Treatment principles

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Treatment principles

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Major depressive disorder:
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Goals of treatment
Slide information
References

The optimal outcome for a patient with major depressive disorder (MDD) is a full recovery from the major depressive episode and to never become depressed again.[Nierenberg & DeCecco, 2001] Treatment of MDD is divided into three phases, corresponding to different stages of the illness.[Sadock et al., 2009] Each of these phases has a different treatment goal.[Sadock et al., 2009]

Acute treatment phase

‘Acute phase treatment’ of MDD occurs during a major depressive episode; it runs from the initiation of treatment until remission is achieved.[Bauer et al., 2013; Kupfer, 1991] The goals of acute phase treatment are to achieve remission (removal of symptoms, such that the criteria for a major depressive episode are no longer met), and an improvement in functioning and quality of life.[Bauer et al., 2013; APA, 2017] Remission is a clinically-meaningful endpoint: patients who achieve remission are less likely to relapse than those who do not achieve remission.  [Nelson et al., 2008; Rush et al., 2006] Response, i.e., a 50% improvement from baseline in a depression rating scale score, is an intermediate treatment goal; it is used to evaluate whether or not a treatment is benefiting the patient.[Bauer et al., 2013]

Continuation treatment phase

‘Continuation phase treatment’ of MDD follows on from acute phase treatment, i.e., it starts when remission is achieved.[Bauer et al., 2013; Kupfer, 1991] The goals of continuation phase treatment are to prevent a relapse (a return of symptoms sufficient to meet the criteria for a major depressive episode) in the vulnerable period immediately following remission, to eliminate any unresolved symptoms, and to 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.[Bauer et al., 2013; APA, 2017] Continuation phase treatment continues until recovery is achieved (the end of a major depressive episode).[Bauer et al., 2013] The moment of recovery is difficult to identify in clinical practice.[Bauer et al., 2013]

Maintenance treatment phase

‘Maintenance phase treatment’ of MDD follows on from continuation phase treatment, provided the patient did not experience a relapse.[Bauer et al., 2013; Kupfer, 1991] The goals of maintenance phase treatment are to prevent a new episode of depression (recurrence), to prevent suicide, and to enable full and lasting functional recovery.[Bauer et al., 2013] Typically, maintenance treatment is indicated in patients with chronic/recurrent MDD (i.e., those susceptible to recurrence).[APA, 2017]

Nierenberg AA, DeCecco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry 2001; 62 (Suppl 16): 5–9. 

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009. 

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385. 

Kupfer DJ. Long-term treatment of depression. J Clin Psychiatry 1991; 52 (Suppl 5): 28–34. 

American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. © American Psychiatric Association, 2010. http://psychiatryonline.org/guidelines.aspx. Accessed November 2017.

Nelson JC, Pikalov A, Berman RM. Augmentation treatment in major depressive disorder: focus on aripiprazole. Neuropsychiatr Dis Treat 2008; 4 (5): 937–948. 

Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163 (11): 1905–1917. 

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Treating depression – non-pharmacological therapies
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Non-pharmacological therapy for depression
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There are many non-pharmacological approaches to the treatment of depression. Some of those approaches are summarised in these slides.

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Psychotherapy – behavioural therapy
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References

Non-pharmacological therapy options comprise psychotherapies and brain stimulation methods. Psychotherapies may be used together with antidepressants.[Sadock et al., 2009]

Generally, there is a lack of evidence surrounding the use of non-pharmacological therapies for MDD – few well-controlled studies have been conducted to date.[Gartlehner et al., 2017; Farah et al., 2016] A recent review of systematic reviews aimed to provide an overview of the general efficacy and risk of harms of pharmacological and non-pharmacological interventions for treating patients with MDD.[Gartlehner et al., 2017] Out of >100 potential interventions, the review identified only five for which there was some reliable evidence in the treatment of acute MDD.[Gartlehner et al., 2017] Cognitive behavioural therapy (CBT) was the only psychotherapeutic intervention identified as having similar efficacy, based on evidence of ‘moderate strength’, to second-generation antidepressant pharmacology.[Gartlehner et al., 2017]

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Gartlehner G, Wagner G, Matyas N, et al. Pharmacological and non-pharmacological treatments for major depressive disorder: review of systematic reviews. BMJ Open 2017; 7: e014912.

Farah WH, Alsawas M, Mainou M, et al. Non-pharmacological treatment of depression: a systematic review and evidence map. Evid Based Med 2016; 21 (6): 214–221.

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Psychotherapy – interpersonal psychotherapy
Slide information
References

Non-pharmacological therapy options comprise psychotherapies and brain stimulation methods. Psychotherapies may be used together with antidepressants.[Sadock et al., 2009]

Generally, there is a lack of evidence surrounding the use of non-pharmacological therapies for MDD – few well-controlled studies have been conducted to date.[Gartlehner et al., 2017; Farah et al., 2016] A recent review of systematic reviews aimed to provide an overview of the general efficacy and risk of harms of pharmacological and non-pharmacological interventions for treating patients with MDD.[Gartlehner et al., 2017] Out of >100 potential interventions, the review identified only five for which there was some reliable evidence in the treatment of acute MDD.[Gartlehner et al., 2017] Cognitive behavioural therapy (CBT) was the only psychotherapeutic intervention identified as having similar efficacy, based on evidence of ‘moderate strength’, to second-generation antidepressant pharmacology.[Gartlehner et al., 2017]

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Gartlehner G, Wagner G, Matyas N, et al. Pharmacological and non-pharmacological treatments for major depressive disorder: review of systematic reviews. BMJ Open 2017; 7: e014912.

Farah WH, Alsawas M, Mainou M, et al. Non-pharmacological treatment of depression: a systematic review and evidence map. Evid Based Med 2016; 21 (6): 214–221.

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Psychotherapy – group therapy
Slide information
References

Non-pharmacological therapy options comprise psychotherapies and brain stimulation methods. Psychotherapies may be used together with antidepressants.[Sadock et al., 2009]

Generally, there is a lack of evidence surrounding the use of non-pharmacological therapies for MDD – few well-controlled studies have been conducted to date.[Gartlehner et al., 2017; Farah et al., 2016] A recent review of systematic reviews aimed to provide an overview of the general efficacy and risk of harms of pharmacological and non-pharmacological interventions for treating patients with MDD.[Gartlehner et al., 2017] Out of >100 potential interventions, the review identified only five for which there was some reliable evidence in the treatment of acute MDD.[Gartlehner et al., 2017] Cognitive behavioural therapy (CBT) was the only psychotherapeutic intervention identified as having similar efficacy, based on evidence of ‘moderate strength’, to second-generation antidepressant pharmacology.[Gartlehner et al., 2017]

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Gartlehner G, Wagner G, Matyas N, et al. Pharmacological and non-pharmacological treatments for major depressive disorder: review of systematic reviews. BMJ Open 2017; 7: e014912.

Farah WH, Alsawas M, Mainou M, et al. Non-pharmacological treatment of depression: a systematic review and evidence map. Evid Based Med 2016; 21 (6): 214–221.

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Psychotherapy – cognitive-behavioural therapy (CBT)
Slide information
References

Non-pharmacological therapy options comprise psychotherapies and brain stimulation methods. Psychotherapies may be used together with antidepressants.[Sadock et al., 2009]

Generally, there is a lack of evidence surrounding the use of non-pharmacological therapies for MDD – few well-controlled studies have been conducted to date.[Gartlehner et al., 2017; Farah et al., 2016] A recent review of systematic reviews aimed to provide an overview of the general efficacy and risk of harms of pharmacological and non-pharmacological interventions for treating patients with MDD.[Gartlehner et al., 2017] Out of >100 potential interventions, the review identified only five for which there was some reliable evidence in the treatment of acute MDD.[Gartlehner et al., 2017] Cognitive behavioural therapy (CBT) was the only psychotherapeutic intervention identified as having similar efficacy, based on evidence of ‘moderate strength’, to second-generation antidepressant pharmacology.[Gartlehner et al., 2017]

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Gartlehner G, Wagner G, Matyas N, et al. Pharmacological and non-pharmacological treatments for major depressive disorder: review of systematic reviews. BMJ Open 2017; 7: e014912.

Farah WH, Alsawas M, Mainou M, et al. Non-pharmacological treatment of depression: a systematic review and evidence map. Evid Based Med 2016; 21 (6): 214–221.

Other reference used on slide
Cuijpers P, Berking M, Andersson G, et al. A meta-analysis of cognitive-behavioural therapy for adult depression, alone and in comparison with other treatments. Can J Psychiatry 2013; 58 (7): 376–385.

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Psychotherapy – mindfulness-based cognitive therapy (MBCT)
Slide information
References

Non-pharmacological therapy options comprise psychotherapies and brain stimulation methods. Psychotherapies may be used together with antidepressants.[Sadock et al., 2009]

Generally, there is a lack of evidence surrounding the use of non-pharmacological therapies for MDD – few well-controlled studies have been conducted to date.[Gartlehner et al., 2017; Farah et al., 2016] A recent review of systematic reviews aimed to provide an overview of the general efficacy and risk of harms of pharmacological and non-pharmacological interventions for treating patients with MDD.[Gartlehner et al., 2017] Out of >100 potential interventions, the review identified only five for which there was some reliable evidence in the treatment of acute MDD.[Gartlehner et al., 2017] Cognitive behavioural therapy (CBT) was the only psychotherapeutic intervention identified as having similar efficacy, based on evidence of ‘moderate strength’, to second-generation antidepressant pharmacology.[Gartlehner et al., 2017]

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Gartlehner G, Wagner G, Matyas N, et al. Pharmacological and non-pharmacological treatments for major depressive disorder: review of systematic reviews. BMJ Open 2017; 7: e014912.

Farah WH, Alsawas M, Mainou M, et al. Non-pharmacological treatment of depression: a systematic review and evidence map. Evid Based Med 2016; 21 (6): 214–221.

Other reference used on slide
Kuyken W, Hayes R, Barrett B, et al. Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomised controlled trial. Lancet 2015; 386: 63–73.

Ma SH, Teasdale JD. Mindfulness-based cognitive therapy for depression: replication and exploration of differential relapse prevention effects. J Consult Clin Psychol 2004; 72 (1): 31–40.

Mind website. https://www.mind.org.uk/information-support/drugs-and-treatments/mindful.... Accessed January 2018.

National Institute for Health and Care Excellence (NICE). Depression in adults: the treatment and management of depression in adults. Clinical guideline 90. © NICE, October 2009, updated April 2016. http://guidance.nice.org.uk/CG90. Accessed November 2017.

Segal ZV, Bieling P, Young T, et al. Antidepressant monotherapy versus sequential pharmacotherapy and mindfulness-based cognitive therapy, or placebo, for relapse prophylaxis in recurrent depression. Arch Gen Psychiatry 2010; 67 (12): 1256–1264.

Teasdale JD, Segal ZV, Williams JM, et al. Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. J Consult Clin Psychol 2000; 68 (4): 615–623.

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Brain stimulation methods – electroconvulsive therapy (ECT)
Slide information
References

Other than psychotherapy, non-pharmacological therapy options for the treatment of MDD include brain stimulation methods, such as electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), and transcranial magnetic stimulation (TMS).[Sadock et al., 2009; Bauer et al., 2013] The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders give the following recommendations:[Bauer et al., 2013]

Electroconvulsive therapy – among the indications for ECT as a first-line treatment are:

  • severe major depression with psychotic features
  • severe major depression with psychomotor retardation
  • ‘true’ treatment-resistant major depression
  • refusal of food intake or in other special situations when rapid relief from depression is required (e.g., in severe suicidality) or when medication is contraindicated (e.g., in pregnancy)
  • patients who have experienced a previous positive response to ECT, and patients who prefer ECT for a specific reason.

Vagus nerve stimulation – VNS may be an option in patients with depression with insufficient response to trials of pharmacotherapy.

Transcranial magnetic stimulation – there is currently insufficient evidence to recommend the clinical efficacy of TMS in the standard clinical setting. Further research is needed.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

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Brain stimulation methods – vagus nerve stimulation (VNS)
Slide information
References

Other than psychotherapy, non-pharmacological therapy options for the treatment of MDD include brain stimulation methods, such as electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), and transcranial magnetic stimulation (TMS).[Sadock et al., 2009; Bauer et al., 2013] The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders give the following recommendations:[Bauer et al., 2013]

Electroconvulsive therapy – among the indications for ECT as a first-line treatment are:

  • severe major depression with psychotic features
  • severe major depression with psychomotor retardation
  • ‘true’ treatment-resistant major depression
  • refusal of food intake or in other special situations when rapid relief from depression is required (e.g., in severe suicidality) or when medication is contraindicated (e.g., in pregnancy)
  • patients who have experienced a previous positive response to ECT, and patients who prefer ECT for a specific reason.

Vagus nerve stimulation – VNS may be an option in patients with depression with insufficient response to trials of pharmacotherapy.

Transcranial magnetic stimulation – there is currently insufficient evidence to recommend the clinical efficacy of TMS in the standard clinical setting. Further research is needed.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

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Brain stimulation methods – transcranial magnetic stimulation (TMS)
Slide information
References

Other than psychotherapy, non-pharmacological therapy options for the treatment of MDD include brain stimulation methods, such as electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), and transcranial magnetic stimulation (TMS).[Sadock et al., 2009; Bauer et al., 2013] The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders give the following recommendations:[Bauer et al., 2013]

Electroconvulsive therapy – among the indications for ECT as a first-line treatment are:

  • severe major depression with psychotic features
  • severe major depression with psychomotor retardation
  • ‘true’ treatment-resistant major depression
  • refusal of food intake or in other special situations when rapid relief from depression is required (e.g., in severe suicidality) or when medication is contraindicated (e.g., in pregnancy)
  • patients who have experienced a previous positive response to ECT, and patients who prefer ECT for a specific reason.

Vagus nerve stimulation – VNS may be an option in patients with depression with insufficient response to trials of pharmacotherapy.

Transcranial magnetic stimulation – there is currently insufficient evidence to recommend the clinical efficacy of TMS in the standard clinical setting. Further research is needed.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

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Brain stimulation methods – deep brain stimulation
Slide information
References

Other than psychotherapy, non-pharmacological therapy options for the treatment of MDD include brain stimulation methods, such as electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), and transcranial magnetic stimulation (TMS).[Sadock et al., 2009; Bauer et al., 2013] The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders give the following recommendations:[Bauer et al., 2013]

Electroconvulsive therapy – among the indications for ECT as a first-line treatment are:

  • severe major depression with psychotic features
  • severe major depression with psychomotor retardation
  • ‘true’ treatment-resistant major depression
  • refusal of food intake or in other special situations when rapid relief from depression is required (e.g., in severe suicidality) or when medication is contraindicated (e.g., in pregnancy)
  • patients who have experienced a previous positive response to ECT, and patients who prefer ECT for a specific reason.

Vagus nerve stimulation – VNS may be an option in patients with depression with insufficient response to trials of pharmacotherapy.

Transcranial magnetic stimulation – there is currently insufficient evidence to recommend the clinical efficacy of TMS in the standard clinical setting. Further research is needed.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

Other reference used on slide
Puigdemont D, Portella M, Pérez-Egea R, et al. A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention. J Psychiatry Neurosci 2015; 40 (4): 224–231.

Raymaekers S, Luyten L, Bervoets C, et al. Deep brain stimulation for treatment-resistant major depressive disorder: a comparison of two targets and long-term follow-up. Transl Psychiatry 2017; 7 (10): e1251.

Sharma M, Naik V, Deogaonkar M. Emerging applications of deep brain stimulation. J Neurosurg Sci 2016; 60 (2): 242–255.

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Treating depression – pharmacotherapy
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Overview of pharmacological therapy
Slide information
References

The history of antidepressant therapy stretches back more than fifty years, to the development of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs).[Lieberman, 2003; Hillhouse & Porter, 2015]  Increasingly now, in order to meet the unmet needs in the treatment of depression, researchers are looking further afield, to drugs with modes of action that stretch beyond the monoamine hypothesis, including drugs targeting glutamate signalling, and drugs with a multimodal mechanism of action.[Hillhouse & Porter, 2015]

Lieberman JA. History of the use of antidepressants in primary care. Primary Care Companion J Clin Psychiatry 2003; 5 (Suppl 7): 6–10.

Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol 2015; 23 (1): 1–21. 

Other references used on slide
Bauer M, Monz BU, Montejo AL, et al. Prescribing patterns of antidepressants in Europe: results from the Factors Influencing Depression Endpoints Research (FINDER) study. Eur Psychiatry 2008; 23 (1): 66–73.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

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Antidepressants
Slide information
References

The Factors Influencing Depression Endpoints Research (FINDER) study was a pan-European study, of >3,000 adults about to start antidepressant medication either for their first episode of depression or for a new episode of recurrent depression.[Bauer et al., 2008]

The study was conducted to determine the prescribing patterns of antidepressants across 12 European countries, and investigate some of the factors determining drug choice.[Bauer et al., 2008] Of all the antidepressants available, selective serotonin reuptake inhibitors (SSRIs) were the most widely used – 63.3% of all patients.[Bauer et al., 2008] The second most widely prescribed antidepressants were serotonin–noradrenaline reuptake inhibitors (SNRIs) – 13.6% of all patients.[Bauer et al., 2008]

It is notable that prescribing patterns varied from country to country: in France, for example, the proportion of SSRI prescriptions were as high as 81.5%; in The Netherlands, SNRI prescriptions were as high as 25.5%.[Bauer et al., 2008] In terms of drivers of antidepressant choice, the FINDER study found that patient and physician characteristics influenced drug choice, including a patient’s previous experience with an antidepressant, and the age of the physician.[Bauer et al., 2008]

Bauer M, Monz BU, Montejo AL, et al. Prescribing patterns of antidepressants in Europe: results from the Factors Influencing Depression Endpoints Research (FINDER) study. Eur Psychiatry 2008; 23 (1): 66–73.

Other references used on slide
Davidson JR. Major depressive disorder treatment guidelines in America and Europe. J Clin Psychiatry 2010; 71 (Suppl E1): e04.

Sleath B, Shih YCT. Sociological influences on antidepressant prescribing. Soc Sci Med 2003; 56 (6): 1335–1344.

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Definitions – use of antidepressants
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References

Not all patients will respond to the first therapy they receive, and so there are several strategies that are used in this patient group, including adjunctive treatment and combination therapy, as shown on the slide.[Connolly & Thase, 2011]

In the real-world STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study, approximately half of the patients did not achieve response with a first-line antidepressant, and approximately three quarters of the patients did not achieve response with second-line antidepressant monotherapy.[Rush, 2006]

Connolly KR, Thase ME. If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs 2011; 71 (1): 43–64.

Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163 (11): 1905–1917.

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Antidepressant monotherapy
Slide information
References

The prospective STAR*D study examined the effectiveness of antidepressants in a naturalistic population of outpatients with MDD seeking medical care:[Rush et al., 2006]

  • All participants (n=3,671) received an SSRI as their first-line treatment, and one third of these patients achieved remission.
  • Patients who failed to respond to the SSRI were randomly assigneda to one of seven possible second-line treatments. Of the 727 patients who received second-line pharmacotherapy, a quarter achieved remission.
  • Patients who failed on any of the seven possible second-line treatments were randomly assigneda to one of four possible third-line treatments. Of the 226 patients who received third-line monotherapy, only 11% achieved remission.

aTo mimic clinical practice, patients were allowed to choose the second-line treatment strategy to which they were willing to be randomised.

Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163 (11): 1905–1917. [Rush et al., 2006]

Other references used on slide
American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. Third Edition. © American Psychiatric Association, 2010. http://psychiatryonline.org/guidelines.aspx. Accessed November 2017

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

Frazer A, Blier P. A neuroscience-based nomenclature (NbN) for psychotropic agents. Int J Neuropsychopharmacol 2016; 19 (8): 1–2.

Stahl SM. Using neuroscience for naming psychotropic drugs. CNS Spectrums 2016; 21: 219–220.

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Basic mechanisms of antidepressant action
Slide information
References

In general, antidepressants function by increasing the availability of monoamines (serotonin, noradrenaline, and/or dopamine) in the synapse; these monoamines are thought to be depleted in depression.[Stahl, 2013]

  • SSRIs, SNRIs and TCAs achieve this by blocking one or more of the monoamine transporters, thus preventing the neurotransmitters from being taken back into the axon terminal that released them.[Stahl, 2013]
  • MAOIs achieve this by inhibiting the activity of the monoamine oxidase enzyme (acting as an ‘enzyme inhibitor’) and thus preventing the breakdown of neurotransmitters.[Stahl, 2013]

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

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Other mechanisms of antidepressant action – glutamate
Slide information
References

Changes in glutamate physiology have been detected in patients with MDD relative to control individuals.[Sanacora et al., 2008] However, because glutamate is found throughout the body, it can be hard to pinpoint the exact source of glutamate in peripheral tissues.[Sanacora et al., 2008; Purves et al., 2008] Methods have moved on to using techniques, such as magnetic resonance spectroscopy (MRS), which can be used to measure the glutamate content within the brain.[Sanacora et al., 2008]

Glutamate receptors in the brain are separated into two classes:[Purves et al., 2008; Jaso et al., 2017]

  • ionotropic receptors that function by allowing movement of cations across the membrane (e.g., calcium, sodium)
  • metabotropic receptors, which are seven-transmembrane domain receptors that either activate or inhibit signalling pathways within the cell.

Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 2008; 7 (5): 426–437.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4rd Edition. Sinauer Associates, 2008. 

Jaso BA, Niciu MJ, Iadarola ND, et al. Therapeutic modulation of glutamate receptors in major depressive disorder. Curr Neuropharmacol 2017; 15 (1): 57–70.

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Second-line pharmacotherapy
Slide information
References

Second-line options include switching to another antidepressant, augmenting the initial antidepressant with a non-antidepressant drug, or combining it with another antidepressant.[Davidson, 2010] In clinical practice, although there is no evidence to support it, switching is generally used in cases of non-response to antidepressant monotherapy, whereas adjunctive and combination strategies are generally used to build upon a partial symptomatic response to antidepressant monotherapy.[Davidson, 2010]

Davidson JR. Major depressive disorder treatment guidelines in America and Europe. J Clin Psychiatry 2010; 71 (Suppl E1): e04. 

Other references used on slide
American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. © American Psychiatric Association, 2010. http://psychiatryonline.org/guidelines.aspx. Accessed November 2017.

Connolly KR, Thase ME. If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs 2011; 71 (1): 43–64.

Moreira R. The efficacy and tolerability of bupropion in the treatment of major depressive disorder. Clin Drug Investig 2011; 31 (Suppl 1): 5–17.

National Institute for Health and Care Excellence (NICE). Depression in adults: the treatment and management of depression in adults. Clinical guideline 90. © NICE, October 2009, updated April 2016. http://guidance.nice.org.uk/CG90. Accessed November 2017.

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Strategies for patients with inadequate response
Slide information
References

This slide compares the guideline recommendations for patients with inadequate response to antidepressant monotherapy from four internationally-recognised bodies:

  1. American Psychiatric Association (APA)[APA, 2010]
  2. National Institute for Health and Care Excellence (NICE)[NICE, 2009]
  3. British Association for Psychopharmacology (BAP)[Cleare et al., 2008]
  4. World Federation of Societies of Biological Psychiatry (WFSBP)[Bauer et al., 2013]
  5. Canadian Network for Mood and Anxiety Treatments (CANMAT)[Kennedy et al., 2016; Parikh et al., 2016]

Each body rates their guideline recommendations according to the level of clinical evidence available

There are four categories, ranked from the strongest to the least evidence:

  • Substantial clinical confidence (strongest supporting evidence)
  • Moderate clinical confidence
  • Low clinical confidence
  • No clinical confidence (no or little supporting evidence)

1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. © American Psychiatric Association, 2010. http://psychiatryonline.org/guidelines.aspx. Accessed November 2017

2. National Institute for Health and Care Excellence (NICE). Depression in adults: the treatment and management of depression in adults. Clinical guideline 90. © NICE, October 2009, updated April 2016. http://guidance.nice.org.uk/CG90. Accessed November 2017.

3. Cleare A, Pariante CM, Young AH, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol 2015; 29 (5): 459–525. 

4. Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385. 

5. Kennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. Pharmacological treatments. Can J Psychiatry 2016; 61 (9): 540–560.

6. Parikh SV, Quilty LC, Ravitz P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 2. Psychological treatments. Can J Psychiatry 2016; 61 (9): 524–539. 

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Guidelines for the treatment of depression
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Treatment guidelines
Slide information
References

There is no universal treatment guideline for MDD – various evidence-based treatment guidelines have been developed to aid clinicians.[Davidson, 2010] As shown on the slide, guidelines that have been developed are usually stratified according to the severity of depression – mild, moderate, or severe.

The American Psychiatric Association (APA) in the US, the National Institute for Health and Care Excellence (NICE) in the UK, and the World Federation of Societies of Biological Psychiatry (WFSBP) have each developed clinical practice guidelines for the treatment of MDD.[APA, 2010; Bauer et al., 2013; NICE, 2009] Pharmacological treatment recommendations from these treatment guidelines are discussed on the following slides. The British Association for Psychopharmacology (BAP), Canadian Network for Mood and Anxiety Treatments (CANMAT), and Texas Medication Algorithm Project (TMAP) have also published treatment guidelines.[Davidson, 2010] The major American and European guidelines for the treatment of depression provide similar basic principles of treatment, which include planning treatment on an individual basis, preparing the patient for potential long-term treatment, providing measurement-based care, and treating to remission.[Davidson, 2010]

Davidson JR. Major depressive disorder treatment guidelines in America and Europe. J Clin Psychiatry 2010; 71 (Suppl E1): e04. 

American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. © American Psychiatric Association, 2010. http://psychiatryonline.org/guidelines.aspx. Accessed November 2017

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

National Institute for Health and Care Excellence (NICE). Depression in adults: the treatment and management of depression in adults. Clinical guideline 90. © NICE, October 2009, updated April 2016. http://guidance.nice.org.uk/CG90. Accessed November 2017.

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Treatment guidelines (pharmacotherapy strategies) – APA
Slide information
References

This slide provides an outline of the American Psychiatric Associations (APA) guidelines for the treatment of MDD. The guidelines are the third edition released by the APA, which were published in October 2010.[APA, 2010] 

American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. © American Psychiatric Association, 2010. http://psychiatryonline.org/guidelines.aspx. Accessed November 2017.

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Treatment guidelines (pharmacotherapy strategies) – NICE
Slide information
References

This slide provides an outline of the UK National Institute for Health and Care Excellence (NICE) guidelines for the treatment of MDD. These guidelines were released in October 2009, and were a partial update of earlier guidance released in December 2004, and updated in April 2007.[NICE, 2009]

National Institute for Health and Care Excellence (NICE). Depression in adults: the treatment and management of depression in adults. Clinical guideline 90. © NICE, October 2009, updated April 2016. http://guidance.nice.org.uk/CG90. Accessed November 2017. [NICE, 2009]

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Treatment guidelines (pharmacotherapy strategies) – WFSBP (I)
Slide information
References

This slide provides an outline of the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the treatment of MDD. These guidelines were published in 2013, and are an update of previous guidelines published in 2002 and updated in 2007.[Bauer, 2013]

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

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Treatment guidelines (pharmacotherapy strategies) – WFSBP (II)
Slide information
References

This slide provides an outline of the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the treatment of MDD. These guidelines were published in 2013, and are an update of previous guidelines published in 2002 and updated in 2007.[Bauer, 2013]

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

Other reference used on slide
Bauer M, Whybrow PC, Angst J, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 2: maintenance treatment of major depressive disorder and treatment of chronic depressive disorders and subthreshold depressions. World J Biol Psychiatry 2002; 3 (2): 69–86.

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Treatment guidelines – summary of pharmacotherapy recommendations
Slide information
References

A summary of the guidelines for the treatment of MDD are shown on the slide. As already discussed, guidelines generally recommend treatment with an SSRI, close supervision, followed by maintenance therapy.[APA, 2010; Bauer et al., 2013; NICE, 2009; Kennedy et al., 2016; McIntyre et al., 2017]

American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. © American Psychiatric Association, 2010. http://psychiatryonline.org/guidelines.aspx. Accessed November 2017

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

National Institute for Health and Care Excellence (NICE). Depression in adults: the treatment and management of depression in adults. Clinical guideline 90. © NICE, October 2009, updated April 2016. http://guidance.nice.org.uk/CG90. Accessed November 2017.

Kennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. Pharmacological treatments. Can J Psychiatry 2016; 61 (9): 540–560.

McIntyre RS, Suppes T, Tandon R, Ostacher M. Florida best practice psychotherapeutic medication guidelines for adults with major depressive disorder. J Clin Psychiatry 2017; 78 (6): 703–713.

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The global approach to treatment of depression
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The global approach to treatment of depression
Slide information
References

The slide summarises the global approach to the treatment of MDD, and indicates deviations from this global approach where relevant.

References used on slide
American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. © American Psychiatric Association, 2010. http://psychiatryonline.org/guidelines.aspx. Accessed November 2017

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

Kennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. Pharmacological treatments. Can J Psychiatry 2016; 61 (9): 540–560.

McIntyre RS, Suppes T, Tandon R, Ostacher M. Florida Best Practice Psychotherapeutic Medication Guidelines for Adults With Major Depressive Disorder. J Clin Psychiatry 2017; 78 (6): 703–713.

National Institute for Health and Care Excellence (NICE). Depression in adults: the treatment and management of depression in adults. Clinical guideline 90. © NICE, October 2009, updated April 2016. http://guidance.nice.org.uk/CG90. Accessed November 2017.

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Adverse effects of pharmacological treatment
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Side effects of selected antidepressants – a rough guide
Slide information
References

This slide shows the side effects associated with selected antidepressants.

Reference used on slide
Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

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The safety profile of MAOIs
Slide information
References

The acceptability of monoamine oxidase inhibitor (MAOI) drugs for the treatment of MDD is limited by the adverse effect profile, which is outlined on the slide.[Stahl, 2013; Cassano & Fava, 2004] The potential for life-threatening interactions with tyramine-containing foods, or with other serotonergic agents, particularly limits the use of MAOIs.[Stahl, 2013; Cassano & Fava, 2004] MDD treatment guidelines recognise these limitations; for instance, the American Psychiatric Association (APA) guidelines recommend that MAOI drugs be used only in patients who have not responded to other treatments, because of the necessity for dietary restrictions with MAOIs and the potential for deleterious drug–drug interactions.[APA, 2010]

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

Cassano P, Fava M. Tolerability issues during long-term treatment with antidepressants. Ann Clin Psychiatry 2004; 16 (1): 15–25. 

American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. © American Psychiatric Association, 2010. http://psychiatryonline.org/guidelines.aspx. Accessed November 2017.

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The safety profile of TCAs
Slide information
References

As with MAOIs, the tricyclic antidepressants (TCA) are associated with a spectrum of adverse drug effects.[Stahl, 2013; APA, 2010] These are typically anticholinergic and sedating side effects, orthostatic hypotension, as well as cardiac arrhythmias.[Cassano & Fava, 2004] The cardiovascular effects of TCAs, which create a high potential for lethality in overdose, are of particular concern in suicidal patients.[Cassano & Fava, 2004]

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. © American Psychiatric Association, 2010. http://psychiatryonline.org/guidelines.aspx. Accessed November 2017.

Cassano P, Fava M. Tolerability issues during long-term treatment with antidepressants. Ann Clin Psychiatry 2004; 16 (1): 15–25.

Other reference used on slide
Assion HJ, Heinemann F, Laux G. Neuroleptic malignant syndrome under treatment with antidepressants? A critical review. Eur Arch Psychiatry Clin Neurosci 1998; 248 (5): 231–239.

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The safety profile of SSRIs
Slide information
References

SSRIs are generally well tolerated. However, as a class, SSRIs are associated with a spectrum of adverse effects.[Bauer et al., 2013; Cassano & Fava, 2004] The range of adverse effects varies between individual agents within the class; although all drugs within the SSRI class share the same mechanism of action (inhibition of serotonin reuptake), the secondary receptor profiles are different, leading to differences in propensity to cause certain adverse reactions and differences in efficacy.[Lam & Mok, 2008; Stahl, 2013]

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

Cassano P, Fava M. Tolerability issues during long-term treatment with antidepressants. Ann Clin Psychiatry 2004; 16 (1): 15–25.

Lam RW, Mok H. Depression. Oxford University Press, 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

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The safety profile of SNRIs
Slide information
References

Compared with SSRIs, the SNRI class of antidepressants are less well tolerated, and generally cause greater levels of discontinuations due to adverse events.[Lam & Mok, 2008] The SNRI side-effect profile is similar to that seen with SSRIs, with the addition of effects that reflect the noradrenergic activity of agents within this class, as outlined on the slide.[APA, 2010; Bauer et al., 2013; Cassano & Fava, 2004]

Lam RW, Mok H. Depression. Oxford University Press, 2008.

American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Edition. © American Psychiatric Association, 2010. http://psychiatryonline.org/guidelines.aspx. Accessed November 2017.

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

Cassano P, Fava M. Tolerability issues during long-term treatment with antidepressants. Ann Clin Psychiatry 2004; 16 (1): 15–25.

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The safety profile of dopamine–serotonin receptor antagonists
Slide information
References

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 extrapyramidal symptoms, and a varying risk of metabolic adverse effects.[Nasrallah, 2008; Wright et al., 2013; Sadock et al., 2009] 

Metabolic adverse effects, such as weight gain, dyslipidaemia, and glucose dysregulation, have serious implications on the prognosis of MDD due to a risk of treatment-related diabetes and/or cardiovascular disease.[Nasrallah, 2008]

In addition, dopamine–serotonin receptor antagonists are associated with orthostatic hypotension (low blood pressure when standing up) and dry mouth.[Wright et al., 2013; Sadock et al., 2009] Longer-term treatment with dopamine–serotonin receptor antagonists is associated with tardive dyskinesia, although this is rare.[Wright et al., 2013; Coplan et al., 2013] Although tardive dyskinesia is common in patients taking dopamine antagonists (so-called first-generation antipsychotics), with the increasing use of dopamine–serotonin receptor antagonists, fewer episodes and less severe symptoms are seen.[Sadock et al., 2009]

A meta-analysis in MDD (n=3,543) showed that the odds ratio for rate of discontinuation for any reason with a dopamine–serotonin receptor antagonists (second-generation antipsychotic) versus placebo was 1.30 (p<0.01); this did not differ significantly between antipsychotics.[Nelson & Papakostas, 2009] Another meta-analysis in MDD (n=3,526) showed that dopamine–serotonin receptor antagonists differ substantially in their reported adverse event profiles.[Spielmans et al., 2013] Differences between agents are thought to arise due to differences in receptor-affinity profiles.[Nasrallah, 2008]

Tardive dyskinesia – a condition, associated with long-term antipsychotic therapy, characterised by involuntary, repetitive movements of the facial muscles, the tongue, and the muscles of the limbs.

Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008; 13 (1): 27–35.

Wright BM, Eiland EH 3rd, Lorenz R. Augmentation with atypical antipsychotics for depression: a review of evidence-based support from the medical literature. Pharmacotherapy 2013; 33 (3): 344–359.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. Ninth Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Coplan J, Gugger JJ, Tasleem H. Tardive dyskinesia from atypical antipsychotic agents in patients with mood disorders in a clinical setting. J Affect Disord 2013; 150 (3): 868–871.

Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 2009; 166 (9): 980–991.

Spielmans GI, Berman MI, Linardatos E, et al. Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes. PLoS Med 2013; 10 (3): e1001403. 

Other reference used on slide
Connolly KR, Thase ME. If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs 2011; 71 (1): 43–64.

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Unmet needs in the treatment of depression
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Inadequate response and treatment-resistant depression
Slide information
References

The slide explains how patients with MDD who do not respond adequately to antidepressant treatment are at risk of worse outcomes, including an increased risk of relapse,[Pintor et al., 2004] and a prolonged loss of quality of life, functional status, and well-being.[Mauskopf et al., 2009]

Response is generally defined as a ≥50% improvement from baseline in a depression rating scale score; partial response is most frequently defined as an improvement from baseline of ≥25 and <50%; no standard definition exists for non-response.[Nierenberg & DeCecco, 2001] 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 monotherapy.[Rush et al., 2006] Antidepressant drugs are also limited in terms of sustaining remission; in the real-world STAR*D study, >90% of the patients who achieved remission subsequently relapsed or dropped out of the study over 12 months of continuing care.[Pigott et al., 2010]

There is an unmet need, therefore, for novel treatments that improve the response and remission rates in patients with MDD.[Möller, 2008]

Pintor L, Torres X, Navarro V, et al. Is the type of remission after a major depressive episode an important risk factor to relapses in a 4-year follow up? J Affect Disord 2004; 82 (2): 291–296. 

Mauskopf JA, Simon GE, Kalsekar A, et al. Nonresponse, partial response, and failure to achieve remission: humanistic and cost burden in major depressive disorder. Depress Anxiety 2009; 26 (1): 83–97. 

Nierenberg AA, DeCecco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry 2001; 62 (Suppl 16): 5–9.

Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163 (11): 1905–1917.

Pigott HE, Leventhal AM, Alter GS, Boren JJ. Efficacy and effectiveness of antidepressants: current status of research. Psychother Psychosom 2010; 79 (5): 267–279. 

Möller HJ. Outcomes in major depressive disorder: the evolving concept of remission and its implications for treatment. World J Biol Psychiatry 2008; 9 (2): 102–114.

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Rapid identification of non-response
Slide information
References

A meta-analysis, including >6,000 patients with depression across 41 clinical trials, aimed to assess whether early improvement with antidepressant treatment successfully predicts treatment outcome.[Szegedi et al., 2009] The results suggested that a lack of improvement in depressive symptoms in the first 2 weeks of treatment indicates that changes in the clinical management of the patient should be considered.[Szegedi et al., 2009] Other evidence indicates that the earlier an augmentation strategy or treatment switching is implemented, the better the chance of achieving remission.[Warden et al., 2007]

There have been many attempts to identify biomarkers of antidepressant treatment response, including cognitive, electrophysiological, and neuroimaging markers, which have met varying degrees of success.[Voegeli et al., 2017]

Rapid identification of non-response is an unmet need in the treatment of depression.[Szegedi et al., 2009; Warden et al., 2007]

Szegedi A, Jansen WT, van Willigenburg AP, et al. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry 2009; 70 (3): 344–353.

Warden D, Rush AJ, Trivedi MH, et al. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep 2007; 9 (6): 449–459.

Voegeli G, Cléry-Melin ML, Ramoz N, Gorwood P. Progress in elucidating biomarkers of antidepressant pharmacological treatment response: a systematic review and meta-analysis of the last 15 years. Drugs 2017; 77 (18): 1967–1986.

Other references used on slide
Chang TE, Jing Y, Yeung AS. Effect of communicating depression severity on physician prescribing patterns: findings from the Clinical Outcomes in MEasurement-based Treatment (COMET) trial. Gen Hosp Psychiatry 2012; 34 (2): 105–112.

Kudlow PA, McIntyre RS, Lam RW. Early switching strategies in antidepressant non-responders: current evidence and future research directions. CNS Drugs 2014; 28 (7): 601–609. 

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Irritability and anxiety
Slide information
References

While symptoms of irritability and anger are not central to the diagnosis of MDD, and are not necessarily measured by depression rating scales, these symptoms are highly prevalent during major depressive episodes.[Judd et al., 2013] In the real-world STAR*D study, irritability during a depressive episode was associated with younger age, greater overall severity, poorer quality of life, and suicidality (although the latter two were not statistically significant after adjusting for age, sex, and severity).[Perlis et al., 2009]

Anxiety is also highly prevalent in MDD; in the real-world STAR*D study, 45% of patients had anxious features at baseline.[Rush et al., 2006] In a German inpatient setting, 49% of patients had anxious depression, defined as high levels of anxiety symptoms.[Wiethoff et al., 2010] In the German inpatient setting, patients with high levels of anxiety were more likely to report greater illness severity and a longer episode duration.[Wiethoff et al., 2010]

As stated on the slide, 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.5 Anxious mood and irritability were listed more often by physicians who actually prescribed an adjunctive antipsychotic during the survey than those who did not.[McIntyre, 2015]

There is an unmet need in the treatment of MDD for adjunctive strategies to address the symptoms of irritability and anger, and to treat patients who experience depression with anxiety.[Judd et al., 2013; Perlis et al., 2009; Rush et al., 2006; Wiethoff et al., 2010; McIntyre, 2015; Fava et al., 2008]

 Judd LL, Schettler PJ, Coryell W, et al. Overt irritability/anger in unipolar major depressive episodes: past and current characteristics and implications for long-term course. JAMA Psychiatry 2013; 70 (11): 1171–1180. 

Perlis RH, Fava M, Trivedi MH, et al. Irritability is associated with anxiety and greater severity, but not bipolar spectrum features, in major depressive disorder. Acta Psychiatr Scand 2009; 119 (4): 282–289.

Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163 (11): 1905–1917.

Wiethoff K, Bauer M, Baghai TC, et al. Prevalence and treatment outcome in anxious versus nonanxious depression: results from the German Algorithm Project. J Clin Psychiatry 2010; 71 (8): 1047–1054.

McIntyre RS, Weiller E. Real-world determinants of adjunctive antipsychotic prescribing for patients with major depressive disorder and inadequate response to antidepressants: a case review study. Adv Ther 2015; 32 (5): 429–444.

Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry 2008; 165 (3): 342–351.

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Suicide
Slide information
References

Suicide, suicidal thoughts, and thoughts of death are an established component of MDD.[APA, 2013; Lam & Mok, 2008]

Attempting to synthesise the research into suicide and mental disorders, Harris and Barraclough identified 249 publications from 1966–1993 and compared the observed suicide rates with the expected rate, calculating a standardised mortality rate (SMR) for each disorder studied.[Harris & Barraclough, 1997] Of the 44 disorders studied, 36 had a significantly raised SMR for suicide, meaning that many mental disorders had an increased risk of suicide.[Harris & Barraclough, 1997] The MDD population in the analysis consisted of >8,000 patients, across 23 publications.[Harris & Barraclough, 1997] The risk of suicide in the MDD population was 20 times greater than expected.[Harris & Barraclough, 1997]

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th Edition (DSM-5™). © American Psychiatric Association, 2013.

Lam RW, Mok H. Depression. Oxford University Press, 2008.

 Harris EC, Barraclough B. Suicide as an outcome for mental disorders. A meta-analysis. Br J Psychiatry 1997; 170: 205–228.

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Rapid symptom relief
Slide information
References

There are those who argue that the expectations of physicians in the treatment of MDD are too low, and that it should not be simply accepted that antidepressants take weeks or months to work; rapid onset of antidepressant action, occurring within hours or days rather than weeks or months, should be the overall goal.[Machado-Vieira et al., 2008] In order to achieve rapid onset of antidepressant action, two approaches should be pursued:[Machado-Vieira et al., 2008]

  • specific symptom clusters should be identified that respond quickly to current antidepressant treatments, and that predict sustained improvement in these patients who respond quickly
  • novel antidepressants with rapid onset of action need to be developed and marketed.

Machado-Vieira R, Salvadore G, Luckenbaugh DA, et al. Rapid onset of antidepressant action: a new paradigm in the research and treatment of major depressive disorder. J Clin Psychiatry 2008; 69 (6): 946–958.

Other references used on slide
Muzina DJ, Chambers JS, Camacho TA, et al. Adjunctive aripiprazole for depression: predictive value of early assessment. Am J Manag Care 2011; 17 (12): 793–801.

Habert J, Katzman MA, Oluboka OJ, et al. Functional recovery in major depressive disorder: focus on early optimized treatment. Prim Care Companion CNS Disord 2016; 18 (5).

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Cognition
Slide information
References

Cognitive dysfunction is now a well-established component of MDD, both as an independent part of the symptom complex and as a residual symptom persisting when mood symptoms are in remission.[APA, 2013; Conradi et al., 2011; Millan et al., 2012; Rund et al., 2006] In a three-year prospective study of patients treated for MDD, patients spent 44% of the time when not experiencing a major depressive episode still experiencing cognitive problems.[Conradi et al., 2011] The proportion of time experiencing cognitive problems when also experiencing a major depressive episode was 94%.[Conradi et al., 2011] This shows that cognitive dysfunction associated with MDD (specifically poor concentration and indecisiveness) is a common residual symptom of the condition.[Conradi et al., 2011]

Despite this, of the two most widely used and validated scales for MDD, the MADRS and the HAM-D17, only one scale includes a question on cognitive functioning – the MADRS item ‘concentration’.[Hamilton, 1967; Montgomery & Asberg, 1979] This means that analysing the cognitive functioning of patients with MDD requires the use of a specific scale, or neuropsychiatric testing. One example of a specialised, validated scale that is sensitive to cognitive dysfunction in adults with MDD is the THINC-integrated tool, which includes variants of the Choice Reaction Time Identification Task (IDN), One-Back Test (OBK), Digit Symbol Substitution Test (DSST), Trail Making Test-Part B (TMT-B), and the Perceived Deficits Questionnaire for Depression-5-item (PDQ-5-D).[McIntyre et al., 2017]

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th Edition (DSM-5™). © American Psychiatric Association, 2013.

Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med 2011; 41 (6): 1165–1174.

Millan MJ, Agid Y, Brüne M, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov 2012; 11 (2): 141–168.

Rund BR, Sundet K, Asbjørnsen, et al. Neuropsychological test profiles in schizophrenia and non-psychotic depression. Acta Psychiatr Scand 2006; 113 (4): 350–359.

Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6 (4): 278–296.

Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–389.

McIntyre RS, Best MW, Bowie CR, et al. The THINC-Integrated Tool (THINC-it) screening assessment for cognitive dysfunction: validation in patients with major depressive disorder. J Clin Psychiatry 2017; 78 (7): 873–881.

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Functioning
Slide information
References

Achieving full functional recovery in patients with MDD is challenging, partly because patient functioning may be less responsive to treatment than mood symptoms.[McKnight & Kashdan, 2009; Saltiel & Silvershein, 2015]

Recommendations were published in 2017, based on a consensus of expert opinion, which underscore the importance of treating MDD early, and successfully, in order to preserve the neurocognitive function of the patient and restore them to full functioning.[Oluboka et al., 2017] Among the considerations in these recommendations are: factors to consider when selecting an antidepressant; how to assess the progress of treatment; obstacles to treatment adherence; and what affect comorbidities have on the long-term treatment plan.[Oluboka et al., 2017] It is hoped that by using a patient-centred approach throughout treatment of MDD, the treatment plan will be aligned with the patients’ individual characteristics and needs, and their own goals for recovery.[Oluboka et al., 2017]

McKnight PE, Kashdan TB. The importance of functional impairment to mental health outcomes: a case for reassessing our goals in depression treatment research. Clin Psychol Rev 2009; 29 (3): 243–259.

Saltiel PF, Silvershein DI. Major depressive disorder: mechanism-based prescribing for personalized medicine. Neuropsychiatr Dis Treat 2015; 11: 875–888.

Oluboka OJ, Katzman MA, Habert J, et al. Functional recovery in major depressive disorder: providing early optimal treatment for the individual patient. Int J Neuropsychopharmacol 2017 Epub.

Other references used on slide
Guy W. ECDEU Assessment Manual for Psychopharmacology, revised. Rockville, MD, National Institute of Mental Health (US), 1976.

Patterson TL, Goldman S, McKibbin CL, et al. UCSD Performance-Based Skills Assessment: development of a new measure of everyday functioning for severely mentally ill adults. Schizophr Bull 2001; 27 (2): 235–245.

Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol 1996; 11 (Suppl 3): 89–95.

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Emotional blunting and anhedonia
Slide information
References

Emotional blunting appears to be present in almost half of patients with depression taking antidepressants.[Goodwin et al., 2017] One hypothesis of the cycle of anhedonia in patients with depression is shown on the slide; this hypothesis comes from a series of experiments performed on a sample of psychology students.[Setterfield et al., 2016] The students were given the Beck Depression Inventory (BDI), and only those who displayed either high (BDI score >20) or low (<10) depressive symptomatology were included in the study.[Setterfield et al., 2016] As well as completing a series of questionnaires, their helping behaviour was tested during the debriefing process when, in what was made to seem like an accident, a researcher dropped a pile of papers near the participant – latency to help, and the degree of help provided was used as a proxy for helping behaviour, and social anhedonia.[Setterfield et al., 2016] Higher levels of participants not helping were seen in the high depressive symptomatology group.[Setterfield et al., 2016]

There have been attempts to assay the effectiveness of newer antidepressants against the symptoms of anhedonia; one such study found that treatment over eight weeks with a melatonin receptor agonist decreased severity scores on depression scales, as well as scores on the Snaith-Hamilton Pleasure Scale that measures anhedonia.[Gargoloff et al., 2016] However, effectiveness on symptoms of anhedonia remains an unmet need in the treatment of MDD.[Goodwin et al., 2017; Setterfield et al., 2016; Gargoloff et al., 2016]

Goodwin GM, Price J, De Bodinat C, Laredo J. Emotional blunting with antidepressant treatments: a survey among depressed patients. J Affect Disord 2017; 221: 31–35.

Setterfield M, Walsh M, Frey AL, McCabe C. Increased social anhedonia and reduced helping behaviour in young people with high depressive symptomatology. J Affect Disord 2016; 205: 372–377.

Gargoloff PD, Corral R, Herbst L, et al. Effectiveness of agomelatine on anhedonia in depressed patients: an outpatient, open-label, real-world study. Hum Psychopharmacol 2016; 31 (6): 412–418.

Other references used on slid
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th Edition (DSM-5™). © American Psychiatric Association, 2013.

Bauer M, Pfennig A, Severus E, et al.; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Unipolar Depressive Disorders. WFSBP guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry 2013; 14 (5): 334–385.

Hughes S, Lacasse J, Fuller RR, Spaulding-Givens J. Adverse effects and treatment satisfaction among online users of four antidepressants. Psychiatry Res 2017; 255: 78–86.

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Safety and tolerability
Slide information
References

As outlined on the slide, a survey of 672 patients with MDD found adverse effects of medication to be a common reason for discontinuation of medication.[Bull et al., 2002] In the survey, adverse effects were stratified between those experienced early (the first three months of treatment) and those experienced later (between months four and six of treatment).[Bull et al., 2002] For patients who switched early, drowsiness/fatigue was the most frequently cited reason.[Bull et al., 2002] For patients who switched late, drowsiness/fatigue was equally cited along with sexual dysfunction.[Bull et al., 2002] The study authors speculated that some adverse effects, such as sexual dysfunction, were either perceived by patients to emerge later in treatment, or perhaps become more bothersome to patients as they feel less depressed.[Bull et al., 2002] Interestingly, patients who recalled having the possible adverse effects of their medication explained to them were more likely to rate the adverse effects as mild or moderate in severity, than those who did not recall being told of the potential side effects.[Bull et al., 2002]

There is an unmet need in the treatment of MDD for antidepressant medications with a better tolerability profile.[Bull et al., 2002; Möller, 2008; Stahl, 2013]

Bull SA, Hunkeler EM, Lee JY, et al. Discontinuing or switching selective serotonin-reuptake inhibitors. Ann Pharmacother 2002; 36 (4): 578–584.

Möller HJ. Outcomes in major depressive disorder: the evolving concept of remission and its implications for treatment. World J Biol Psychiatry 2008; 9 (2): 102–114.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

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