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Treatment principles Major depressive disorder 1
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The goals of acute phase treatment are to:2,3 Achieve remission (removal of symptoms, such that the criteria for a major depressive episode are no longer met) Prevent suicide Achieve an improvement in functioning and quality of life Goals of treatment MDD=major depressive disorder 1. Kupfer. J Clin Psychiatry 1991;52(Suppl 5):28–34; 2. APA. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. 2010; 3. Bauer et al. World J Biol Psychiatry 2013;14(5):334–385 2 The goals of continuation phase treatment are to:2,3 Prevent a relapse in the vulnerable period immediately following remission Eliminate any unresolved symptoms Prevent suicide Restore the patient’s level of psychosocial and occupational functioning – at least to levels seen prior to the current episode and, if possible, to levels seen prior to the onset of MDD The goals of maintenance phase treatment are to:3 Prevent a new episode of depression (recurrence) Prevent suicide Enable full and lasting functional recovery Severity No depression Progression to disorder Symptoms Syndrome Relapse Recurrence Remission Recovery Response Continuation Acute Maintenance Treatment phases: The course of MDD1
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Treating depression – non-pharmacological therapies 3
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Non-pharmacological therapy for depression Psychotherapies: Behavioural therapy Interpersonal psychotherapy Group therapy Cognitive-behavioural therapy (CBT) Mindfulness-based cognitive therapy (MBCT) Brain stimulation methods Electroconvulsive therapy (ECT) Vagus nerve stimulation (VNS) Transcranial magnetic stimulation (TMS) Deep brain stimulation (DBS) 4
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Psychotherapy – behavioural therapy Behavioural therapy is based on the concept that a deficit of ‘reinforcers’, such as pleasant activities and positive interpersonal contacts, leaves patients vulnerable to depression1 Sample interventions: increase activity level, structured goal setting, interpersonal skills training1 1. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. 2009 5
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Psychotherapy – interpersonal psychotherapy Interpersonal psychotherapy is based on the concept that depression arises from problematic patterns in relationships1 Sample interventions: develop awareness of patterns in primary relationships and the therapeutic relationship, interpersonal skills training, communication analysis1 In general, interpersonal psychotherapy has shown efficacy equivalent to pharmacological therapy in randomised, controlled trials1 1. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. 2009 6
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Psychotherapy – group therapy As well as individual psychotherapy, CBT and behavioural therapy may be administered to a group1 Group therapies have demonstrated efficacy in MDD1 MDD=major depressive disorder 1. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. 2009 7
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Psychotherapy – cognitive-behavioural therapy (CBT) Cognitive therapy is based on the concept that habitual negative thinking patterns leave patients vulnerable to depression in response to specific situations.1 Therefore, the patient is taught to challenge the beliefs and assumptions that contribute to depression1 Over time, cognitive therapy has evolved to include behavioural elements; it is now known as ‘cognitive-behavioural therapy’ Sample interventions: identify and challenge automatic thoughts, engage in activities that provide evidence to disprove dysfunctional beliefs, modify core beliefs by reviewing evidence1 In general, CBT has shown efficacy equivalent to pharmacological therapy in randomised, controlled trials.2 Furthermore, the combination of CBT and pharmacotherapy is superior to pharmacotherapy alone2 1. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. 2009; 2. Cuijpers et al. Can J Psychiatry 2013;58(7):376–385 8
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Psychotherapy – mindfulness-based cognitive therapy (MBCT) ‘Mindfulness’ describes a greater awareness of what is happening in the present moment.1 Mindfulness techniques are a way of connecting with thoughts and feelings, in order that a person can change the way they react to them1 MBCT has been studied in randomised controlled trials, compared against ‘treatment as usual’, which showed that treatment with MBCT reduced the risk of depressive relapse2,3 MBCT has also been studied in trials versus antidepressant monotherapy, which showed that the time to relapse with MBCT did not differ from treatment with antidepressant monotherapy4,5 As such, MBCT is recommended in treatment guidelines for MDD, e.g., the UK NICE guidelines, for individuals who are currently well but have experienced three or more previous episodes of depression6 MDD=major depressive disorder; NICE=National Institute for Health and Care Excellence 1. www.mind.org.uk; 2. Ma & Teasdale. J Consult Clin Psychol 2004;72(1):31–40; 3. Teasdale et al. J Consult Clin Psychol 2000;68(4):615–623; 4. Kuyken et al. Lancet 2015;386(9988):63–73; 5. Segal et al. Arch Gen Psychiatry 2010;67(12):1256–1264; 6. NICE. CG90. 2009 9
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Brain stimulation methods – electroconvulsive therapy (ECT) ECT is a medical treatment in which a small, carefully-controlled electrical current is applied to the brain, thereby triggering a seizure.1 It is a non-invasive (transcranial) technique1 ECT is considered to be an effective treatment for depression, even in patients who have not responded to previous medications.1 The mechanism of action is uncertain.1 Typically, multiple sessions are needed to achieve remission1 ECT is generally low risk, but is performed under general anaesthesia, which has inherent risks.1 Cognitive side effects, such as memory loss (which is generally temporary), are a major limitation.1 The concurrent use of pharmacotherapy with ECT may increase the risk of cognitive adverse events1 1. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. 2009 10
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Brain stimulation methods – vagus nerve stimulation (VNS) VNS is the direct, intermittent electrical stimulation of the left vagus nerve in the neck via a pulse generator implanted in the chest.1 It is, therefore, an invasive (surgical) technique1 The implantations (neck and chest) are performed under general anaesthesia, but the subsequent electrical stimulation can be turned on and off by the patient using a magnet.1 Chronic stimulation of the vagus nerve fibres changes the activity in the brainstem nuclei that alter serotonergic activity in cortical and limbic structures1 VNS has shown efficacy in some patients with depression who failed to achieve remission with antidepressants.1 Its onset of action is generally slow1 VNS is generally well tolerated; some patients experience voice alteration, breathlessness, or neck pain, but – unlike ECT – VNS is not associated with cognitive side effects1 ECT=electroconvulsive therapy 1. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. 2009 11
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Brain stimulation methods – transcranial magnetic stimulation (TMS) TMS is a medical treatment in which rapidly-alternating magnetic fields are applied to the scalp to indirectly induce small, pulsed, electrical currents in the brain.1 These highly-focussed electrical currents can trigger the firing of functional neuronal circuits; in psychiatric disorders, TMS is used in an attempt to alter pathological cortical excitability1 TMS is a non-convulsive and non-invasive (transcranial) technique.1 Unlike ECT and VNS, anaesthesia is not required1 In randomised, controlled trials, TMS has shown a moderate antidepressant effect, comparable to that of pharmacotherapy.1 However, further research is needed to verify its efficacy2 TMS is generally considered to be of minimal risk in patients without seizure risk factors; however, it can induce seizures at high doses in those with risk factors1 ECT=electroconvulsive therapy ; VNS=vagus nerve stimulation 1. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. 2009; 2. Bauer et al. World J Biol Psychiatry 2013;14(5):334–385 12
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Brain stimulation methods – deep brain stimulation DBS is a surgical procedure involving implantation of electrodes into the brain, which are then used to stimulate specific brain areas1,2 Classically, DBS has been used to treat movement disorders, but it is now being explored in a range of neuropsychiatric disorders, including depression1 Although poorly studied to date in high-quality trials, DBS has shown the potential for treating depression – particularly in treatment-refractory patients2,3 1. Sharma et al. J Neurosurg Sci 2016;60(2):242–255; 2. Puigdemont et al. J Psychiatry Neurosci 2015;40(4):224–231; 3. Raymaekers et al. Transl Psychiatry 2017;7(10):e1251 13
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Treating depression – pharmacotherapy 14
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Overview of pharmacological therapy The first class of antidepressants to be developed were monoamine oxidase inhibitors (MAOIs) in the 1950s.1,2 Tricyclic antidepressants (TCAs) a separate class, were developed at around the same time.1,2 Both of these classes demonstrated good efficacy in depression, but their use was hindered by significant safety and toxicity issues1,3 Selective serotonin reuptake inhibitors (SSRIs) were developed in the 1970s and 1980s based on the notion that serotonin deficiencies played an important role in the pathogenesis of depression.1 The improved tolerability profile of SSRIs, along with their ease of use and comparable efficacy to TCAs and MAOIs, allowed antidepressants to become widely used in primary care1 SSRIs were followed by antidepressants with dual serotonin and noradrenaline action – the serotonin–noradrenaline reuptake inhibitors (SNRIs)1 Other antidepressants have been developed, with a wide range of mechanisms of action, but primarily targeted at modulating the function of the neurotransmitters serotonin, noradrenaline, and/or dopamine2,4 1. Lieberman. Primary Care Companion J Clin Psychiatry 2003; 5 (Suppl 7): 6–10; 2. Hillhouse & Porter. Exp Clin Psychopharmacol 2015;23(1):1–21; 3. Stahl. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. 2013; 4. Bauer et al. Eur Psychiatry 2008;23(1):66–73 15
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Antidepressants Antidepressants are the main pharmacological agents used in the treatment of MDD1,2 Antidepressants may be used together with some non-pharmacological therapies1,2 Several classes of antidepressant are available; selective serotonin reuptake inhibitors (SSRIs) are generally the most commonly prescribed1 The selection of a specific antidepressant drug depends on the characteristics of the patient and the physician2 A patient requiring an antidepressant for a first major depressive episode will generally receive monotherapy3 If the patient demonstrates an inadequate response to the first-line antidepressant, provided that the dose is optimised and sufficient time has passed, second-line options include switching to another antidepressant, augmenting the antidepressant with a non-antidepressant drug, or combining it with another antidepressant3 MDD=major depressive disorder 1. Bauer et al. Eur Psychiatry 2008;23(1):66–73; 2. Sleath & Shih. Soc Sci Med 2003;56(6):1335–1344; 3. Davidson. J Clin Psychiatry 2010;71(Suppl E1):e04 16
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Definitions – use of antidepressants 1. Connolly & Thase. Drugs 2011;71(1):43–64 17 Monotherapy Adjunctive (or augmentation) therapy Combination therapy The use of one antidepressant The use of an antidepressant together with an agent that is not conventionally used as first-line monotherapy in MDD1 The use of two antidepressants, each of which is approved as monotherapy for MDD1
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Antidepressant monotherapy Classes of antidepressant Irreversible monoamine oxidase inhibitors (MAOIs) Tricyclic antidepressants (TCAs) Tetracyclic antidepressants (TeCA) Selective serotonin reuptake inhibitors (SSRIs) Serotonin–noradrenaline reuptake inhibitors (SNRIs) Other: Noradrenaline reuptake inhibitors (NRIs) Noradrenaline–dopamine reuptake inhibitors (NDRIs) Noradrenergic and specific serotonergic antidepressants (NaSSAs) Serotonin antagonist/reuptake inhibitors (SARIs) Melatonin agonist and serotonin antagonist Multimodal antidepressants Increasingly, terms such as ‘antidepressant’ and ‘antipsychotic’ are outmoded, as the ‘neuroscience-based nomenclature’ (NbN) is being adopted1,2 The NbN classifies drugs on the basis of the targeted neurotransmitter/molecule/system being primarily modified (in which there are ten or eleven pharmacological domains and ten modes/mechanisms of action)1,2 1. Stahl. CNS Spectrums 2016;21:219–220; 2. Frazer & Blier. Int J Neuropsychopharmacol 2016;19(8):1–2; 3. Bauer et al. World J Biol Psychiatry 2013;14(5):334–385; 4. APA. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. 2010 18 The efficacy of antidepressants as first-line medications is generally comparable between classes and within classes3,4
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Basic mechanisms of antidepressant action – reuptake inhibition and enzyme inhibition aIncluding ionotropic and metabotropic receptors MAOI=monoamine oxidase inhibitor; TCA=tricyclic antidepressant; SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin–noradrenaline reuptake inhibitor Stahl. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. 2013 19
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Other mechanisms of antidepressant action – glutamate Given the near-ubiquitous nature of glutamate, it is implicated in the pathology of many diseases, including mood disorders1 Although difficult to study, changes in glutamate have been seen in patients with MDD relative to control individuals in:1 Plasma Serum Cerebrospinal fluid Brain tissue Several different types of glutamate receptors exist, including the three ‘ionotropic’ receptors: NMDA, AMPA, and kainate2,3 Once used as a dissociative anaesthetic, a certain NMDA antagonist has been extensively studied in patients with MDD3 Given as an infusion (intravenous) the NMDA antagonist effectively treats the mood symptoms of MDD, including in some patients who have been resistant to other treatments3 However, there is little evidence about the long-term effects of using a dissociative anaesthetic NMDA antagonist in treating MDD3 Other glutamatergic agents are actively being studied in MDD, including modulators of other glutamate receptors. It is hoped that the future may see glutamate-modulating therapies as an option for patients with MDD3 AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; MDD=major depressive disorder; NMDA=N-methyl-d-aspartate 1. Sanacora et al. Nat Rev Drug Discov 2008;7(5):426–437; 2. Purves et al. Neuroscience. 2008; 3. Jaso et al. Curr Neuropharmacol 2017;15(1):57–70 20
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Second-line pharmacotherapy Second-line options (for patients demonstrating an inadequate response to an optimised dose of the first-line antidepressant) include switching to another antidepressant, augmenting the initial antidepressant with a non-antidepressant drug, or combining it with another antidepressant1 Switching strategies When patients switch antidepressants, they may receive an antidepressant drug of the same class, or a different class, to the one they received as first line2,3 A washout or cross-titration period may be required2,3 Adjunctive therapy strategies Certain dopamine–serotonin receptor antagonists have indications for the adjunctive treatment of MDDa Additionally, certain classes of non-antidepressant drugs have been used off-label as adjuncts to antidepressants, including psychostimulants and a certain mood stabiliser4 Combination therapy strategies (off-label) Combination strategies must be selected with care to avoid drug–drug interactions2 Typical combination strategies include SSRI/SNRIs combined with an NDRI or a NaSSA4,5 aLocal variations may apply; please consult your country’s SPCs/PIs SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin–noradrenaline reuptake inhibitor; NaSSA=noradrenergic and specific serotonergic antidepressant; NDRI=noradrenaline–dopamine reuptake inhibitor 1. Davidson. J Clin Psychiatry 2010;71(Suppl E1):e04; 2. APA. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 2010; 3. NICE. CG90. 2009; 4. Connolly & Thase. Drugs 2011;71(1):43–64; 5. Moreira. Clin Drug Investig 2011;31(Suppl 1):5–17 21
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Strategies for patients with inadequate response APA=American Psychiatric Association; BAP=British Association for Psychopharmacology; CANMAT=Canadian Network for Mood and Anxiety Treatments; NICE=National Institute for Health and Clinical Excellence; SPC=summary of product characteristics; WFSBP=World Federation of Societies of Biological Psychiatry 1. APA. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. 3rd ed. 2010; 2. NICE. CG90. 2009; 3. Cleare et al. J Psychopharmacol 2015;29(5):459–525; 4. Bauer et al. World J Biol Psychiatry 2013;14:334–385; 5. Kennedy et al. Can J Psychiatry 2016;61(9):540–560; 6. Parikh et al. Can J Psychiatry 2016;61(9):524–539 22
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Guidelines for the treatment of depression 23
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Treatment guidelines There is no universal treatment guideline for MDD – various evidence-based treatment guidelines have been developed to aid clinicians Mild MDD Guidelines vary in their recommendations for the treatment of mild MDD, with suggested first-line therapy ranging from ‘watchful waiting’ to psychotherapy or antidepressants Moderate MDD First-line treatment recommendations for moderate MDD include antidepressant monotherapy, psychotherapy, and the combination of an antidepressant and psychotherapy Severe MDD First-line treatment recommendations for severe MDD include the combination of an antidepressant and psychotherapy, or ECT If psychotic features are present, the combination of an antidepressant and an antipsychotic is suggested as a first-line treatment Davidson. J Clin Psychiatry 2010;71(Suppl E1):e04 24
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Treatment guidelines (pharmacotherapy strategies) – APA APA=American Psychiatric Association; ECT=electroconvulsive therapy; MDD=major depressive disorder; NDRI=noradrenaline–dopamine reuptake inhibitor; TeCA=tetracyclic antidepressant; SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin–noradrenaline reuptake inhibitor APA. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. 2010 25 APA (2010) To reduce the risk of relapse, patients who have been treated successfully with antidepressant medications in the acute phase should continue the same medication at the same dose for 4–9 months To reduce the risk of recurrence, patients who have had three or more prior major depressive episodes, who have chronic MDD, or who have additional risk factors for recurrence should continue with the same medication at the same dose that produced symptom remission during the acute phase and maintained remission during the continuation phase The duration of maintenance treatment should depend on the individual, and may be required indefinitely Treatment in the acute phase should be aimed at inducing remission of the major depressive episode and achieving a full return to the patient’s baseline level of functioning, with attention paid to the patient’s suicide risk Recommended first-line pharmacotherapy: SSRI, SNRI, or certain TeCAs or NDRIs If the patient develops side effects: reduce the dose, switch the antidepressant, or treat the side effect If response is absent or minimal in the initial weeks: consider increasing the dose, if the drug is tolerated If response is absent or minimal after 4–8 weeks: consider increasing the dose if the drug is tolerated, combining or augmenting, switching to a different antidepressant, changing to or augmenting with psychotherapy, or ECT Acute phase Continuation phase Maintenance phase
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Treatment guidelines (pharmacotherapy strategies) – NICE MAOI=monoamine oxidase inhibitor; MDD=major depressive disorder; NICE=National Institute for Health and Care Excellence; TCA=tricyclic antidepressant; SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin–noradrenaline reuptake inhibitor NICE. C90. 2009 26 Acute phase Continuation phase Maintenance phase NICE (2009) Recommended first-line pharmacotherapy: SSRI If the patient develops side effects: consider continuing the antidepressant (if side effects are mild and acceptable to the patient), stopping the antidepressant, switching to a different antidepressant, or short-term concomitant treatment with a benzodiazepine if anxiety, agitation and/or insomnia are problematic If response is absent or minimal after 3–4 weeks: consider increasing the dose, or switching drugs If a dose increase does not lead to response, consider switching drugs: initially to a different SSRI or a better tolerated newer-generation antidepressant, and subsequently to an antidepressant of a different pharmacological class that may be less well tolerated (e.g., an SNRI, a TCA, or an MAOI) Alternatively, consider combining or augmenting In primary care, combinations of medications should only be started in consultation with a consultant psychiatrist To reduce the risk of relapse, all patients who have benefited from taking an antidepressant should be advised to continue the same medication at the same dose for at least 6 months after remission of an episode of depression To reduce the risk of recurrence, patients at risk of relapse should be advised to continue antidepressants for at least 2 years Patients who are at significant risk of relapse or have a history of recurrent depression should also consider augmentation of medication
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Treatment guidelines (pharmacotherapy strategies) – WFSBP (I) ECT=electroconvulsive therapy; SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin–noradrenaline reuptake inhibitor; TCA=tricyclic antidepressant; WFSBP=World Federation of Societies of Biological Psychiatry Bauer et al. World J Biol Psychiatry 2013;14(5):334–385 27 Inadequate response but tolerance to 2–4 week treatment with the current medication at adequate dosage, including dose increase where appropriate (e.g., TCAs), after 1–2 weeks If initial antidepressant SSRI, combine with presynaptic autoimmune inhibitor Consider adding ECT Augmentation strategies 1st choice: a certain mood stabiliser, certain antipsychotics 2nd choice: thyroid hormone (T3 or T4), certain antipsychotics Consider adding psychotherapy at any time during treatment Switching to a new antidepressant with evidence of better tolerance Switching antidepressant(s) to a new antidepressant with the potential of superior efficacy Intolerance to current medication SSRI (or an SNRI or certain other antidepressants) WFSBP recommended pharmacotherapy in the acute phase of treatment Acute phase WFSBP (2013)
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Treatment guidelines (pharmacotherapy strategies) – WFSBP (II) MDD=major depressive disorder; WFSBP=World Federation of Societies of Biological Psychiatry 1. Bauer et al. World J Biol Psychiatry 2013;14(5):334–385; 2. Bauer et al. World J Biol Psychiatry 2002;3(2):69–86 28 Continuation phase Maintenance phase WFSBP (2013) In the continuation phase, the medication of first choice is the antidepressant with which remission was achieved in the acute phase (at the same dose), for at least 6 months following remission1 If no relapse occurs during continuation therapy following a first episode, a gradual discontinuation of the antidepressant medication is recommended1 In the maintenance phase, the medication of first choice is the antidepressant with which remission was achieved in the acute and continuation phase (at the same dose), or a certain mood stabiliser2 Treatment should generally continue for at least 3 years in patients with a history of recurrent MDD2
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Treatment guidelines – summary of pharmacotherapy recommendations First-line pharmacotherapy: SSRI, or other newer agent (varies by guideline) Evaluate patient at 1–4 weeks (varies by guideline) for need for dose increase (if tolerated) Evaluate patient at 2–8 weeks (varies by guideline) for need for change of treatment (augmentation, combination, or switch [especially if not tolerated]) Adjunctive dopamine–serotonin receptor antagonists should be considered as an option for second-line therapy Continuation treatment should last for at least 4–6 months (varies by guideline) For patients who require maintenance treatment, it should last for at least 2–3 years (varies by guideline) SSRI=selective serotonin reuptake inhibitor Adapted from: APA. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. 2010; NICE. CG90. 2009; Bauer et al. World J Biol Psychiatry 2013;14(5):334–385; McIntyre et al. J Clin Psychiatry 2017;78(6):703–713; Kennedy et al. Can J Psychiatry 2016;61(9):540–560 29
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The global approach to treatment of depression 30
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Adverse effects of pharmacological treatment 31
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Side effects of selected antidepressants – a rough guide Deeper red colour represents increasing strength of the side effect ‘Anticholinergic’ refers to symptoms commonly caused by muscarinic receptor blockade, including dry mouth, blurred vision, constipation and urinary retention Bauer et al. World J Biol Psychiatry 2013;14(5):334–385 32
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The safety profile of MAOIs MAOIs are associated with a risk of potentially-fatal hypertensive crisis after ingesting foods rich in tyramine (a monoamine found in, e.g., aged cheese, marmite, unpasteurised beer, or dried, smoked, fermented, spoiled, or improperly stored meat)1 In addition, the use of an MAOI in combination with a serotonergic agent (e.g., an SSRI) can result in excessive stimulation of post-synaptic serotonin receptors (‘serotonin syndrome’) which is potentially fatal1,2 The most common side effects with MAOIs are:2 Insomnia Sedation Orthostatic hypotension Sexual dysfunction Weight gain Myoclonic jerking (sudden, involuntary muscle contractions) MAOI=monoamine oxidase inhibitor; SSRI=selective serotonin reuptake inhibitor 1. Stahl. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. 2013; 2. Cassano & Fava. Ann Clin Psychiatry 2004;16(1):15–25 33
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The safety profile of TCAs TCAs have a poor tolerability1 Specifically, TCAs are associated with:1 Sedation Weight gain Anticholinergic effects (dry mouth, blurred vision, urinary retention, constipation) Orthostatic hypotension Dizziness In addition, TCAs in rare cases appear to be connected with neuroleptic malignant syndrome,2 and overdose with TCAs is associated with an increased risk of coma/seizure, and potentially-fatal cardiac arrhythmia/arrest1 TCA=tricyclic antidepressant 1. Stahl. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. 2013 2. Assion et al. Eur Arch Psychiatry Clin Neurosci 1998;248(5):231–239 34
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The safety profile of SSRIs SSRIs and SNRIs are generally better tolerated than TCAs and MAOIs1 However, SSRIs are associated with:1,2 Gastrointestinal effects (nausea, vomiting, diarrhoea) Fatigue Agitation Insomnia Sexual dysfunction Weight gain Headaches Increased risk of bleeding ‘Serotonin syndrome’ in rare cases MAOI=monoamine oxidase inhibitor; SNRI=serotonin–noradrenaline reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant 1. Bauer et al. World J Biol Psychiatry 2013;14(5):334–385; 2. Cassano & Fava. Ann Clin Psychiatry 2004;16(1):15–25 35
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The safety profile of SNRIs SNRIs and SSRIs are generally better tolerated, than TCAs and MAOIs1 SNRIs are associated with similar side effects to SSRIs, but are also associated with side effects that reflect noradrenergic activity, including:1-3 Increased pulse rate Dilated pupils Dry mouth Excessive sweating Constipation ‘Serotonin syndrome’ in rare cases MAOI=monoamine oxidase inhibitor; SNRI=serotonin–noradrenaline reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant 1. Bauer et al. World J Biol Psychiatry 2013;14(5):334–385; 2. APA. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. 2010; 3. Cassano & Fava. Ann Clin Psychiatry 2004;16(1):15–25 36
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The safety profile of dopamine–serotonin receptor antagonists As a class, across indications and as adjunctive treatment in MDD, dopamine–serotonin receptor antagonists (also known as second-generation antipsychotics) are associated with some risk of EPS, and a varying risk of metabolic adverse effects1-3 As adjunctive treatment in MDD, some dopamine–serotonin receptor antagonists are associated with sedating side effects, while others are more often associated with ‘activating’ side effects2,4 Dopamine–serotonin antagonists, can cause orthostatic hypotension and dry mouth2,3 Longer-term treatment is associated with tardive dyskinesia, although this is rare2,5 Despite their efficacy in the adjunctive treatment of MDD, the side effect profiles of dopamine–serotonin receptor antagonists may be unfavourable to some patients, limiting their use in clinical practice2,6 Differences between agents are thought to arise due to differences in receptor-affinity profiles:1 EPS=extrapyramidal symptoms 1. Nasrallah. Mol Psychiatry 2008;13(1):27–35; 2. Wright et al. Pharmacotherapy 2013;33(3):344–359; 3. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 2009; 4. Spielmans et al. PLoS Med 2013;10(3):e1001403; 5. Coplan et al. J Affect Disord 2013;150(3):868–871; 6. Connolly & Thase. Drugs 2011;71(1):43–64 37
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Unmet needs in the treatment of depression 38
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Inadequate response and treatment-resistant depression In the real-world STAR*D study, approximately half of patients did not achieve response with a first-line antidepressant, and three quarters of patients did not achieve response with second-line antidepressant monotherapy1 Patients with MDD who do not respond adequately to antidepressant treatment are at risk of worse outcomes, including: An increased risk of relapse2 A prolonged loss of quality of life, functional status, and well-being3 MDD=major depressive disorder; MDE=major depressive episode 1. Rush et al. Am J Psychiatry 2006;163(11):1905–1917; 2. Pintor et al. J Affect Disord 2004;82(2):291–296; 3. Mauskopf et al. Depress Anxiety 2009;26(1):83–97; 4. Möller. World J Biol Psychiatry 2008;9(2):102–114 39 n=138 0.2 Cumulative survival Time from remission to relapse (months) 0.0 0.4 0.6 0.8 1.0 0 10 20 30 40 50 Complete remission Partial remission Time to relapse according to type of remission achieved, in patients with an MDE who were followed over a 4-year period2 There is an unmet need in the treatment of MDD for agents with improved response/ remission rates1-4
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Rapid identification of non-response Many patients with MDD do not adequately respond to first-line treatment. However, there is evidence that, in primary care, most patients with partial or non-response do not change their antidepressant regimen1 For some patients, combination and augmentation strategies earlier in treatment may increase the likelihood of remission2 If early improvement is not observed within the first 2–4 weeks of antidepressant treatment, there is little chance of stable response or remission3,4 1. Chang et al. Gen Hosp Psychiatry 2012;34(2):105–112; 2. Warden et al. Curr Psychiatry Rep 2007;9(6):449–459; 3. Kudlow et al. CNS Drugs 2014;28(7):601–609; 4. Szegedi et al. J Clin Psychiatry 2009;70(3):344–353 40 There is an unmet need in the treatment of MDD for the rapid identification of patients with inadequate response to first-line antidepressant therapy – preferably within 2–4 weeks of initiation of a new treatment – in order to optimise their treatment strategy1-4
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Irritability and anxiety In a survey of prescribing patterns in 411 physicians based in the US or Europe, 295 (71.8%) indicated that they preferred to reserve antipsychotics for patients with MDD who had specific symptoms, most commonly:2 Psychotic symptoms Psychomotor agitation Hostility Irritability Impulsivity Anger bursts Anxiety is highly prevalent in MDD; in the real-world STAR*D study, 45% of patients had anxious features at baseline3 Compared to non-anxious depression, patients with anxious depression were more likely to:4 Be more severely depressed Be unemployed Have diminished quality of life Have suicidal ideation Have a greater number of comorbidities Have a lower response and remission rate MDD=major depressive disorder 1. Judd et al. JAMA Psychiatry 2013;70(11):1171–1180; 2. McIntyre & Weiller. Adv Ther 2015;32(5):429–444; 3. Rush et al. Am J Psychiatry 2006;163(11):1905–1917; 4. Fava et al. Am J Psychiatry 2008;165(3):342–351 41 There is an unmet need for strategies that address the symptoms of irritability and anxiety1-4 The presence of irritability/anger during a major depressive episode is associated with increased severity of depression, longer duration of the episode, and increased likelihood of comorbidity1
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Suicide MDD is associated with a high risk of mortality, much of which is accounted for by suicide:1 Recurrent thoughts of death, suicidal ideation, or suicide attempts, are common in MDD The severity of suicidal thoughts ranges from a passive wish to not awaken in the morning or a belief that others would be better off if the individual were dead, to transient but recurrent thoughts of committing suicide, to a specific suicide plan A meta-analysis of over 8,000 people with MDD followed for up to 48 years, found that the risk of suicide was increased 20 times in people with MDD2 Over the past decade, there has been increasing attention to the possibility that SSRIs and other antidepressants could worsen suicidality in some patients (potentially by worsening anxiety and agitation)3 The issue of SSRI-induced suicidality was first raised in paediatric antidepressant trials, but has also been queried in adults3 However, meta-analyses have demonstrated that suicide items on rating scales of depression markedly improve with antidepressant treatment3 Nevertheless, patients should be carefully monitored when initiating antidepressant pharmacotherapy3 MDD=major depressive disorder; SSRI=selective serotonin reuptake inhibitor 1. APA. DSM-5. 2013; 2. Harris & Barraclough. Br J Psychiatry 1997;170:205–228; 3. Lam & Mok. Depression. 2008 42 Prevention of suicide remains an unmet need in the treatment of MDD1-3
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Rapid symptom relief According to a review of published data relating to the timing of antidepressant action, a delayed onset of action is a major limitation of all existing antidepressant pharmacotherapies1 Antidepressants may take over a month to show an effect that separates from placebo, during which time patients can remain symptomatic, functionally impaired, and potentially at risk of suicide1 It is noteworthy that lack of early improvement is highly predictive of treatment failure, and conversely that early improvement predicts subsequent remission2 There is also evidence which suggests that when MDD is treated more rapidly, the likelihood of achieving full functional recovery is greater3 MDD=major depressive disorder 1. Machado-Vieira et al. J Clin Psychiatry 2008;69(6):946–958; 2. Muzina et al. Am J Manag Care 2011;17(12):793–801; 3. Habert et al. Prim Care Companion CNS Disord 2016;18(5) 43 Rapid symptom relief is an unmet need in the treatment of MDD – onset within hours or days, not weeks or months1-3
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Cognition Cognitive dysfunction is a component of MDD, and can persist after the remission of mood symptoms1,2 According to a review of published data relating to cognitive dysfunction in psychiatric disorders, cognitive symptoms in patients with MDD are common, persistent, and often debilitating3 Unresolved cognitive dysfunction during remission is also a problem, compromising real-world functioning, and social and professional ability3 Cognitive deficits are generally not improved by psychiatric pharmacotherapy and, in some cases, may even be worsened3 The THINC-integrated tool is a validated measure of cognitive dysfunction in MDD4 *p <0.05 versus control MDD=major depressive disorder 1. Conradi et al., Psychol Med 2011;41(6):1165–1174; 2. APA. DSM-5. 2013; 3. Millan et al. Nat Rev Drug Discov 2012;11(2):141–168; 4. McIntyre et al. J Clin Psychiatry 2017;78(7):873–881; 5. Rund et al. Acta Psychiatr Scand 2006;113(4):350–359 44 Treating the cognitive symptoms of MDD is an unmet need1-5 Working memory -2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 Executive function Visual memory Verbal memory Visual info processing Reaction time Attention/ vigilance Control Depression Schizophrenia * * Scores on neurocognitive composite scores for patients with schizophrenia or MDD5 Composite z-scores versus control
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Functioning Despite the range of treatment options available for MDD, achieving a full functional recovery remains a challenge for many patients1 Although slightly contentious, there is evidence that untreated depression may result in brain changes, which could have consequences for the functional capacity of the patient1 Crucially though, improvements in patient functioning, including cognitive functioning, appear to lag behind improvements in mood symptoms, meaning that functional recovery is an unmet need in the treatment of MDD2,3 MDD=major depressive disorder 1. Oluboka et al. Int J Neuropsychopharmacol 2017 Epub; 2. McKnight & Kashdan. Clin Psychol Rev 2009;29(3):243–259; 3. Saltiel & Silvershein. Neuropsychiatr Dis Treat 2015;11:875–888; 4. Guy. ECDEU Assessment Manual for Psychopharmacology. 1976; 5. Sheehan et al. Int Clin Psychopharmacol 1996;11(Suppl 3):89–95; 6. Patterson et al. Schizophr Bull 2001;27(2):235–245 45 Scales used for measuring functioning Improvement of functioning is an unmet need in the treatment of MDD1-6
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Emotional blunting and anhedonia Loss of interest or pleasure is part of the diagnostic criteria for MDD, and is known as a ‘melancholic’ feature1,2 A survey of >650 patients with depression found emotional blunting to be present in 46% of patients being treated for depression, with a slightly higher rate for men versus women (52% versus 44%)3 The survey also found that the presence of emotional blunting was associated with a poorer quality of remission3 MDD=major depressive disorder 1. APA. DSM-5. 2013; 2. Bauer et al. World J Biol Psychiatry 2013;14(5):334–385; 3. Goodwin et al. J Affect Disord 2017;221:31–35; 4. Hughes et al. Psychiatry Res 2017;255:78–86; 5. Setterfield et al. J Affect Disord 2016;205:372–377 46 Theoretical cycle of anhedonia5 2. Patients engage less in helping behaviour 3. Patients undergo social withdrawal 4. Patients experience less exposure to potentially positive feedback 1. Patients with depression expect to respond less positively to their environment Although there is evidence that some newer agents are more efficacious than others in preventing emotional blunting,4 there is an unmet need for therapies which effectively treat emotional blunting and anhedonia1-5
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Safety and tolerability In a survey of patients with MDD who initiated therapy on an SSRI, adverse events, particularly drowsiness/fatigue, were the most common reasons for discontinuing SSRI treatment within the first 3 months1 All antidepressants are associated with a characteristic collection of adverse events2 Adjunct therapies are also associated with specific adverse events2 In order to promote continuity of drug treatment, and improve patient adherence with antidepressants, novel agents with better tolerability need to be vigorously pursued3 MDD=major depressive disorder; SSRI=selective serotonin reuptake inhibitor 1. Bull et al. Ann Pharmacother 2002;36(4):578–584; 2. Stahl. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. 2013; 3. Möller. World J Biol Psychiatry 2008;9(2):102–114 47 Incidence and severity of SSRI-associated adverse effects during the first 3 months of treatment1 There is an unmet need in the treatment of MDD for therapies with improved safety and tolerability1-3a