Pharmacological management of unipolar depression

Transcription

1 Acta Psychiatr Scand 2013: 127 (Suppl. 443): 6 23 All rights reserved DOI: /acps John Wiley & Sons A/S. Published by Blackwell Publishing Ltd ACTA PSYCHIATRICA SCANDINAVICA Clinical overview Pharmacological management of unipolar depression Malhi GS, Hitching R, Berk M, Boyce P, Porter R, Fritz K. Pharmacological management of unipolar depression. Objective: To be used in conjunction with Psychological management of unipolar depression [Lampe et al. Acta Psychiatr Scand 2013;127(Suppl. 443):24 37] and Lifestyle management of unipolar depression [Berk et al. Acta Psychiatr Scand 2013;127(Suppl. 443):38 54]. To provide clinically relevant recommendations for the use of pharmacological treatments in depression derived from a literature review. Method: Using our previous Clinical Practice Guidelines [Malhi et al. Clinical practice recommendations for bipolar disorder. Acta Psychiatr Scand 2009;119(Suppl. 439):27 46] as a foundation, these clinician guidelines target key practical considerations when prescribing pharmacotherapy. A comprehensive review of the literature was conducted using electronic database searches (PubMed, MEDLINE), and the findings have been synthesized and integrated alongside clinical experience. Results: The pharmacotherapy of depression is an iterative process that often results in partial and non-response. Beyond the initiation of antidepressants, the options within widely used strategies, such as combining agents and switching between agents, are difficult to proscribe because of the paucity of pertinent research. However, there is some evidence for second-line strategies, and a non-prescriptive algorithm can be derived that is based broadly on principles rather than specific steps. Conclusion: Depression is by its very nature a heterogeneous illness that is consequently difficult to treat. Invariably, situation-specific factors often play a significant role and must be considered, especially in the case of partial and non-response. Consulting with colleagues and trialling alternate treatment paradigms are essential strategies in the management of depression. G. S. Malhi 1,2, R. Hitching 1,2, M. Berk 3,4,5,6,7, P. Boyce 2, R. Porter 8, K. Fritz 1,2 1 CADE Clinic, Department of Psychiatry, Royal North Shore Hospital, Sydney, NSW, Australia, 2 Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, NSW, Australia, 3 Deakin University, Geelong, Vic., Australia, 4 Department of Psychiatry, The University of Melbourne, Melbourne, Vic., Australia, 5 Brain Sciences Institute, Swinburne University of Technology, Melbourne, Vic., Australia, 6 The Mental Health Research Institute, Parkville, Vic., Australia, 7 Orygen Youth Health Research Institute, Parkville, Vic., Australia and 8 Department of Psychological Medicine, University of Otago, Christchurch, New Zealand Key words: major depressive disorder; antidepressants; treatment algorithm; clinical practice guidelines; recommendations Gin Malhi, CADE Clinic, Department of Psychiatry, Level 5 Building 36, Royal North Shore Hospital, St. Leonards, Sydney, NSW 2065, Australia. gin.malhi@sydney.edu.au Clinical recommendations Major depression is a heterogeneous disorder that requires both empirical evidence and clinical experience when treating. Patient adherence is essential and should be appreciated by the patient and monitored by the physician. For partial and non-response, physicians should re-evaluate the diagnosis, consider alternate treatment paradigms and, if necessary, consult colleagues. Additional comments The proposed algorithm and recommendations should be used in conjunction with other recognized sources to guide the management of depression. The recommendations set out in this supplement are intended for adults who suffer from unipolar depression. Special populations, such as adolescents, pregnant women and the elderly, are not discussed in detail. This review is not intended to be a comprehensive guide to antidepressant medication. 6

2 Pharmacological management of depression Introduction Pharmacotherapy is an important component within the biopsychosocial and lifestyle approach to treating depression. It builds upon the SET A PACE approach (1), and in doing so, expands the 5P Model, which is a widely used approach for formulation. The latter considers the presenting problem alongside predisposing, precipitating, perpetuating and protective factors and adopts a longitudinal personalized perspective (2). In addition to psychological interventions (3) and lifestyle management (4), which are addressed in separate articles of this supplement, pharmacotherapy is an important treatment option that can be the key ingredient for reaching remission. However, it requires informed administration and monitoring and may not be effective for all individuals. The practical issues of medication choice, partial and non-response to an initial antidepressant treatment, and pharmacological strategies beyond prescription of the initial medication are major concerns in clinical practice and form the focus of this article. Pharmacotherapy treatment strategies for achieving optimal response and managing potential non-response are discussed and addressed by drawing upon both research evidence and clinical experience. The latter is particularly important when considering complex management decisions in which research remains challenging. Aims of the study The study aims to provide clinically relevant, evidence-based recommendations for an individualized formulation for pharmacotherapeutic management. Material and methods Using our previous Clinical Practice Guidelines (1) as a foundation, these clinician recommendations target key practical considerations when prescribing pharmacotherapy. A comprehensive review of the literature was conducted using electronic database searches (PubMed, MEDLINE), and the findings have been synthesized and integrated along with clinical experience. Results Understanding depression and its context To develop an appropriate management plan, it is essential to understand the context in which depression emerges and this can be facilitated by use of the 5P Model. The aim is essentially to build a detailed picture of the problem and tailor treatment accordingly. When applying the 5P Model to pharmacotherapy, predisposing factors include past treatments and prior response. With respect to the latter, pharmacological sensitivity to specific medications is likely to be determined by the unique biology of an individual. Pharmacogenomics addresses this very issue and although this field is in its infancy, it is likely to have mainstream application in the future (5). Precipitating factors are more predictable and include non-compliance, medical disorders, especially inflammatory disorders, ineffective treatments and iatrogenic causes, for example, the side-effects of medications used to treat diseases (levodopa, a drug for Parkinson s disease or interferon). Further, it is important to note that with long-term medication, antidepressant effects are intended to be protective, and any associated side-effects are likely to become more pronounced with remission and can seemingly perpetuate symptoms. A detailed correctly mapped out 5P Model is essential for optimal treatment, and misidentifying the 5Ps can result in compromising and prolonging treatment. Partial and non-response are exceedingly common and as will be discussed later, response rates to pharmacotherapy differ based on individual characteristics. This no doubt contributes to poor response, and although some patients respond well after only one treatment trial, most require multiple treatment trials before achieving remission. For those who respond only partially, or not at all, to multiple pharmacotherapeutic trials, re-evaluation should be considered alongside consultation with a colleague. Reviewing the 5P Model is useful because there are often additional features (i.e. personality issues, anxiety symptoms, persisting interpersonal or psychosocial problems) that may help explain why the patient is not recovering. This study aims to outline the pharmacotherapeutic options for the treatment of depression at each stage of management including initial choice of medication, strategies for negotiating partial or non-response to initial medication, and suggestions for when patients do not reach remission following multiple therapeutic trials. Therefore, evaluating and monitoring treatment response is important, and standardized rating scales are useful for assessing change. In this regard, a unidimensional scale, such as the Bech Rafaelsen Melancholia Scale (6), or non-unidimensional scales like the Hamilton Depression Scale (HAM-D) (7), the Montgomery Asberg Depression Rating Scale (MADRS) and the Inventory of Depressive Symptomatology are of particular benefit. Asking the patient to rate 7

3 Malhi et al. their mood on a 0 10 scale is practical way of charting treatment response. Pharmacotherapy Our clinical practice recommendations (1) for the management of unipolar non-psychotic depression highlight the need to assess what factors may influence treatment response and prognosis. It is important to be able to foresee the patient s treatment outcome (prognosis) when initiating treatment. The features to consider can be recalled with the mnemonic 4C, which represents the four actions, each of which begins with the letter c : characterize identify the clinical symptoms and subtype; calibrate gauge the severity and chronicity of the symptoms; corroborate identify any comorbidities and the context that is contributing to the illness; and consider identify coping styles and adaptive features. Identifying factors that are likely to influence treatment outcome in combination with a detailed 5P Model helps guide which pharmacological treatment is most likely to be effective for a particular patient at a specific juncture and which patients would not benefit from antidepressant medication. Selecting an antidepressant. There are a large variety of antidepressant medications, all of which have similar efficacy when treating communitybased depression (8); however, they differ in terms of tolerability and response to specific features of depression (e.g. anxiety, insomnia) (Table 1). To assist in selecting which option would most likely benefit the patient, our previous recommendations that evaluate antidepressants on the basis of risk, adherence, tolerability and efficacy (RATE) remain pertinent (1). Risk: Tricyclics antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and the serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine, in particular, carry high risks of toxicity in overdose and interactions with other medications. Therefore, alternative antidepressants, in particular selective serotonin reuptake inhibitors (SSRIs), are a much safer and consequently a more popular treatment option (Table 2). Adherence: Treatment adherence is essential, but remarkably difficult to achieve, particularly longer term. In this regard, medication choice is critical, and the dosing of medications should be simple and convenient, and side-effects need to remain minimal to facilitate adherence/compliance. Patient preference should always be considered, as it will facilitate adherence. Tolerability: Tolerability is intertwined with adherence. Medication side-effects impact tolerability, which, in turn, affects adherence. Therefore, common treatment side-effects should be discussed with the patient at the outset of treatment and side-effects should be assessed routinely. Starting on a low dose will help in minimizing side-effects early in treatment. Efficacy: Efficacy remains the sine qua non of any treatment option, but the clinical effects of antidepressants can take 7 10 days to emerge, and therefore, to ensure adherence, patients must be made aware of the likely delay. Risk, adherence and tolerability are prioritized because most antidepressant options are equally effective when treating clinical depression of mildto-moderate severity (Fig. 1). SSRIs are undoubtedly better tolerated and less complicated to administer than older antidepressants, and hence adherence is better. Contrasting SSRIs and older antidepressants in terms of efficacy provides perhaps the only example of a significant gradient or difference in potency among the antidepressant armamentarium. However, this differential is only discernible with melancholia and psychotic depression (9). Further, the first and foremost consideration in pharmacotherapy is safety. In this regard, antidepressants, especially SSRIs, are relatively safe, yet adverse effects can never be fully ruled out. For instance, the potential risk of increasing self-harm in the initial stages of treatment, especially in youth, continues to be a concern. Research suggests there is a small trend for increased suicidality in young adults (18 24 years), but that equally there is reduced risk and increased protective effects of SSRIs and newer antidepressants on suicide attempts in adults (10, 11). As mentioned previously, adherence is necessary for any medication to be effective, and thus is essential to gain therapeutic benefit. Early discontinuation rates are high (12, 13), even though guidelines recommend that the minimum duration of antidepressant treatment for depression should be 6 12 months. During this time, approximately 30% of patients discontinue within the first 30 days and more than 40% discontinue within 90 days of treatment (13). Given the high discontinuation rates, it is important to optimize adherence to treatment, especially when prescribing antidepressants that are likely to produce significant side-effects. Strategies such as 8

4 Pharmacological management of depression Table 1. Summary of antidepressant clinical use, principal mechanisms of action and key features of depression for which the medication is useful Antidepressant class Generic name of medication Principal mechanism of action 1st line SSRI ( ) Selective 5-HT uptake blockade NARI ( ) Reboxetine, Atomoxetine Reuptake inhibitor for norepinephrine and epinephrine NaSSA Mirtazapine Blocks the reuptake of serotonin via 5-HT 2A and 5-HT 2C receptors Agomelatine Melatonergic agonist and 5-HT 2C antagonist NDRI Bupropion Blocks the action of the norepinephrine transporter and dopamine transporter 2nd line SNRI (132) Venlafaxine, Desvenlafaxine, Milnacipran and Duloxetine Similar to TCAs but lack broad spectrum properties TCA ( , ) Amitriptyline, Clomipramine Block reuptake of multiple monoamines Nefazodone 5-HT 2A antagonist 3rd line MAOI Irreversibly inhibit the mitochondrial enzymes Monoamine oxidase A (prefers 5-HT) & B (prefers NA & EPH) Adjunctive SARI Trazodone Blocks reuptake of serotonin, noradrenaline and/or dopamine Features of depression for which medicine is particularly useful Anxiety Reboxetine may be useful for activation. Atomoxetine is prescribed for ADHD and is therefore not recommended 1st line for depression. Insomnia Sleep problems Melancholia; severe depression Melancholia; severe depression Venlafaxine: anxiety Duloxetine: pain Pain Melancholia Melancholia Atypical symptoms* Treatment resistant depression Used when patients do not respond well to 1st line SSRI, selective serotonin reuptake inhibitor; NARI, noradrenaline reuptake inhibitor; NaSSA, noradrenaline and specific serotonergic antidepressant; NDRI, norepinephrine-dopamine reuptake inhibitor; SNRI, serotonin and noradrenaline reuptake inhibitor; TCA, tricyclics antidepressant; MAOI, monoamine oxidase inhibitor; SARI, serotonin antagonist and reuptake inhibitors; NA, noradrenaline; EPH, epinephrine. *Evidence is equivocal. Low dose. Table 2. Side-effects associated with common antidepressant groups. +, ++, +++: <10%, 11 29%, >30% Weight gain Sexual dysfunction CNS effect (e.g. sedation, fatigue) Anticholinergic effect (e.g. dry mouth, tremor) GI distress SSRI NARI NaSSA Agomelatine NDRI SNRI TCA MAOI* Nefazodone SARI SSRI, selective serotonin reuptake inhibitor; NARI, noradrenaline reuptake inhibitor; NaSSA, noradrenaline and specific serotonergic antidepressant; NDRI, norepinephrine-dopamine reuptake inhibitor; SNRI, serotonin and noradrenaline reuptake inhibitor; TCA, tricyclics antidepressant; MAOI, monoamine oxidase inhibitor; SARI, serotonin antagonist and reuptake inhibitors. *MAOIs require dietary restrictions to prevent hypertensive crisis, some combinations with other drugs can be fatal. education, self-management by patients and collaborative care by practitioners have been shown to enhance patient adherence (14). Side-effects are one of the main reasons cited for early discontinuation of antidepressants; thus, tolerability is essential and this is the domain (as opposed to efficacy) in which most antidepressants differentiate from each other. The SSRIs, SNRIs and some newer agents (such as agomelatine) are recommended first-line because they have better safety and tolerability profiles than older antidepressants, such as the TCAs and MAOIs (15 17). The variety of first-line medications makes initiating treatment a process that requires careful consideration. Meta-analyses have revealed modest differences in efficacy 9

5 Malhi et al. SSRIs NARIs NASSAs Agomela NDRI SNRIs* TCAs MAOIs Nefazodone SARIs Clinical u lity _ 0 + depressants First-line Second-line Legend Acute efficacy Tolerability difficul es Fig. 1. The clinical utility of antidepressant agents rated according to efficacy and tolerability. *Efficacy for SNRIs is plotted for severe depression. SSRI, selective serotonin reuptake inhibitor; NARI, noradrenaline reuptake inhibitor; NaSSA, noradrenaline and specific serotonergic antidepressant; NDRI, norepinephrine-dopamine reuptake inhibitor; SNRI, serotonin and noradrenaline reuptake inhibitor; TCA, tricyclics antidepressant; MAOI, monoamine oxidase inhibitor; SARI, serotonin antagonist and reuptake inhibitors. Adapted from Clinical practice recommendations for depression (1). between newer antidepressants, such as venlafaxine over SSRIs (8), escitalopram over comparators (18) and sertraline over other antidepressants (19). However, tolerability has shown to be inferior in venlafaxine compared with SSRIs (20). In trials, it is difficult to establish superior efficacy of one medication over another because of the large sample sizes this requires. Hence, most research groups have not systematically compared the efficacy of individual agents but instead compared the effects against placebo. Pharmaceutical companies have conducted the majority of comparison studies, largely for registration. Overall, escitalopram, mirtazapine, sertraline and venlafaxine have some benefits as compared to other antidepressants when considering dosage and severity of the depressive episode, and reboxetine is the only antidepressant to have a significantly lower response rate than other agents (21, 22). Other factors to consider when choosing an antidepressant include the symptom profile, medical and psychiatric comorbidity, previous response to antidepressants, patient preference and cost of treatment. Additionally, drug drug interaction is an important consideration (particularly when medical comorbidity exists), especially because it can increase side-effects and loss of efficacy can result (23). Selection should also take into consideration the prevailing symptoms, such as insomnia and anxiety, because particular antidepressants may be better suited to treating specific symptoms because of their unique chemical profile. For example, mirtazapine is often sedative (as a result of its effect on histaminic receptors) and therefore may be of benefit where insomnia is a prominent symptom (but balanced against weight gain), and reboxetine may be useful in drive-deficient anergic states where sustained motivation is lacking. Depressed patients who suffer from a disturbed sleep wake cycle may benefit from agomelatine because of its ability to improve both night-time sleep and daytime functioning (24). Escitalopram is an antidepressant that is also used for anxiety disorders, thus is favourable for depressed patients where anxiety is a prominent symptom (Table 1). Initializing treatment. Once it has been determined that the patient would benefit from antidepressants and a specific medication has been chosen, prior to commencing the medication the patient should be informed about possible side-effects (in particular, the possibility of activating side-effects and agitation initially), the importance of adherence, the delay prior to the antidepressant becoming effective and self-management techniques, which is designed to foster personal empowerment and responsibility. The patient should give consent to treatment and this should be recorded. Where possible it is helpful to include a significant other in the initiation of treatment. Planned follow-up should be scheduled with regular monitoring of side-effects and adjustment of treatment dosage as needed. The patient (and carer) may choose to keep a mood diary to self-monitor their progress in which they can record their mood on a simple 0 10 scale (it is now possible to do this using a smart phone app). Monitoring response. In clinical practice, response is easily gauged as simply getting better. However, to objectively assess the efficacy of medication, the use of both observer-rated and self-rated questionnaires can be useful. The latter are commonly used in research settings and in recent years have become more widely adopted in general practice and primary care practice. When measuring the efficacy of medication, a 50% improvement on rating scales (e.g. HAM-D or a self-report scale) is typically the point used to define a clinical response, even though, in reality, this may not equate to substantive clinical improvement. Measuring and tracking efficacy rates in patients can be difficult, and the process is further complicated because the trajectory of response is unique in every case. Ideally, both initial (Fig. 2) and long-term responses (Fig. 3) should be charted to determine the likely outcome and establish whether the current treatment is providing sufficient benefit to the patient. 10

6 Pharmacological management of depression Return to func oning High impairment a on of treatment Week 4 Time Remission (A) Delayed response* (A2) Par al response (B) Delayed & Par l response (B2) Non response (C) Week 12 Fig. 2. Schematic representation of potential response patterns following an initial antidepressant treatment. *Delayed response followed by remission. Return to func oning High impairment Fig. 3. Long-term response patterns to treatment. Successive response with eventual remission (A) Plateau (B) Poor response (C) No response (D) After commencing antidepressant treatment, there is usually a delay of 7 10 days before a discernible response emerges (25, 26) and, in practice, evidence of an antidepressant effect is most likely to occur within the first 2 weeks of treatment (25 27). Figure 2 shows the initial patterns of response that are common following the commencement of treatment. Remission following treatment of the first antidepressant trial, as illustrated by curve A, only occurs in a quarter to a third of patients with major depression (28). In some patients, there may be considerable delay before symptoms improve (curve A2). Therefore, it is important to administer an adequate dosage during a trial of 2 4 weeks, while ensuring compliance. However, approximately two-thirds of patients who begin treatment for depression experience either partial response (curve B and B2) or no response (curve C), as demonstrated by a 20 50% reduction on a depression rating scale. Both groups will be discussed in further detail below. When such a scenario occurs, key medication strategies include i) switching, ii) augmentation, iii) combination treatment, and iv) alternative options. There are a range of pharmacological interventions that are more suitable at each stage of iteration, and as discussed in more detail later, there is considerable evidence to support the efficacy of each strategy. However, there is little information as to how the strategies compare against each other or sequencing specificities, especially in the case of partial response. Therefore, the following suggestions are based on expert opinion. Following the initial response to an antidepressant, the long-term response is equally variable (Fig. 3). Once a patient shows short-term improvement, the symptoms either continue to improve and reach remission, or the response plateaus. When the latter scenario occurs, a treatment strategy change may be necessary. The STAR*D study (28) showed that with successive trials of antidepressants, a cumulative response rate of 60% can be achieved, although it may require 2 3 antidepressant trials before remission is reached. Longterm response patterns also show that despite switching to an alternative medication or adding an augmenting agent, a significant proportion of patients with depression still only achieve a partial response (B, C) or may remain refractory (D). These patients require a more extensive re-evaluation of both the diagnosis and causal factors, and a paradigm shift is warranted. The following sections outline pharmacotherapy processes for patients with partial response and non-response patterns. Partial response. If remission is still not achieved after an appropriate time, an iterative process is necessary to achieve further symptom remission and a better outcome. First, there should be a review of the diagnosis to determine whether antidepressant medication is necessary and whether there are any factors that could be maintaining the depression. Second, make sure that the dosage was optimized with the current antidepressant [TCAs, venlafaxine and escitalopram generally have antidepressant activity across a broader dose range (29 31)] and, finally, adherence was appropriate. If the dose was not optimized, increase the dose. If, after assessing the necessary factors, it transpires that further improvement is unlikely on the current antidepressant, the first treatment strategy that should be considered is that of augmentation (refer to the section Combination and augmentation ). Augmentation is the preferred course of action over switching treatments because when some level of improvement has already occurred, enhancement of an ongoing treatment is ideal (28). Further, switching is likely to introduce the added risk of relapse because of withdrawal of the primary antidepressant (Fig. 4). 11

7 Malhi et al. Fig. 4. Treatment algorithm for managing varying response following first-line antidepressant. Prior to commencing a new treatment strategy, it is important to re-evaluate symptoms to ensure the diagnosis is correct and that pharmacotherapy is a suitable option. Once the patient has been on the augmenting agent for a month, evaluate the progress using a validated scale. If marked improvement is present, continue with treatment and assess again in a month with the goal of reaching remission. If remission is achieved, the augmenting agent should be tapered down after a month of remission. If the symptoms plateau with the augmenting agent, consider stopping the augmenting agent and switching the primary agent. When switching antidepressants, carefully choose a new antidepressant with evidence for superiority to the initial antidepressant. If remission is not achieved by 3 months, a paradigm shift is warranted. Identify and investigate any unique factors that may be contributing to the patient s depression, including any social, lifestyle or other variables that may influence the delay in treatment progression. Also consider that the treatment algorithm (Fig. 5) and clinical management and therapeutic strategies that are commonly used may not be appropriate for the patient. Treatment resistance/non-response. Despite a clinician s best effort to subtype and tailor a patient s treatment, some patients do not respond to treatment as anticipated. When there has been no improvement following an optimized dose of an antidepressant, the first step should be a paradigm shift. While taking into consideration that the treatment algorithm may not be appropriate for this patient, re-evaluate the diagnosis, taking note that the patient may have developed new symptoms, the depression is more complex than originally thought or an alternative diagnosis better fits the patient s symptoms. During this assessment, other unique and individualized factors should be taken into consideration, such as the patient s personality structure and lifestyle, social factors or substance abuse. Seek advice from colleagues if necessary. If it has been established that the original diagnosis was accurate, switch the patient to a new antidepressant. When choosing a new antidepressant, consider one that has shown evidence for superiority to the original antidepressant (refer back to the section, Selecting an antidepressant ). Before switching the patient s medication, consider which switching strategy (refer to the section Substitute/ switching treatments ) will be utilized and 12

8 Pharmacological management of depression educate the patient about the strategy and the new medication. Once the patient has been on the new antidepressant for a month, evaluate the patient s progress using a validated scale. If there is a decline in symptoms, continue with the treatment and assess again in a month with the goal of reaching remission. If the symptoms plateau, consider adding an augmenting agent or combining with another antidepressant (refer to the section Combination and augmentation ). If, after further evaluation of the patient, it is determined that the patient is still not responsive to antidepressant medication, the patient is considered to have treatment resistant depression (TRD), defined as a lack of improvement following adequate trials of two or more antidepressants. With TRD, research supports the addition of an evidence-based psychotherapy (32), switching to a neurostimulation treatment such as ECT (33), and continuing with pharmacological strategies. These strategies are addressed below and expand on our previous treatment guidelines (1). Strategies Re-evaluate diagnosis Review adherence & dose Seek consul on Re-assess for Therapeu c Clinical Strategies Management Increase dose. As mentioned previously, before altering any treatment, allow a trial of appropriate duration, usually 2 6 weeks, at adequate dosage (34, 35). Many antidepressants have a relatively narrow therapeutic range in which the agent is considered effective and safe, and research shows that increasing the dose on these medications is not any more effective (36). However, others, such as venlafaxine and TCAs (other than nortryptiline), have very broad dose ranges with up to a ten-fold increase in oral dosage. For instance, venlafaxine can be safely administered at effective doses from 37.5 to 375 mg (37). However, clinical monitoring at high doses is especially important as side-effects and therapy discontinuations usually increase with dosage. It is difficult to be exact regarding duration of medication at any particular stage of treatment because both clinical improvement and lack of response are susceptible to many factors that can alter outcome. For example, relationship and ECT Augment/ Combine Fig. 5. Managing partial or non-response with clinical management and therapeutic strategies (1). occupational factors can often impact clinical symptoms and either accelerate or hinder improvement. Therefore, duration recommendations are only a guide. If an adequate dose has been administered for 6 weeks and there is non-response, switch medications, but if there is partial response, continue the current medication for a further 6 weeks (at the same dose; but a future dose increase can be considered if remission is not achieved). If after 12 weeks the patient does not improve, follow the guidelines for partial or non-response strategies. Combination and augmentation. Combining antidepressants (38), which entails either adding an antidepressant to another antidepressant, or augmentation (14), which includes adding a boosting agent to an antidepressant or increasing the dose, are both seemingly effective strategies. Both are commonly employed to enhance the effect of ongoing antidepressant treatment; however, evidence for either is limited, and that which is available is constrained by the small sample sizes of most studies and the lack of comparisons to placebo. Clinically, combining two or more antidepressants to enhance therapeutic effects or decrease side-effects is common practice (39), yet research on the efficacy of specific antidepressant combinations is more sparse than augmentation strategies. Both combining and augmentation share problems concerning safety and tolerability. Therefore, it is important to monitor the patient carefully for side-effects and potential toxicity. Combination. Research has shown that combinations of antidepressants can be more effective than monotherapy without compromising tolerance (40, 41). However, long-term placebo-controlled comparator studies are needed to substantiate a recommendation of polypharmacy (42). When determining which antidepressants to combine, a rationale based on pharmacokinetic advantage or synergistic action should inform the decision, in addition to past experience and knowledge. For example, venlafaxine and mirtazapine are pharmacologically synergistic or complementary because of their distinct receptor profiles (43). A double-blind randomized trial where patients were treated with combinations of mirtazapine and fluoxetine, or venlafaxine or buproprion showed that these were equally effective for depression as fluoxetine monotherapy and that they were well tolerated (40). A recent meta-analysis found that mirtazapine and tricyclic antidepressants in combination with SSRIs are better than SSRI 13

9 Malhi et al. monotherapy in achieving remission (44). Additionally, of the studies that reported drop-out rates and side-effects, there was no difference between the combined and monotherapy groups. Similarly, a double-blind study that compared mirtazapine monotherapy and paroxetine monotherapy against a combination of both antidepressants reported that remission rates after 6 weeks were highest for the latter (45). However, not all research has supported the use of combinations and not all combinations are pharmacologically sound (34). Augmentation. Similar to combining antidepressants, augmenting agents, such as lithium, T3 (46 48) and some antipsychotics, can enhance the effect of an antidepressant, especially in treatment strategies for TRD. T3 is beneficial for patients with subclinical hypothyroidism who suffer from depression as a consequence. However, T3 is also used as an augmentation agent for depressed patients without hypothyroidism. Patients augmented with T3 should be monitored in the same way as patients with hypothyroidism, with TSH, free T4 and T3 levels regularly checked (48). Lithium, a widely supported and used augmentation agent, is found to be more effective than placebo in augmentation of TCAs, SSRIs and other antidepressants (49, 50). It is recommended that lithium be administered once daily at an oral dose that achieves plasma levels within the therapeutic range ( meq/l) (51). If there is no response to lithium within 7 10 days, alternative strategies should be considered. Care should be taken when discontinuing the use of lithium as research shows that antidepressant augmentation by lithium results in significantly higher relapse rates after abrupt withdrawal (52). Atypical antipsychotics are widely used clinically as add-on agents for TRD, and in addition to empirical evidence, research studies support this strategy (53, 54). Placebo-controlled studies have found that aripiprazole, olanzapine and risperidone can be effective as augmentation agents. These are generally administered at much lower doses than those recommended for schizophrenia and bipolar disorder (54 56), but this practice is off-label and these agents are not formally indicated for augmentation. Further, adverse effects of these agents must be closely monitored, as weight gain, potential metabolic syndrome and extrapyramidal side-effects are of great concern, especially in the context of longterm therapy. Substitution/switching medication. There are two main considerations when switching antidepressants: first, which antidepressant to trial next and second, which strategy to employ when switching. Switching antidepressants. Randomized control trials have found that switching to a different antidepressant improves response and remission rates when switching for both non-response (57) and intolerability reasons. Switching within a class (e.g. from one SSRI to another) is no more effective when compared to switching out of class (e.g. from an SSRI to a non-ssri) (28, 58, 59), but if treatment has been curtailed (e.g. medication has only been taken for a few days) because of side-effects, then switching within a class to another agent may be a worthwhile option. The majority of patients begin with a first-line antidepressant, such as an SSRI. Patients who are intolerant to the initial SSRI often benefit from a second SSRI. It is recommended that patients use a lower dose of the second SSRI initially, and it may be necessary to taper the first SSRI for a longer period (e.g. switching from citalopram to escitalopram can be done immediately; switching from fluoxetine to another antidepressant, washout period of at least a week is suggested before commencing the second agent at a lower dose). However, if the patient was non-responsive to the initial SSRI, switching out of class to a SNRI (i.e. venlafaxine), norepinephrine-dopamine reuptake inhibitor (NDRI) or TCA is recommended (58, 60). Switching to a TCA carries the benefit of higher response rates but is disadvantaged by greater risk of side-effects. If a patient begins with a TCA, which is uncommon, switching to another TCA has the advantage that a switch can occur without a wash-out period, and the dose on the new TCA can remain the same. As SSRIs are typically the starting point for antidepressant treatment, the majority of research examines the switch from SSRIs to another antidepressant. Therefore, there is a lack of research evidence for other combinations but most combinations have been supported. Switching strategies. There are three main strategies that should be considered when deciding the best way to switch medications: i) overlap medications, ii) taper or stop/start medications; and iii) have a washout period. The most common strategy utilized in practice is to introduce and withdraw medication gradually to minimize any un-medicated period and avoid the risk of the serotonin syndrome. However, the preferred switching strategy chosen should depend on the degree of response achieved from the initial antidepressant trial (Fig. 6). 14

10 (a) Concurrent switch (c) Sequential switch (b) Overlapping switch al response Pharmacological management of depression when medication is at a subtherapeutic dose. Therefore, this strategy is preferable for those who did not respond to the initial medication, because this switch can be done quickly without a washout period and has the advantage of not overlapping medications, which increases side-effects. However, switching to, or from, an MAOI requires a clear washout period of at least a week to avoid the risk of severe drug drug interactions. *Non- response Fig. 6. Schematic representation of strategies for switching antidepressant medication. The preferred switching strategy chosen should depend on the degree of response achieved from the initial antidepressant trial: (a) changes in dose of both medications are implemented simultaneously, thus, beneficial for partial response; (b) dose changes are only implemented in one medication at a time, while holding the initial medication constant at the original dose until the second medication has reached optimal dose; thus, this strategy is suitable for partial response; (c) this option is the safest way (least likely to cause any interactions) of substituting one medication for another and is preferable for those who did not respond to the initial medication. (A) Concurrent switch: Changes in dose of both medications are implemented simultaneously, thus, overlapping medications. Although this option offers the advantage that the individual is always medicated, there is an increased likelihood of interactions and side-effects because the medications are administered jointly. (B) Overlapping switch: Dose changes are only implemented in one medication at a time. The initial medication is continued at full dose while gradually commencing the new medication. Begin tapering the medication that is being substituted once optimal dose has been met on the new medication. This strategy is preferred for partial response because the cross-over is important to help retain any benefit achieved from the initial medication thus far. Similar to concurrent switch, there is an increased risk of interactions and sideeffects because the medications are overlapped. However, iatrogenic side-effects are more easily identified because only one medication is modified at a time. (C) Sequential switch: Taper the initial medication and once this has been fully withdrawn, gradually introduce and titrate the new medication to optimal dosage. This option is the cleanest way of substituting one medication for another but takes much longer, especially if it also includes a washout period. This option also increases the chance of worsening because there is a considerable period Electroconvulsive therapy (ECT) Electroconvulsive therapy involves applying electrical current to the brain to induce a convulsion (seizure) and is an effective alternative treatment option in cases of marked severity, risk or ongoing non-response to medication or psychological treatments (33, 61 63). The recommended frequency is two to three times per week under monitored conditions to achieve rapid and effective antidepressant effects (64, 65). Of note, the speed of response is usually faster with three administrations per week; however, the degree of cognitive impairment is likely to be greater even if the overall number of ECT treatments is the same (64). ECT should be used in conjunction with ongoing antidepressant treatment (66). The advantage of this strategy is that it decreases the frequency of early post-ect relapse, which can be quite high in the first 6 months if ECT is used on its own (67). If concurrent antidepressant treatment is not used with ECT, an antidepressant trial should be reintroduced following ECT treatment as antidepressants are often effective after ECT, even if they were not particularly beneficial prior. Overall, ECT is very effective, with response rates of up to 80 90% (68), but is considerably lower for patients who have failed to respond to adequate antidepressant medication trials (69). However, the lower response rates in these instances may reflect the greater severity of the illness, as ECT is commonly used as a last resort once antidepressants have failed. Of note, ECT is more effective than antidepressant monotherapy for patients with melancholia (70) and especially those with psychotic depression (68). Additionally, ECT is also recommended for treating severe depression during pregnancy as it poses less of a risk to the foetus and mother (71) compared with antidepressant use (72, 73). Novel treatments Other options that include neurostimulation are repetitive transcranial magnetic stimulation (rtms), vagus nerve stimulation (VNS) and deep 15

11 Malhi et al. brain stimulation (DBS), the latter two of which are more invasive than ECT. rtms involves generating a superficial current by way of electromagnetic induction in the dorsolateral prefrontal cortex. Unlike ECT, it has shown minimal adverse neurocognitive effects (74). The VNS device has a good safety profile but the efficacy is still being evaluated. DBS involves implanting a stimulating electrode in a specified area of the brain. Early results in open-label trials of DBS use for depression treatment are promising (75 77), but need RCT evidence before it can be recommended for clinical practice. Substantial resources are being devoted to the genetic epidemiology of depression and are another source for novel treatment options for depression. Although the overall genetic contribution to depression is likely to be minor (78), preliminary research suggests that efficacy of antidepressants may be predicted by genetic markers (79), yet more research is necessary to replicate these findings. Escitalopram response was predicted by a marker in the gene encoding interleukin-11 and IL-6 gene, in which the latter has been established as a candidate gene for depression (80). Additionally, response to nortriptyline has been shown to be associated with the UST gene, although this gene has yet to be an established genetic marker for depression. Brain-derived neurotrophic factor (BDNF) has been examined as a susceptibility locus for the development of depression, but the results have been inconclusive as there are contradictory findings in recent research (81 83). Additionally, the gene environment hypothesis focused on the link between the serotonin transporter-linked polymorphic region (5-HTTLPR) and stressful life events on increased risks of depression. Although the results suggest that persistent depression increases with this specific gene x environment interaction, further research has failed to replicate these findings (84, 85). Importance of re-evaluating diagnosis It is unlikely that core features of major depression, such as depressed mood and feelings of hopelessness, occur in isolation from symptoms of anxiety, substance misuse, personality disorders or eating disorders. In fact, a large proportion (estimated 50 70%) of patients with depression report anxiety symptoms (86 88). These commonly occurring comorbidities complicate diagnosis and treatment and contribute to a poorer prognosis (89, 90). Therefore, re-evaluating the diagnosis following partial and non-response to antidepressant treatment is crucial, keeping in mind that depression may not be the primary or sole diagnosis. Bipolar depression is another complex layer that should be explored when diagnosing and treating, as 10 20% of patients diagnosed with unipolar depression will experience hypomania or mania in the course of their illness, resulting in a revision of diagnosis to bipolar disorder (91, 92). There is also growing evidence to suggest that hypomanic symptoms commonly occur in a subset of patients with depression and these contribute to treatment nonresponse (93). Predictive factors for bipolar disorder that have been robust across studies include early age at illness onset (94 96), presence of psychosis (94, 97, 98) and family history of mania (94, 95, 97 99). Even if manic symptoms were previously explored, critically examine the patient s past and recent history specifically targeting symptoms of mania or hypomania. Paradigm shift In the event that the iterative treatment options have been explored and the patient is still nonresponsive, consider individual factors, unique characteristics and other variables that may be influencing treatment resistance. Additionally, consider other treatment options outside of the treatment algorithm. The patient may have developed new symptoms; the depression is more complex than originally thought; or there are social/ lifestyle factors that may be a contributing factor. For example, since the commencement of the initial antidepressant, the patient may have lost his job, which in turn negatively affects his relationship and housing situation. In this instance, an overall reassessment is needed while taking into consideration the patient s lifestyle, psychological treatments, substance abuse and/or more aggressive treatment options (e.g. ECT). It is possible that the original diagnosis may be wrong. Returning to the 5P Model and reassessing the patient s problems are in the best interest for the patient and may open up new possibilities for treatment. If it has been established that the original diagnosis is correct and the patient s symptoms are nonresponsive to the previously suggested treatment options, novel treatment options may be warranted. Remission/recovery Duration of treatment. Long-term antidepressant treatment should be considered on an individual basis, while taking into consideration the risks of continued medication use and benefits of preventative care. Research recommendations suggest that 16

12 Pharmacological management of depression antidepressant treatment should continue for at least 1 year following the onset of symptoms for an initial episode and at least 2 years if the patient carries any risk factors, such as having many prior depressive episodes, particularly if they are severe, chronic and difficult to treat with residual symptoms, significant comorbidity or the patient is of older age ( ). If psychotic features are present, then continue treatment for up to 3 years (104). Meta-analysis results suggest that to maintain remission, the treating dose should be continued; decreasing the dose significantly increases relapse/recurrence rates (105). During antidepressant maintenance, the patient s condition should continually be assessed as the risk of relapse is relatively high and is increased by a variety of factors (Fig. 7). Relapse rates are highest immediately following remission and diminish with time (106). In addition to antidepressant treatment, cognitive behavioural therapy (CBT) has shown long-term effects in preventing relapse and recurrences. Thus, integrating CBT with antidepressant treatment may decrease both relapse rates and the need for longterm antidepressant maintenance (32). Ensuring adherence. Patient improvement with pharmacotherapy heavily relies on adherence; thus, it is crucial that adherence is actively addressed and monitored. Patients who are depressed are unmotivated and feel down, so engaging in an unnatural routine of taking medication, which is an anomalous habit for healthy individuals, is even more difficult for those who are depressed. To increase adherence, educational interventions should be used in conjunction with behavioural changes in order to gain maximum benefit. Complex behavioural changes are the most effective in improving antidepressant medication Concurrent factors Gender Female Life events/social stress Comorbid medical illness Time Severity of depression on of episode Presence of psychosis Residual symptoms Treatment resistance Fig. 7. Factors increasing the risk of acute relapse in depression. Concurrent factors should be taken into consideration when choosing treatment options. Note. Specific factors that increase the risk of relapse are labelled at the point of where they are likely to impact treatment. adherence (107). Prior to starting antidepressant treatment, both the physician and patient must understand what the ultimate goal of treatment is and why medication is important. The patient should be clear of what is necessary to achieve this goal, including what should be done if a dose is missed. Missing a dose should be actively addressed so the patient understands that missing a dose does not result in failed treatment, but rather, repeatedly neglecting the prescribed dosage causes ineffective treatment. Patients should be advised not to double-up their medication should they miss a dose. When assessing the patient at each visit, physicians should include questions regarding adherence, which should become routine during each visit. Although side-effects and tolerance are often viewed as negative, they are another indicator of patient adherence. Thus, if the patient reports no side-effects, the patient s adherence should be questioned. When side-effects such as weight gain or sexual dysfunction compromise adherence to medication, it is worthwhile switching to an antidepressant with a more favourable sideeffect profile, such as agomelatine that does not carry these side-effects (108, 109), to ensure maintenance of treatment. Titrating treatment. Treatment guidelines recommend upward dose titration during the initial stage of antidepressant treatment ( ). Titration upwards normally involves increasing the antidepressant dose gradually while monitoring for efficacy, and as mentioned, it is an iterative process that may involve many dose increases depending on the antidepressant being prescribed. However, the starting dose needs to be taken into consideration when weighing the advantages and disadvantages of titration. The initial antidepressant dose is likely to vary depending on whether the clinician has planned titration a priori or has made a decision to increase dosage post hoc. The latter is usually the consequence of a partial or non-response. In general, titration is a useful approach for reducing side-effects, but it delays the achievement of a therapeutic dose, and the likelihood of a clinical response. However, research shows that patient adherence is significantly greater when patients begin on a low dose with future titration compared to patients who commence treatment at therapeutic levels. Patients who commenced antidepressant treatment at a dose less than or equal to the dose recommended in the APA guidelines and who titrated their antidepressant dose within 60 days were 2.6 times more likely to adhere to treatment than patients who began at a dose recommended 17

13 Malhi et al. by APA guidelines. These findings apply to a range of SSRI and SNRI medications (113). Commencing a patient on antidepressant levels at, or less than, the recommended dose with the intention to titrate treatment is particularly useful for patients who are frail (e.g. elderly, those with comorbid medical illness) (114, 115) or when commencing certain classes of antidepressants. For example, tricyclic antidepressants need to be titrated because of potential cardiac toxicity associated with peak plasma levels (116). Additionally, in practice, patients on SSRIs and SNRIs can decrease their risk of transitory side-effects by commencing treatment on low doses and titrating the dose slowly to reach therapeutic levels (115, 117). Although this initial titration of treatment increases the complexity of management, it does foster closer clinician follow-up and ensures adherence. Therefore, the combined effect of titration and regular clinician follow-up should significantly improve patient outcome. Discussion Psychological/social/lifestyle factors Depression is a complex neuropsychiatric disorder that is unlikely caused solely by biological factors, but rather includes psychological, personality and social components (118). Therefore, the election of treatment for depression should incorporate pharmacological, psychological and lifestyle aspects and be individually tailored for the patient. Our companion paper on Psychological Management of Unipolar Depression (3) explains in more detail various therapeutic approaches and appropriate treatment appraisal based on presenting symptoms and patient characteristics/preferences and history. The likely outcome from treatment also needs to consider the patient s lifestyle and personal choices. Our companion paper on the Lifestyle Management of Unipolar Depression (4) will also assist clinicians in diminishing the likelihood of partial and non-response. Moreover, the inclusion of all three recommendations is ideal in the maintenance phase of treatment. Integration of care Role of primary care physician and general practitioner. Primary care physicians are pivotal to mental health care, especially if they have been treating the patient long term. The amount of involvement the primary physician has with treating the patient s depression depends on the complexity of the patient s illness and the level of involvement of the psychiatrist. Patients who are treated by a psychiatrist on a regular basis will have less contact with their primary physician for the depression treatment, yet the GP should continue to be aware of the treatment in case of emergency and the patient needs medical assistance on short notice. Patients with mild cases of depression are likely to continue seeing their primary physician for monitoring and treatment maintenance as they are less likely to engage with a psychiatrist full time. Regardless of the patient s severity, the psychiatrist and primary physician should communicate with each other regarding changes in mental or physical state and changes in treatment. Family and friends. Depressed patients are likely to experience stress associated with their family and other relationships, which is often a factor contributing to the patient s illness (119). However, positive social networks are fundamental for patient improvement, and these relationships should be maximized throughout treatment. In conclusion, the pharmacotherapy of depression is a complex process because it is a heterogeneous disorder and each individual, when affected, requires consideration of unique factors. In addition, effective treatment relies on both empirical evidence and clinical experience. In practice, first and foremost, adherence is essential, and this needs to be fully appreciated by the patient and regularly monitored by the physician. Response rates to initial antidepressant treatment are lower than those reported in clinical trials and as such follow-up with subsequent treatments is often necessary. Careful and comprehensive clinical assessment of the symptomatic profile is critical and should include the use of a standardized rating scale (e.g. HAM-D) to gauge severity and track change. Although there are many strategies and within these there are multiple options, the extant research suggests that adding an augmentation agent and switching to a new antidepressant are effective tactics and that these are best suited for partial and non-responders respectively. In cases of TRD, it is important to consult with colleagues to gain a different perspective and consider alternate treatment paradigms. It is also useful to thoroughly re-evaluate the diagnosis noting that there may be additional contributing factors as the illness has most likely evolved from the time of initial presentation. Acknowledgements This publication has been made possible through infrastructure support from NHMRC Program Grant (510135) and 18

14 Pharmacological management of depression CADE Clinic, Department of Psychiatry, The University of Sydney, and an unrestricted educational grant from Eli Lilly. Declaration of interest In the past 3 years, Professor Gin Malhi has served on a number of international and national pharmaceutical advisory boards, received funding for research and has been in receipt of honoraria for talks at sponsored meetings worldwide involving the following companies: AstraZeneca, Lundbeck, Sanofi- Aventis, Eli Lilly, Janssen-Cilag, Organon, Pfizer, Servier and Wyeth. Professor Michael Berk has received funding for research from Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo Smith K-line, Organon, Novartis, Mayne Pharma, Servier, AstraZeneca, has received honoraria for speaking engagements from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Glaxo Smith K-line, Janssen-Cilag, Lundbeck, Organon, Pfizer, Sanofi Synthelabo, Solvay, Wyeth and served as a consultant to AstraZeneca, Bristol Myers Squibb, Eli Lilly, Glaxo Smith K-line, Janssen- Cilag, Lundbeck, Pfizer. In the last 5 years, Professor Richard Porter has received honoraria for speaking engagements from Janssen-Cilag and Sanofi-Aventis. Professor Philip Boyce has served on a number of international and national pharmaceutical advisory boards, received funding for research and has been in receipt of honoraria for talks at sponsored meetings worldwide involving the following companies: AstraZeneca, Lundbeck, Eli Lilly, Servier, Janssen-Cilag and Boehringer Ingelheim. Kristina Fritz and Rita Hitching have no competing interests to report. References 1. Malhi GS, Adams D, Porter R et al. Clinical practice recommendations for depression. Acta Psychiatr Scand 2009;119(Suppl. 439): Malhi GS, Hitching R, Coulston CM, Boyce P, Porter R, Fritz K. Preface: individualized management of unipolar depression. Acta Psychiatr Scand 2013;127(Suppl. 443): Lampe L, Coulston CM, Berk L. Psychological management of unipolar depression. Acta Psychiatr Scand 2013;127(Suppl. 443): Berk M, Sarris J, Coulson CE, Jacka FN. Lifestyle management of unipolar depression. Acta Psychiatr Scand 2013;127(Suppl. 443): Serretti A, Drago A, Spina E. 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