Depression is a condition that can negatively affect how a person feels, thinks and behaves (Hardy, 2021). Although the symptoms of depression vary in every person, commonly people feel sad and find it difficult to engage in the activities they usually enjoy. A variety of emotional and physical problems are experienced, which reduce a person's capacity to perform both at work and at home. Depression has been cited as the second leading cause of disability globally (Vos et al, 2013). Recovery is affected by personality, resilience, family history, premorbid difficulties, relationships and social problems.
The level of severity in depression is determined as sub-threshold depression, mild depression, moderate depression, major depressive disorder (or severe depression). Some people experience persistent depressive disorder where symptoms are mild but affect functioning due to the duration experienced. The severity of depression can be measured using the Patient Health Questionnaire (PHQ-9). This is a nine-question tool which has been validated for use in primary care (Ford et al, 2020).
Treatment for depression
Depression is mainly managed in primary care settings (Arroll et al, 2016). Treatment delivered in this setting include non-medicinal treatments and medication.
Non-medicinal treatment
Health professionals in primary care are recommended to offer non-medicinal treatments for people with sub-threshold and mild-to-moderate depression (National Institute for Health and Care Excellence (NICE), 2009). These include active monitoring and support to aid physical, psychological, and social wellbeing:
- Active monitoring – the clinician and person with depression jointly decide not to treat the condition, and to regularly re-assess progress along an agreed follow-up timescale (Rubio-Valera et al, 2015), usually 2 weeks (NICE, 2009)
- Support to aid physical, psychological, and social wellbeing:
- Physical – provision of advice, encouragement and support regarding lifestyle and taking medication as prescribed
- Psychological – education regarding self-help techniques
- Social – suggesting various educational and community activities.
The above non-medicinal treatments can also be offered to people with more severe depression, in addition to referral for therapy delivered by other agencies, and medication. Therapy delivered by other agencies includes treatment for harmful drinking, self-help groups, cognitive behavioural therapy (CBT), interpersonal therapy (IPT), behavioural activation and counselling.
Medication for depression
It is important that antidepressant medication is prescribed appropriately. A report looking at trends in prescribing in primary care (Spence et al, 2014) found a 165% increase in the prescribing of antidepressant drugs in England between 1998 and 2012. They explain that, although there has been an increase in the prevalence of depression recorded by GPs, this change cannot fully account for the increased dispensing of antidepressants.
Antidepressant medication is not effective for people with mild depression, so should not routinely be prescribed in these cases. It is, however, an effective treatment for people with moderate-to-severe depression and can be used in persistent depressive disorder. It works quickly, with response to treatment usually occurring within 2 weeks. The medication helps to improve a person's concentration and lift their energy levels; this enables them to engage in the psychological treatments and increases their rate of recovery (NICE, 2009).
Types of antidepressant medication
The different classes of antidepressant medication are (NHS, 2021):
- Selective serotonin reuptake inhibitors (SSRIs)
- Serotonin and noradrenalin reuptake inhibitors (SNRIs)
- Noradrenergic and specific serotonergic antidepressants (NaSSAs)
- Tricyclic antidepressants (TCAs)
- Serotonin antagonists and reuptake inhibitors (SARIs)
- Monoamine oxidase inhibitors (MOIs).
Selective serotonin reuptake inhibitors
SSRIs include fluoxetine, citalopram, paroxetine and sertraline. Serotonin (along with noradrenaline and dopamine) is one of the main neurotransmitters in mood disorders and it is hypothesised that depression is associated with a lack of serotonin (Hardy and Gray, 2012). Antidepressant drugs exert their effect by boosting serotonin levels in the brain. SSRIs do this by inhibiting the reuptake of serotonin into the neurone effectively duping the brain into producing more of the neurotransmitter. The most frequent adverse effects associated with SSRIs are nausea, diarrhoea, dizziness, agitation, insomnia, tremor and sexual dysfunction. There is also an increased risk of bleeding when taking this medication.
Serotonin and noradrenalin reuptake inhibitors
The two SNRIs most commonly used in primary care are venlafaxine and duloxetine (also used for neuropathic pain). SNRIs inhibit the neuronal uptake of serotonin, norepinephrine, and dopamine in the central nervous system. They have a different molecular structure to SSRIs so are often useful in people who have not responded to treatment with SSRIs (Hardy and Gray, 2012).
‘When people do not respond to one antidepressant medication, there will be a need to switch to another; for example, fluoxetine to venlafaxine’
The common side effects include nausea, headache, sedation, dry mouth, dizziness, insomnia, constipation, nervousness, raised blood pressure, tiredness, sweating, reduced appetite and sexual dysfunction. Duloxetine can also cause unpleasant or distressing restlessness. SNRIs are more likely to be toxic in overdose than SSRIs.
Noradrenergic and specific serotonergic antidepressants
Mirtazapine is the only drug in the NaSSA class. It increases noradrenergic and serotonergic neurotransmission in the central nervous system. Its effectiveness is equal to that of SSRIs but usually has fewer sexual side effects. Some people experience extreme drowsiness when first taking mirtazapine. The drowsiness is not related to the dose taken and should wear off. Weight gain is a common side effect with mirtazapine. A very rare side effect is reversible agranulocytosis (Hardy and Gray, 2012).
Tricyclic antidepressants
The most commonly prescribed TCAs in primary care are amitriptyline (also used off licence for neuropathic pain) and lofepramine (dosulepin is restricted to specialist use and should not be prescribed routinely in primary care because of an increased cardiac risk and toxicity in overdose). They inhibit the reuptake of serotonin, norepinephrine and dopamine. TCAs were breakthrough drugs when they were first introduced in the 1950s, but they are not well tolerated compared with more modern antidepressants (Hardy and Gray, 2012). Common side effects tend to be dose related and include dry mouth, blurred vision, constipation, urinary retention, sedation, and postural hypotension. In overdose, TCAs are highly cardiotoxic.
More generally, TCA can cause sinus tachycardia, paroxysmal hypertension and ECG changes. TCAs should be avoided in people who have had a recent myocardial infarction or who have an arrhythmia (particularly heart block) as there appears to be an increased risk of mortality. They can increase the risk of ventricular fibrillation in those with ischaemic heart disease.
‘Following a first depressive episode, the person needs to take the antidepressants for at least 6 months after their mood has improved to minimise the risk of a relapse of their symptoms’
Serotonin antagonists and reuptake inhibitors
SARIs may be prescribed when other antidepressants have not worked or have caused side effects. The usual medication prescribed in this class is trazodone (Hardy and Gray, 2012). Common side effects include sleepiness, nausea, headaches, constipation, and a dry mouth.
Monoamine oxidase inhibitors
MAOIs are an old type of antidepressant that are now rarely used. As they can cause potentially serious side effects, they are only prescribed by a specialist doctor. Examples of MAOIs include tranylcypromine, phenelzine and isocarboxazid.
Serotonin syndrome
If a person has too much serotonin they are at risk of developing serotonin syndrome. This is a potentially life-threatening drug reaction that may occur following treatment with antidepressants. It requires immediate medical intervention.
The greatest risk of serotonin syndrome is where the person is taking their antidepressant in combination with another drug that increases serotonin, such as an antiemetic, antimigraine drug, cold remedy, street drugs, herbal remedies or a drug that involves interactions between the antidepressant (includes lithium, carbemazepine, phenelzine, moclobemide, levodopa, codeine, trazodone, venlafaxine, methadone).
Symptoms can be divided into three clinical categories: mental state, neuromuscular features, and autonomic instability (the person may not present with all the features):
- Change in mental state – includes agitation, confusion, delirium, hallucinations, drowsiness and coma
- Neuromuscular features – includes shivering, tremor, teeth grinding, involuntary twitching and overactive reflexes
- Autonomic instability – includes tachycardia, fever, hypertension or hypotension, flushing, excessive sweating and diarrhoea and vomiting.
Other medication used to treat depression
In people who do not respond to antidepressants, other medication may be prescribed by mental health specialists. These include agomelatine and antipsychotics.
Agomelatine
Agomelatine is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C antagonist. Melatonin has a significant role in synchronising circadian rhythms, which are known to be disturbed in depressed states.
One advantage of this drug is that it less likely to cause sexual dysfunction than the other classes of antidepressants.
Antipsychotic medication
Antipsychotics are licensed to treat certain types of mental health problems where symptoms include psychotic experiences. They may be beneficial when used short term in people with treatment resistant depression who have specific symptoms such as severe ruminations, melancholia, and major sleep disturbance (Mulder et al, 2018).
The newer types of antipsychotics are referred to as second generation or atypical antipsychotics and the older as first generation or typical. Examples of atypical antipsychotics include olanzapine, quetiapine, aripiprazole, clozapine and risperidone. Common side effects experienced are dry mouth, blurred vision, constipation, dizziness or light-headedness, weight gain, problems sleeping, extreme tiredness, and weakness. Less common side effects are tachycardia and hyperglycaemia.
Examples of typical antipsychotics include haloperidol, chlorpromazine, trifluoperazine and fluphenazine. Side effects experienced are muscle rigidity, significantly slowed movements, involuntary muscle movements and contractions, muscle tremors, akathisia, and tardive dyskinesia. Rarely, a life-threatening condition known as neuroleptic malignant syndrome may occur.
Best practices for prescribing antidepressants
Before prescribing
Before prescribing antidepressant medication the health professional should be sure that it is appropriate for the type of depression the person is experiencing. They should also check whether the person is taking any over the counter treatment such as St John's Wort and advise them to stop before commencing what is prescribed.
Herbal medicines are not recommended because of concerns about appropriate doses, duration of effect, variation in preparations and potential for serious drug interactions.
‘Receiving the most appropriate antidepressant medication may be affected by the knowledge of the primary care prescriber and by limitations set by local commissioning bodies’
When to review
People who are newly prescribed antidepressants or have a change in dose or type, should be reviewed 2 weeks later to assess the effect.
Which antidepressant to use
The authors of the NICE guidance for depression (NICE, 2009) recommend that health professionals prescribe SSRIs first. If there is no response, a different SSRI should be used before trying another type of antidepressant. As the risk of bleeding is increased in people taking SSRIs, they should not be prescribed to those taking medications that increase the risk of bleeding such as triptans, warfarin, heparin, non-steroidal anti-inflammatory drugs or aspirin. In people who fail to respond to SSRIs, about half will improve with either with a different SSRI or class of antidepressant.
SNRIs should not be prescribed for people with uncontrolled hypertension or a high risk of a serious cardiac ventricular arrhythmia. If they have established cardiac disease, they can be prescribed with caution by monitoring their blood pressure and performing electrocardiograms as appropriate. Blood pressure should be monitored regularly in all people taking SNRIs; if it increases, the dose of SNRI should be reduced or discontinued.
People prescribed SNRIs should be advised to look out for fever, sore throat, sore mouth or other signs of infection as these may be symptoms of a very rare side effect, reversible agranulocytosis. If they do experience any of these symptoms, the medication should be stopped and a full blood count performed. Specialist advice should be sought before considering other treatments for depression. Agomelatine may be useful when sleep is a problem and/or sexual dysfunction is experienced when taking SSRIs.
Managing serotonin syndrome
Mild symptoms of serotonin syndrome (flushing, teeth grinding, tiredness, poor concentration, nausea) can be managed by stopping or reducing the antidepressant, offering supportive care and treating with a benzodiazepine. Moderate and severe cases (seizures, hyperthermia, rhabdomyolysis, renal failure and coagulopathies) should be treated as an acute medical emergency.
Recommended duration of treatment with antidepressants
In many people, depression is a long-term condition that requires maintenance treatment. Following a first depressive episode, the person needs to take the antidepressants for at least 6 months after their mood has improved to minimise the risk of a relapse of their symptoms. Those who have had two or more episodes of depression need to continue with treatment for at least 2 years after their depression has gone into remission.
Continuous treatment over a number of years may be necessary in people who have had multiple episodes of depression.
Switching antidepressants
When people do not respond to one antidepressant medication, there will be a need to switch to another; for example, fluoxetine to venlafaxine. This switch needs to be carried out carefully to avoid the risk of serotonin syndrome. The general rule is to gradually taper down the dose of the old antidepressant before starting the new medication. The person should not stop the medication abruptly as they will experience unpleasant symptoms (described below).
The national prescribing guidelines for switching or stopping antidepressant medication were revised in 2022 and can be accessed here: https://cks.nice.org.uk/topics/depression/prescribing-information/switching-antidepressants. Alternatively, an online support tool can be used: https://www.switchrx.com.
Stopping antidepressants
Missing doses or abruptly stopping antidepressant medication can induce a discontinuation syndrome (headache, dizziness, nausea, paraesthesia, anxiety, flu-like symptoms, and diarrhoea). People should be advised to reduce their dose of antidepressants gradually. Reducing antidepressant medication usually involves halving tablets and alternate day administration. If it is explained to the person that dose tapering is standard procedure (in order to minimise the discontinuation symptoms) with the provision of written instructions they are more likely to follow the advice.
Promoting adherence
Six strategies can be used in practice to enhance adherence to treatment with antidepressants (adapted from Sudak and Ayub, 2017):
- Provide information regarding depression including common signs and symptoms
- Discuss the importance of taking medication as prescribed and the implications of missed doses
- Frequently enquire and educate people about the type, severity and duration of side-effects
- Tell people to expect to wait for symptoms improve; explore doubt and resistance to therapy.
- Anticipate misinformation about the illness or the treatment process
- Instruct people to continue taking medications when they are feeling better and describe the rationale for maintenance treatment.
Challenges and considerations in prescribing for depression in primary care
As there is a lack of availability of non-pharmacological therapy for moderate depressive disorders, primary care prescribers may find themselves dependent on pharmacological treatments to manage the condition (Woodall and Walker, 2022). This early prescribing of antidepressants without considering other treatment options may lead to the potential long-term use of unnecessary medication (Moir et al, 2022).
Receiving the most appropriate antidepressant medication may be affected by the knowledge of the primary care prescriber and by limitations set by local commissioning bodies. Non-adherence is a problem in all long-term conditions, but it is markedly prominent among people prescribed antidepressants. It has been reported that medication non-adherence is three-fold higher in people with depression compared to other medical conditions (Solmi et al, 2021). The reasons for this include patient factors; for example, younger age, psychiatric and medical comorbidities, cognitive impairment, and substance use disorders; and prescriber factors such as neglecting medical and family histories, selecting poorly tolerated antidepressants, or complex antidepressant regimens (Solmi et al, 2021).
Additionally, stigma related to antidepressant use has been reported to be linked with perceived emotional weakness, severity of illness, an inability to deal with problems and a lack of belief in the therapeutic efficacy of antidepressants (Castaldelli-Maia et al, 2011).
Conclusion
As depression is mainly managed in primary care, health professionals need to know when it is appropriate to prescribe antidepressants, and be conversant with the recommended types and which to prescribe. They should regularly monitor the person for response to the medication, being mindful of the high possibility of non-adherence to treatment.
Key Points
- Depression is a condition which can negatively affect how a person feels, thinks and behaves
- Depression is mainly managed in primary care settings
- Antidepressants are an effective treatment for people with moderate-to-severe depression
- People who are newly prescribed antidepressants should be reviewed 2 weeks later to assess the effect
- A different type of antidepressants should be offered if response to the first prescribed is poor
- Some people are reluctant to take prescribed antidepressant medication
CPD reflective questions
- John is 32. He was diagnosed with depression 3 weeks ago and prescribed sertraline. He missed his follow-up appointment with the GP last week. He has come to see you today for his annual diabetes review and asks you for a repeat prescription of the antidepressant as he only has a week's supply left. He has had some diarrhoea and nausea. What should you do?
- Marilyn is 57 years old. She has come to see you for a blood pressure check. She had been taking dosulepin for years with good effect. Last month, the dosulepin was stopped after it was discovered that she has an arrhythmia. She started mirtazapine last week and is asking if she can reduce the dose because she feels so sleepy. You check her blood pressure, which is within the normal range (126/72). She says she is feeling well. What should you do?
- Melissa is 29 years old. She has attended the practice with her daughter who is booked to have her pre-school booster with you. You notice that she is a little sweaty and flushed and ask her if she is alright. She says that she thought she was coming down with a cold but now thinks it may be her antidepressant tablets, which were doubled last week. This is when the symptoms started. She says she is feeling unusually tired and very ‘spaced out’ but otherwise OK. You also notice when she sits down that her legs are twitching. On questioning you discover she has been taking Solpadeine for her cold. What should you do?
- Hamza, aged 19, was prescribed antidepressants 4 weeks ago. He has come today for a meningitis C injection before he starts university. You notice he has not been back to see his GP. He tells you he is not feeling any better but admits to stopping the antidepressants after 2 days because he feels he should be able to get better on his own. How do you react?