Case Scenario

Josh is a 35-year-old man who picks up his escitalopram 20 mg from your pharmacy. He started this medication 3 months ago after being diagnosed with depression for the first time and is not taking other medications. During his visit to your pharmacy, you have observed that he is unkempt, tired, has a downward gaze, and is about 3 weeks late for his prescription refill. Upon chatting to Josh, you find that he is not doing well. He has been struggling at work, not sleeping well, and thinks the antidepressant is not working. He cannot be bothered attending his clinical psychologist appointments. On further questioning, he discloses having a couple of drinks most nights to help him sleep, and that he does not like taking escitalopram due to the sexual dysfunction adverse effects.

Learning Objectives

After reading this article, pharmacists should be able to:

  • Describe the bio-psycho-social approach to treatment of depression
  • Understand the medicines used in the treatment of depression
  • Discuss factors that influence medicine selection in depression
  • Discuss the medicines used for antidepressant augmentation.

Competencies assessed (2016): 1.1, 1.4, 1.5, 2.1, 2.3, 2.4, 3.1, 3.2, 3.5

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Introduction

Depressive disorders are a group of disorders characterised by depressive mood or the inability to feel pleasure (anhedonia), accompanied by other cognitive, behavioural and somatic symptoms such as a lack of energy (anergia), irritability, poor concentration, and insomnia.1 According to the last National Survey of Mental Health and Wellbeing in 2020–21, around 4.6% of Australians had a depressive episode in the 12 months prior to the survey.2 Depressive episodes can lead to significant disability.3

Depression is a heterogenous disease with several predisposing and precipitating factors. Genetic susceptibility,3 certain personality traits such as premorbid anxiety or dependency, and environmental factors such as experiencing adversity in early life are examples of predisposing factors of depression.4 Negative life events, physical health issues and psychosocial stressors are known to precipitate depressive episodes.5

The neurobiology of depression is complex and not fully understood.6 Themonoamine theory is predominant. This hypothesis suggests abnormality in the monoamine system involving serotonin (5-HT), noradrenaline (NA) and dopamine (DA) pathways. The pharmacology of antidepressants is largely based on the monoamine theory of depression.

Treatment approach

Successful treatment of depression relies on a holistic approach to treatment following the bio-psycho-social model – or, more accurately, the social-psycho-bio model – to give more emphasis on psychosocial interventions as the main form of treatment. Many patients with depression managed in the primary care setting do not require treatment with medicines. Where medicines are required, psychological, social and lifestyle interventions should always be implemented alongside pharmacotherapy. Nevertheless, medicines still play an important role in the management of severe depression, especially in the early stages, to allow for improvement in depressive symptomology before psychosocial interventions can be introduced.

Medicines for depression

All antidepressants are more effective than placebo; however, the comparative efficacy of antidepressants is less clear.7 Selective-serotonin reuptake inhibitors (SSRIs) are recommended by most guidelines as first-line pharmacotherapy treatment due to their superior tolerability and safety profile. Table 1 summarises considerations for selecting antidepressants.

Pharmacokinetics and the pharmacodynamic properties of antidepressants are important, as several antidepressants such as fluvoxamine, paroxetine and duloxetine have significant cytochrome P450 enzyme interactions. 

Comorbidities should be taken into consideration when selecting an antidepressant. An example is to consider SSRIs for their cardioprotective effects and avoid tricyclic antidepressants (TCAs) in patients with cardiovascular disease, due to the reported cardiovascular complications with their use, including QT prolongation, arrhythmia and hypotension.8,9

Symptomology-based medicine selection

The three main neurotransmitters involved in depression are 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA). The symptoms of depression can be broadly linked to the effects of these different neurotransmitters. 5-HTis involved in anxiety, obsession and compulsion, which explains its efficacy in obsessive compulsive disorders, while enhancing NA levels improves alertness, energy, attention and interest.10 DA is involved mainly in symptoms of amotivation and anhedonia.10

Given this, it is possible to select antidepressants based on the mode of action to fit the clinical presentation of the patient. One example is to consider using a selective serotonin-noradrenalin reuptake inhibitor (SNRI) for patients with marked anergia or poor attention as part of their illness rather than an SSRI.10

Vortioxetine is a novel antidepressant medicine with potential procognitiveeffects.11 The exact mechanism of how vortioxetine improves cognition is unknown, but it is hypothesised that it is via its 5-HT7 antagonism in the prefrontal cortex.12 This could be useful for patients who have impaired cognition as part of their depression symptomology.12

Histamine and melatonin receptors are other targets. Mirtazapine has a strong antihistamine effect that produces sedation and weight gain.13 This could be used to advantage in patients with insomnia and weight loss as part of their depressive symptoms. Similarly, agomelatine is a melatonin receptor agonist that produces effects akin to melatonin, which may be beneficial for patients with insomnia.14

Practicality should be considered alongside medicine selection. For example, bupropion, with its selective dopamine reuptake inhibitor activity, may be beneficial in a patient with depression characterised by marked amotivation,15 but the use may be limited by cost (as it is an off-label antidepressant indication and not covered by the PBS).

Table 1 – Factors influencing medicine selection

  • Tolerability
  • Safety (consideration for overdose risk – avoid TCAs)
  • Medical and psychiatric comorbidities
  • Pharmacodynamic and pharmacokinetic interactions
  • Ease of dosing
  • Previous response to treatment
  • Cost to patient
  • Patient preference
  • Depression symptomology

Treatment of refractory depression

About 25–50% of patients experience a poor response to at least two antidepressant medicines. Outcomes can be improved through appropriate review and the use of augmentation agents.16

Lifestyle factors

Alcohol and substance misuse, poor sleep hygiene and lack of exercise can contribute to a depressive episode and poor response to treatment.17,18 It’s important to address these issues, as they can interfere with treatment. Frequent patient contact allows community pharmacists to address lifestyle-related issues and provide brief interventions such as behavioural activation.19-21

Alcohol and substance issues should be screened opportunistically, and pharmacists should provide a brief patient intervention and give information on the safe levels of drinking and/or harmful effects. Heavy alcohol or substance use may require a referral to the local drug and alcohol service or medical practitioner. 

Sleep is important for general well being, and a proportion of patients with depression have sleep issues.17 It is important to explore patients’ sleeping habits and encourage good sleep hygiene.

Medicines review

With suboptimal response to treatment, a review of the patient’s medicines should be considered. Response to treatment is typically assessed after 2 weeks.

If the patient is on an optimum dose of medication for 4 weeks of continuous use with little improvement, consider switching or the use of an augmenting medicine. Increasing the dose above the recommended range for certain antidepressants, such as SSRIs, has poor response in severe depression due to the flat dose-response curve.22

To date there is unclear guidance on when it is best to switch an antidepressant or to augment with another medicine. The pivotal Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was not powered to provide an answer to either switching or augmenting the treatment.23 Switching to another class of antidepressant is usually considered first-line in most guidelines to avoid polypharmacy and its inherent risks.

Antidepressant augmentation is a strategy of adding a second medicine with the goal to improve clinical response. Multiple medicines can be used in antidepressant augmentation. The best studied strategies include lithium, atypical antipsychotics and thyroid hormone.23

Lithium

Lithium has the advantage of being well studied as an antidepressant augmenter, with good response rates in refractory depression.24,25 One advantage of lithium is its antisuicidal properties, which may be beneficial in depressed patients with suicidal ideation.26 However, lithium is dangerous in overdose, so the risk versus benefit should be considered before initiating in patients who are at increased risk of overdose. 

The target level for lithium differs with different guidelines, but the Therapeutic Guidelines recommend a range slightly lower than that used in bipolar disorder (0.4–0.6 mmol/L), and monitoring of kidney and thyroid function is usually required.27

Atypical antipsychotics

Aripiprazole, olanzapine and quetiapine are the most established antipsychotics, with a good evidence base supporting use as an adjunct treatment for depression.28 There is increasing evidence to use newer agents like brexpiprazole and cariprazine as an augmenting agent.25,29

With the exception of quetiapine, atypical antipsychotics are considered off-label in Australia, and no antipsychotics are listed on the PBS for depression augmentation. Nevertheless, given their efficacy, atypical antipsychotics have a place in therapy for treatment-refractory depression. 

There is no significant difference in terms of efficacy when it comes to different atypical antipsychotics.28 The choice of atypical antipsychotic can therefore be based on the adverse-effect profile.29

Olanzapine and quetiapine may be useful if sedation is required; however, the risk of metabolic syndrome is significantly higher than with other atypical antipsychotics. Aripiprazole and brexpiprazole have good metabolic profiles, but adverse effects, such as akathisia, may be troublesome and are usually the cause of discontinuation. Another limiting factor for the use of aripiprazole and brexpiprazole is cost, as they are not available on the PBS.

Thyroid hormone augmentation

Adjunct thyroid hormone has demonstrated effectiveness and good tolerability in managing treatment refractory depression.23,25 Liothyronine is preferred, with significantly more evidence, but levothyroxine is sometimes used due to cost. The dose of liothyronine used is usually 20–40 micrograms per day, and regular monitoring of thyroid function is required.30

Antidepressant combination

Another option for treatment-refractory depression is to combine antidepressants that have a complementary mode of action. Combining antidepressants has been shown to be more effective than monotherapy, with no significant increase in adverse effect.31 A common combination used is an SSRI/SNRI with an α-2 adrenergic receptor antagonist.32 This antagonist enhances the release of noradrenalin and serotonin, while the SSRI/SNRI will inhibit reuptake of noradrenalin and serotonin, greatly boosting levels of both neurotransmitters in the synapse.32 There is a theoretical increased risk of serotonin toxicity; however, this is not commonly observed for doses used in practice.

Esketamine

Esketamine is an N-methyl D-aspartate (NMDA) receptor antagonist that increases glutamate release in the brain, which via multiple poorly understood pathways alleviates symptoms of depression.33

Unlike traditional antidepressants, where it takes a few weeks to see clinically significant improvement, esketamine rapidly reduces symptoms of depression and suicidal ideation, making it useful in managing patients who are acutely depressed and/or suicidal.34,35

The longer term use of esketamine in the maintenance phase of treatment-refractory depression is less clear.35 Some studies found that the antidepressant and antisuicidal effect of adjunct esketamine with standard treatment is not significant compared to placebo with standard treatment after 24 hours.34

Esketamine is administered only in the clinical setting, as patients require close monitoring pre- and post-administration due to the risk of hypotension, and cognitive and motor impairment.33

Pharmacogenetic profiling

Personalising antidepressant therapy based on pharmacogenomic data has been gaining traction in recent years.36,37 Pharmacogenomic screening can help determine the genetic variants that affect drug metabolism, such as the cytochrome P450 systems.36,38 There is insufficient data to recommend the test before beginning a treatment, and it has significant costs and is not currently funded by Medicare. However, the test is a useful tool in more complex or treatment-refractory cases, as it may be useful for determining the cause of treatment resistance or susceptibility to adverse effects.

Knowledge to practice

Managing depression can be challenging for clinicians as multiple factors need to be considered. Pharmacotherapy for depression is not straightforward and needs to be individualised to each patient. 

Pharmacists are skilled in monitoring clinical improvement and adverse effects, and detecting issues that may contribute to suboptimal treatment outcomes, such as non-compliance, poor sleep and/or concurrent substance use. Clinical contact with the patient during prescription refills or home medicines review also enables ongoing psychoeducation and encouragement of lifestyle changes such as better sleep hygiene and increased physical activity. Such brief interventions reinforce the bio-psycho-social treatment approach in managing depression and make a difference to the treatment outcome. 

A referral to the treating medical officer is warranted for any signs of deterioration of the patient’s mental state, if there are intolerable adverse effects, or when there are concerns of escalating risk of harm to the patient.

Further information for patients

Case Scenario Continued

You provide Josh with education on alcohol use in depression and emphasise the importance of clinical psychology sessions, as well as give tips on sleep hygiene. You also refer him back to his general practitioner for medication review. Josh returns a few days later with a new prescription for mirtazapine, and reports that he is sleeping better after following your advice on sleep hygiene. He has decided to stop drinking and will try to attend his clinical psychologist appointments.

Key Points

  • Depression is a heterogenous disease, and treatment should always follow the bio-psycho-social model.
  • Medicines for depression are not straightforward and need to be individualised to each patient.
  • When first-line treatment is suboptimal, check for reasons of treatment failure, such as medication adherence, substance misuse and interfering lifestyle factors.
  • Pharmacists need to be proactive in monitoring for clinical efficacy and adverse effects of treatment of depression, as well as providing ongoing psychoeducation for patients and their carers.

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HUN LIANG OON BBiomedSc, MPharm, PgCertPsychTher, PgDipPsychPharm, MSHP is a clinical pharmacist with over 10 years of experience in mental health and a particular interest in mood disorders. He currently works as the deputy chief pharmacist in the North Metropolitan Health Service – Mental Health Pharmacy Service in Western Australia, and is also a sessional academic staff member at Curtin University.

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