroidism
- Psychoactive substance abuse
- Other psychiatric disorders, e.g psychotic disorders, anxiety disorders, adjustment disorders, personality disorders, eating disorders, dementia
- Normal bereavement
What does the management of depression depend on?
The severity of depression
What should be considered in mild-to-moderate depression?
Watchful waiting, with reassessment of the patient in 2 weeks
What interventions may be used in mild-to-moderate depession?
- Self-help programmes
- Computerised cognitive behavioural therapy (CBT)
- Physical activity programme
- Antidepressants
- Psychotherapy
What is the purpose of computerised cognitive behavioural therapy in mild-to-moderate depression?
It helps educate patients about depression, and challenges negative thoughts
Describe the use of anti-depressants in the management of mild to moderate depression?
They are not recommended as first line therapy, unless depression has lasted for a long time, there is a history of moderate-severe depression, there has been a failure of other interventions, or the depression complicates the care of other physical health problems
When is psychotherapy used in mild-to-moderate depression?
When all other options fail
What should be done in all patients with moderate-severe depression?
Suicide risk assessment
What are the treatment options in moderate-severe depression?
- Anti-depressants
- Consider psychiatry referral
- Referral to CBT and interpersonal therapy
- Social support
- ECT
What social support can be given to people with moderate-severe depression?
- Engaging in activities in the community
- Attending social support groups with others
What are the main classes of antidepressants?
- SSRIs
- SNRIs
- TCAs
- MOAIs
What are the first-line antidepressants in moderate-severe depression?
SSRIs, e.g. citalopram or sertraline
How long should anti-depressants be used for?
- 6 months after resolution of first depressive episode
- 2 years after resolution of second depressive episode
- Long term in individuals who have had multiple severe episodes
Give three examples of SSRIs
- Citalopram
- Sertraline
- Fluoxetine
What is the mechanism of action of SSRIs?
SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft, and therefore causing a greater post-synaptic neuronal activity. It also leads to down-regulation of post-synaptic receptors
How long do SSRIs take to work?
They typically take at least 2 weeks to produce a significant improvement in mood, and a maximum benefit may require 12 weeks or more
What are the indications for SSRIs?
The primary indication for SSRIs is depression, however a number of other psychiatric conditions also respond to SSRIs, including;
- OCD
- Panic disorder
- Generalised anxiety disorder
- PTSD
- Social anxiety disorder
- Premenstural dysphoric disorder
- Bulimia nervosa (fluoxetine only)
How does the side effect profile of SSRIs compared to anti-depressants?
They are considered to have fewer and less severe adverse effects than TCAs and MAOIs
What are the adverse effects of SSRIs?
- Headaches
- Sweating
- Anxiety and agitation
- GI effects, including nausea, vomiting, and diarrhoea
- Weakness and fatigue
- Sexual dysfunction
- Changes in weight
- Sleep disturbances, including insomnia and somnolence
How can the adverse effect of sleep disturbances experienced with SSRIs be manipulated to work in the patients favour?
Patients who are fatigued and complaning of excessive somnolence may benefit from a more activating antidepressant, such as fluoxetine or sertraline.
Patients who are having difficulty sleeping may benefit from an antidepressant that is more sedating than activating, e.g. paroxetine
What symptoms of sexual dysfunction may be experienced by patients on SSRIs?
- Loss of libido
- Delayed ejaculation
- Anorgasmia
What are the options if the side effects of sexual dysfunction are intolerable to the patient?
- Can offer one with fewer sexual side effects, e.g. mirtazapine
- Dose of drug may be reduced
Are SSRIs dangerous in overdose?
Large intakes of SSRIs do not usually cause cardiac arrhythmias, but seizures are a possibility, as all antidepressants lower the seizure threshold
Which SSRIs have the potential to cause a discontinuation syndrome with abrupt withdrawal?
All of them, however there is a higher risk with agents with shorter half lives and inactive metabolites
What SSRI has the lowest risk of discontinuation syndrome?
Fluoxetine
What SSRIs have the highest risk of a discontinuation synrome?
Paroxetine and venlafaxine
How can discontinuation syndrome be prevented?
Slowly reducing antidpressant. You can alternate days of taking and not taking, or snap tablets in half.
Sometimes, it is worth switching to fluoxetine, then reducing the fluoxetine
What are the symptoms of SSRI discontinuation syndrome?
- Headache
- Malaise
- Flu-like symptoms
- Agitation and irritability
- Nervousness
- Changes in sleep pattern
How serious is discontinuation syndrome?
It is unpleasant, but not life-threatening
Which SSRIs have the potential to cause serotonin syndrome?
All
When does serotonin syndrome occur?
When SSRIs are used in the presence of a MAOI or other highly serotonergic drug
How is serotonin syndrome prevented?
An extended period of washout for each drug should occur prior to administration of another class of drugs
What are the cognitive symptoms of serotonin syndrome?
- Headaches
- Agitation
- Hypomania
- Confusion
- Coma
What are the autonomic symptoms of serotonin syndrome?
- Shivering
- Sweating
- Tachycardia
- Nausea
- Diarrhoea
What are the somatic symptoms of serotonin syndrome?
- Myoclonus
- Hyper-reflexia
- Tremor
What is the treatment of serotonin syndrome?
Usually supportive, involving fluids and monitoring
Describe the absorption of SSRIs?
They are all well absorbed after oral administration, with peak levels after 2-8 hours.
Food has little effect on absorption, apart from sertraline where food increaes absorption
Do SSRIs undergo first pass metabolism?
Only sertraline undergoes significant first pass metabolism
What is the half life of SSRIs?
Most SSRIs have half lives that range betwee 16 and 36 hours. Fluoxetine has a much longer half life of 50 hours
What preparation is fluoxetine available in?
A sustained releaes preparation, which allows for once-weekly dosing
How are SSRIs metabolised?
Metabolism by cytochrome P450-dependant enzymes, with extensive glucuronide or sulfate conjuation
How are the SSRIs excreted?
Primarily through the kidneys, except for paroxtine and sertraline. Sertraline undergoes faecal excretion
What should be done when SSRIs are given in hepatic impairment?
Dosages should be adjusted downwards
What considerations should be made when choosing the most suitable SSRI?
- Sertraline is safest in cardiac disease
- Citalopram and escitalopram have a higher risk of QTc prolongation
- Fluoxetine has a higher risk of serotonin syndrome when switching
- Paroxetine has a higher risk of discontinuation syndrome
Give two examples of TCAs?
- Imipramine
- Lofepramine
What does choice of what TCA to use depend on?
All TCAs have similar efficacy, and so specific choice of drug may depend on issues such as patient tolerance to side effects, prior response, pre-existing medical conditions, and duration of actions
What kind of tricyclics are best tolerated?
Newer tricyclics, such as lofepramine or nortriptyline
What effects do TCAs have?
- Elevate mood
- Improve mental alertness
- Reduce morbid preoccupation
What % of patients wiht major depression do TCAs work in?
50-70%
What is the mechanism of action of TCAs?
They are potent inhibitors of neuronal reuptake of noradrenaline and serotonin in the presynpatic nerve terminals. By blocking the major route of neurotransmitter removal, the TCAs cause increased concentrations of monoamines in the synaptic cleft, ulimately resulting in antidepressant efects
They also block serotonergic, alpha-adrenergic, histaminic, and muscarinic receptors, however it is not known if these actions produce TCAs therapeutic benefits. They are, however, responsible for many of the adverse effects.
How long do TCAs take to work?
2 weeks or longer
What are the indications for TCAs?
- Moderate to severe depression
- Some patients with panic disorder respond to TCAs
- Some TCAs, especially amitriptyline, have been used to treat migraine headaches and chronic pain syndromes, for example neuropathic pain
- Low doses can be used to treat insomnia
What causes the adverse effects of TCAs?
- Blockade of muscarinic receptors
- Due to blocking alpha-adrenergic receptors
- Blocking of histamine receptors
What adverse effects of TCAs result from the blockade of muscarinic receptors?
- Blurred vision
- Xerostomia
- Urinary retention
- Sinus tachycardia
- Constipation
- Aggravation of narrow-angle glaucoma
- Affect cardiac conduction, which may precipitate life-threatening arrhythmias in overdose
What adverse effects of TCAs occur due to blocking alpha-adrenergic receptors?
- Orthostatic hypertension
- Dizziness
- Reflex tachycardia
What adverse effects of TCAs may occur as a result of their ability to block histamine receptors?
Sedation
What other adverse effects of TCAs are there?
- Weight gain
- Sexual dysfunction in the form of erectile dysfunction in men and anorgasmia in women
How does the incidence of TCA-induced sexual dysfunction compare to that of SSRIs?
It occurs in a significant minority of patients, but the incidence is lower than with SSRIs
When should caution be taken with the administration of TCAs?
- Bipolar disorder, even in depressed state
- Suicidal patients
- May exacerbate certain medications, including unstable angina, benign prostatic hyperplasia, epilepsy, and pre-existing arrhythmias
- Very young and very old
Why should caution be taken when giving TCAs in bipolar disoder?
They can cause a switch to the manic state
What should be done when giving TCAs to suicidal patients?
They should only be given limited quantities of the drug, and monitored closely
Why should caution be taken when giving TCAs to suicidal patients?
Because they can be toxic in overdose, and cause QTc prolongation and arrhythmias
Describe the absorption of TCAs
TCAs are well absorbed upon oral administration
Describe the distribution of TCAs
Because of their lipophilic nature, they are widely distributed and readily penetrate into the CNS
What is the half life of TCAs?
They have a variable half life due to their lipid solubility
Do TCAs undergo first pass metabolism in the liver?
Variable
What is the result of the variable first-pass metabolism of TCAs in the liver?
TCAs have a low and inconsistent bioavailability
How is the dose of TCAs determined?
The patients response and plasma levels are used to adjust the dosage. The initial treatment period is typically 4-8 weeks, and the dosage can be gradually reduced to improve tolerability, unless relapse occurs
How are the TCAs metabolised?
By the hepatic microsomal system
What is the result of TCAs being metabolised by the hepatic microsomal system?
They may be sensitive to agents that induce or inhibit the CYP450 isoenzymes
How are the TCAs excreted?
By inactive metabolites via the kidney
Give an example of a SNRI?
Venlafaxine
What is the mechanism of action of SNRIs?
They inhibit the reuptake of serotonin and noradrenaline.
What is the mechanism of action of venlafaxine?
Venlafaxine is a potent inhibitor of serotonin reuptake, and at medium to high doses, is an inhibitor of noradrenaline reuptake. It is also a mild inhibitor of dopamine reuptake at high doses
Where are SNRIs useful?
In depression caused by chronic painful symptoms, such as back pain and muscle aches, against which SSRIs are relatively ineffective
Why are SNRIs useful in depression caused by chronic pain symptoms?
Becasue this pain is, in part, modulated by serotonin and noradrenaline in the CNS
What are the indications for SNRIs?
- Depression when SSRIs are ineffective, or where there are associated pain symptoms
- Physical symptoms of neuropathic pain, such as diabetic or peripheral neuropathy
What are the adverse effects of SNRIs?
- Nausea
- Headache
- Sexual dysfunction
- Dizziness
- Insomnia
- Sedation
- Constipation
- Increased HR and BP
What might happen if SNRIs are abruptly stopped?
May precipitate a discontinutation syndrome
What effect does venlafaxine have on the CYP450 isoenzymes?
Minimal inhibition of the CYP450
What is the half life of venlafaxine plus its active metabolite?
Approx. 11 hours
What should you consider when choosing SNRIs?
- Duloxetine has a low dose range
- Venlafaxine is more efficacious, and can go to higher doses. However, caution is needed with heart disease, and blood pressure should be measured at doses higher than 225mg
What can MAOIs be divided into?
Type A, which work more on serotonin, and type B, which work more on dopamine
Where are MAOIs possibily more effective?
Atypical depression
What MAOIs are more dangerous?
Those with irreversilbe effects, such as phenelzine and isocarboxazid (compared to reversible ones like moclobamide and tranylpromine)
What might interact with MAOIs?
There is a potential for significant and dangerous interactions with other drugs, and also a potential for tyramine reactions leading to a hypertensive crisis, therefore the patient should avoid cheese, pickled meats, wine, and other tyramine products
What should be done if changing to another antidepressant from MAOIs?
You need a washout period of 6 weeks
What are the indications for referral in moderate-severe depression?
- Suicide risk is high
- Depression is severe
- Recurrent depression
- Unresponsive to initial treatment
What are the indications for ECT in moderate-severe depression?
- Acute treatment of severe depression that is life threatning
- Rapid response required
- Depression with psychotic features
- Severe psychomotor retardation or stupor
- Failure of other treatments
