Combination of antidepressants vs. augmentation with atypical antipsychotics upon failure to achieve remission in unipolar depression.

ABSTRACT

---

Introduction: achieving functional recovery as quickly as possible in the treatment of unipolar depression is a challenge that clinical practice must try to meet nowadays, since any delay in accomplishing remission of the symptoms is predictive of a larger number of recurrences and higher morbidity and mortality rates. In this topical review we aim to guide clinicians in their choice to augment with atypical antipsychotics or to combine the baseline drug with a second antidepressant, after the dose of the antidepressant initially selected has been optimized and/or the antidepressant has been changed, not achieving remission, or resulting only in a partial response after sufficient time at an appropriate dose. These decisions arise frequently in everyday clinical practice. Methodology: a systematic search in PubMed was performed under several key combinations of words, resulting in 230 reports. After applying inclusion criteria and based in title and abstract, the final number of reports selected for full revision were 113. Two main questions were answered based on these studies: 1) Is there evidence to clearly recommend combination of antidepressants vs. augmentation with antipsychotics (and the correct moment to do it) in non-responsive unipolar depression, once optimization or switching strategies have failed to obtain remission? and 2) Is it possible to identify some clinical features to guide the decision of combination of antidepressants vs. augmentation with antipsychotic agents? Results: According to our analysis, there is no data available to select one strategy from another in a clear-cut manner. Nevertheless, we suggest favoring a combination or augmentation strategy, based in a “treating to target” approach to profile the patient, considering one or two predominant clinical features that remain active as part of a major depression with partial response. Proper analysis of the symptomatic domains present, a critical view of current clinical guidelines and preferred options, considering hidden bipolarity as one of the main differential diagnoses and adopting an energetic but lucid attitude at this stage of treatment are, in our view, fundamental for achieving ad integrum patient recovery.

Key words: unipolar depression, augmentation, combination, atypical antipsychotics.

INTRODUCTION

---

The reported risk of early relapse and recurrence if residual depressive symptoms persist may be as high as 76% in the case of early relapse in patients with residual symptoms v/s. 25% probability of this outcome in patients who achieve full remission. This is obvious in everyday clinical practice, but has also been quantified in controlled, naturalistic studies.(1)

The pressure to achieve early remission with strategies of early dose optimization of the antidepressant selected, and/or switching to a different antidepressant of the same or another class, is a clinical controversy that has been reviewed and commented previously . However, even assuming a clinically guided sequential approach using these two strategies with appropriate doses and times, it is estimated that around 50% of patients will not achieve remission(3). Since there are many different forms to define remission, our perspective is that it should be considered as a relatively brief period of time (few weeks) during which the patient has only minimal symptoms. Thus, full remission could be operationalized as a score of ?7 on the 17-item Hamilton Depression Rating Scale (HAM-D).(4)

The general proceeding of clinicians is summarised in Figure 1. This diagram is taken from, and based on, the works of Shelton et al., Thase and Rush, McIntyre et al. and Ros et al.(5,6,7,8)

If remission is not achieved after trying a dose optimization strategy or switching to another antidepressant for sufficient time at an appropriate dose, various alternatives are available for the clinician. The evidence is not clear as to whether the best plan is to combine two antidepressants of different classes or to augment with a molecule not classified as an antidepressant. Nevertheless, correct profiling of different symptomatic sub- groups of patients, based on what is known as “treating to target strategy”, allows better decisions to be taken between the alternatives formerly mentioned.

The most frequently used combination strategies are SSRI and/or duals as baseline antidepressants, associated with NDRI (Noradrenaline and dopamine reuptake inhibitors), NaSSAs (Noradrenergic and specific serotonergic antidepressants) or NRI (Noradrenaline reuptake inhibitors) as adjuvants in synergic action.

Among augmentation strategies, lithium carbonate and thyroid hormones in unipolar patients who have  not  achieved  remission  are  two  widely used approaches which have not produced robust clinical results. Lithium carbonate has been much studied as an enhancer of SSRI, tricyclics and MAOIs, however its effectiveness in association with  duals  antidepressants  or  mirtazapine  has not yet been demonstrated(9). In the case of lithium, the subsequent evidence of its role as a drug with anti-suicidal effects, regardless of it effect on depressive symptoms, has made this an augmentation strategy of excellent heuristic value not only for patients with suicide risk, but also those with repetitive melancholic episodes(10,11,12), or who present a bipolar affective disorder or strong suspicion of this condition in what has come to be called “hidden” bipolarity(13). The latter situation, in which a patient is mistakenly diagnosed as unipolar and frequently presents resistance to antidepressants, was proposed theoretically by our group in 2010 and then demonstrated empirically in an excellent work published by Cheng-Ta Li et al. in 2012(14,15). Nevertheless,  the  main  difficulty with  the  use of  lithium  in  augmentation  therapy  is  related to its side effects, especially its potential effect on  renal  and  thyroid  functions,  the  induction of hand-tremor upon voluntary movement (i.e., action tremor) and its less frequent but potentially serious effects on hydro-electrolytic equilibrium, especially the induction of hyponatremia. There is some evidence to support the use of thyroid hormones in augmentation, particularly in cases with clinical hypothyroidism, or sub-clinical hypothyroidism associated with high anti-thyroid antibodies. The evidence is less robust than that reported for lithium salts, especially when mega- doses of thyroid hormone are used.(16) The use of either atypical antipsychotics with partial 5HT1A agonist effect or a combination of antidepressants are the most recent alternatives for managing these patients, with interesting evidence in support of their use.

MATERIALS AND METHOD

---

To  select  the  reports  in  which  our  work  is based,   both   authors   made   a   review   of   the literature using PubMed and searching for the following combinations of words: “depression AND remission”, “depression AND response”, “antidepressant combination” and “antidepressant augmentation”. At  this  point  the  following search string was used: (depression[Title/ Abstract]) AND (augmentation[Title/Abstract]) AND (antidepressant[Title/Abstract]) AND (combination [Title/Abstract]).

The search involved all English articles, including: Randomized Controlled Trials (RCT), meta- analysis, review articles, open-label reports, longitudinal follow-up studies, comprehensive reviews, and case reports. Additional articles were included after reviewing the references of selected articles.

Inclusion criteria

Based on title and abstract, both authors selected the  reports  that  underwent  full  revision.  The inclusion criteria used to choose the selected reports were:

1) Studies published in peer-reviewed journals.

2)  Diagnosis  of  depression  with  partial  or  no
response to a first line antidepressant agent.

3) Studies including any combination of two antidepressants or the use of any atypical antipsychotic as an augmentation strategy to enhance antidepressant response.

4) Response or remission rates were informed

RESULTS

---

Applying the search string already mentioned, 230 reports were obtained since 1986 until April 2021. From these reports, and based on the inclusion criteria, 86 studies were selected for complete revision.  Finally,  and  after  including  articles from cross-references, the total number of reports reviewed in full text were 113.

Even though we systematically searched for the articles that we finally included in this topical review,  we  did  not  tabulate  each  one  of  them in  detail.  Basically,  we  made  a  summary  of each selected report to have a comprehensive perspective as fundamental theoretical frame for our work.

Using the information obtained, the authors attempt to answer the following questions:

1) Is there evidence to clearly recommend combination of antidepressants vs. augmentation with antipsychotics (and the correct moment to do it) in non-responsive unipolar depression, once optimization or switching strategies have failed to obtain remission?

2)   Is   it   possible   to   identify   some   clinical features  to  guide  the  decision  of  combination of antidepressants vs. augmentation with antipsychotic agents?

Combination of antidepressants vs. augmentation with atypical antipsychotics in non-responsive unipolar depression: which option should you choose?

As indicated above, the combination of antidepressants of different classes with synergic action is a common strategy in clinical practice after dose optimization or switching has been made. This treatment seeks to recruit unincorporated lines of neurotransmission, avoid side effects, or relieve specific target symptoms; however, it raises the central question in the treatment of episodes where remission is not achieved, which summarizes a large part of the psychopharmacological discussion of the last twenty years: Do two or more action mechanisms promote the remission of a depressive episode better than one?

Combination strategy suggested increased remission in three open-label(17,18,19),   and two double-blind   studies(20,21),   a   randomized   trial was equivocal(22) and a randomized but non- blinded study did not differentiate combination of antidepressants from monotherapy.(23)

One of the first – indirect – answers to this question was offered by the widely known STAR*D study, which reviewed the remission rates  obtained  with  three  pharmacological attempts in a row after failure to achieve remission with initial SSRI treatment. The main conclusion of this study was that remission rates fell with successive treatment regimens; indeed, remission at first attempt was 37%, and four sequential therapeutic attempts (total number of protocol´s attempts) increased the achievement of remission to 67%(24). Notwithstanding these initial results, it is worth to note that STAR*D was not designed to determine whether recruiting a larger number of action mechanisms was associated with higher response and remission rates; its objective was, rather to obtain a panoramic view of what can be accomplished by clinically guided use of sequential schemes to treat a depressive episode. Although it is possible that the lack of enhanced antidepressive     responses     after     successive

treatment rounds might be due to inability to recruit additional  neuropharmacological  mechanisms, this hypothesis seems to be unlikely and rather parsimoniously explained by selection of resistant patients in the population, wherein increasingly refractory patients are left within the study sample as trial rounds advance. Therefore, the design of STAR*D does not allow to answer the question, since it proposes in every case an initial treatment with an SSRI; this makes it impossible to extract any conclusion about responses or remissions obtained with the subsequent strategies, due to the fact that the patients selected had probably greater resistance.

To answer the proposed question properly, the same study group, led by John Rush, designed the CO-MED study, which started to run in 2008. It included 665 patients with recurrent or chronic depression, divided from the start among different arms of the study which compared the response/ remission between: escitalopram plus a placebo (arm  representing  a  single  action  mechanism) vs. bupropion plus escitalopram vs. mirtazapine plus venlafaxine (arm representing the synergic action of two or more action mechanisms). The spirit of the study was to test the treatments in ambulatory patients and use the highest possible doses  in  the  arms  representing  the  synergic action of antidepressants of different classes. The result, contrary to all expectation, showed in the follow-up over 12 weeks and 7 months that no significant differences were obtained in response or  remission  between  any  of  the  three  groups, and that the combination of mirtazapine plus venlafaxine presented the highest rates of side effects(25,26).  Subsequent  analysis  tried  to  show that in the sub-group of more severe patients, or those with melancholic depression, it would be possible to identify significant differences between the different arms of the study. The result again defied logic: no significant differences were shown between the groups.(27)

These  results  were  initially  discouraging  for many psychopharmacologists who were eagerly awaiting scientific corroboration of their empirical observations. Later analyses contextualized these results from what could be considered a Type II error in the CO-MED study, i.e. the sample was too small to prove differences between the groups. Furthermore, the analysis of the dose per drug shows that high doses were not applied as had been the intention when the study was designed. There were other problems with the design, for example that the researchers were not blinded as to the treatment given.

In contrast, the study group led by Pierre Blier was able to demonstrate, in a study with 105 patients, the advantages of synergic combinations of different action mechanisms. This study compared  the  following  study  arms:  fluoxetine in monotherapy vs. mirtazapine plus venlafaxine vs. mirtazapine plus bupropion vs. mirtazapine plus fluoxetine. The remission percentages were significantly higher for the three combination strategies  than  for  fluoxetine  in  monotherapy, with remission rates of 25%, 52%, 58% and 46% respectively for each of the study arms(28). There are many examples in the literature in which even a simple combination like bupropion associated with escitalopram was more effective than either drug  in  monotherapy  after  12  weeks’  follow- up(29). On the contrary, a well-designed study by Stewart et al. comparing the therapeutic result obtained in 245 patients with unipolar depression who were randomly assigned to double-blind treatment with bupropion or escitalopram or the combination dosed to a maximum of bupropion
450 mg and/or escitalopram 40 mg for 12 weeks, failed to demonstrate that combination therapy outperformed both monotherapies in either timing of remission or remission rate.(30)

Thus, medium sized trials, and multiple case reports, suggest there are benefits from combination of antidepressants but the small number of patients in each study prevents any definitive conclusion(31). The only meta-analysis we found was published by Lam et al. and analyzed 27 trials involving
667 patients failing to respond adequately to monotherapy(32). This review focused on treatment resistant depression and reported a 62% response rate with combination of antidepressants. Its main limitations are the small number of randomized controlled trials that were included, and the variability in definitions of treatment-resistant depression and response to treatment.

Additionally, the use of venlafaxine plus mirtazapine, one of the most widely used combinations in clinical practice for non- responsive or treatment resistant patients, has some interesting data to support its use. In one study involving 32 patients with persistent depressive illness, the response rate of this combination  was  44%  and  56%  at  weeks  4 and  5  respectively(33).  Another  study  reported a response rate of 82% and a remission rate of
27% in a cohort of 22 patients with treatment resistant  depression  treated  with  venlafaxine plus  mirtazapine  for  eight  weeks(34).  Finally, a sub-analysis from STAR*D compared the effectiveness and tolerability of tranylcypromine monotherapy with venlafaxine plus mirtazapine in 109 patients that did not respond adequately to three previous antidepressant trials. This analysis is important from a clinical perspective since monoamine oxidase inhibitors are classically described as three-mono-aminergic antidepressant   agents,   with   a   theoretically high potency mechanism. The remission rates informed where modest and not significantly different, 6.9% for the combination therapy and
13.7% in the tranylcypromine group.(35,36)

The   possibility   of   combining   antidepressants with synergic action is evaluated by the clinician not only in the absence of remission, but also to manage residual target symptoms which impair the patient’s quality of life and have been shown to be strong predictors of relapse. Thus, symptoms like insomnia, lack of appetite and weight loss, and  primary  or  secondary  sexual  dysfunction when treated with antidepressants, are generally pharmacological targets that can be addressed with a combination strategy. Although the ideal is to stratify the patient from the start based on the most relevant symptoms, trying to avoid polypharmacy, on occasions the clinician wishes to conserve the response achieved with the primary antidepressant and use a second drug to achieve complete remission or the relief of some specific symptom. There are two classic examples of this. One is the use of bupropion, which – as a noradrenaline and dopamine reuptake inhibitor habitually used to treat depression and for giving up smoking – could be useful in reversing the pernicious effect of SSRI on sexuality or for improving asthenia or diurnal hypersomnia(37); nevertheless, one must always be aware of the possible increase of anxiety crises in patients of this type, as this antidepressant has an activating profile(38). The other classic example is the use of mirtazapine in combination in patients with weight loss and difficulty in falling asleep, where it is certainly a virtuous indication with good remission rates in combination with SSRI(39,40); or else in complex medical scenarios, such as cancer patients.(41)

Furthermore,  the  CO-MED  study  revealed  a higher rate of side effects when antidepressants were combined, aimed at achieving synergic effects, often resulting in drop-outs from the protocol, producing rather unfavorable mid-term clinical outcomes, in addition to potentially life- threatening complications such as serotonergic syndrome. In particular, the combination of a SSRI with venlafaxine, did result in frequent adverse effects in the absence of an improved clinical profile.(42)

Thus, a combination will always be a good alternative for patients who have not achieved remission but have presented a response as classically  defined  (more  than  50%  reduction of symptoms compared to the baseline) after an initial switch or early optimization of the baseline antidepressant.

For resistant or severely recurrent patients, some clinicians  propose  combination  strategies  from the start, but this practice is more appropriate for an expert in psychopharmacology, or in settings of high clinical complexity. The use of a second antidepressant to mitigate a side effect of a first- line choice should be discouraged, in favor of safer alternatives such as dose fractioning, reduction of total dose, switching to an antidepressant with fewer side effects or temporarily adding drugs specifically targeted at managing individual adverse effects (e.g., ?-blockers for akathisia, benzodiazepines for anxiety or Z drugs for insomnia, among others). At this point, it is important to make clear that the goal of using antidepressants in a synergic manner is to increase the chances of remission, as opposed to exclusively treating side effects.

AUGMENTATION WITH ANTIPSYCHOTICS

Since   2001   a   series   of   studies   have   been published regarding augmentation with atypical antipsychotics, such as: olanzapine, quetiapine, aripiprazole     and     brexpiprazole.     Although this  strategy  was  first  described  by  Cohen  in
1958 in a cohort of 29 patients with psychotic depression, the appearance of numerous double- blind randomized controlled trials (RCT) and the subsequent approval of these drugs by the FDA as augmenting molecules in association with antidepressants in non-responsive depression have led to an explosive increase in the prescription of these drugs in different parts of the world.(43)

A systematic review and network meta-analysis published in 2015 assessed the comparative effectiveness of augmentation agents in patients with partial response to antidepressants, finding that the efficacies measured by the odds ratio were: quetiapine (1.92), aripiprazole (1.85), thyroid hormone (1.84) and lithium (1.56), all significantly more effective than placebo. The same study reported that quetiapine, olanzapine, aripiprazole and lithium presented adverse effect rates significantly higher than placebo.(43)

The specific therapeutic effect of antipsychotics is currently thought to be mechanistically explained by  their  specific actions  upon  serotonergic receptor  subtypes,  as  well  as  interactions  with the   noradrenergic   and   dopaminergic   systems. For instance, 5HT1A receptor agonism is related with procognitive and anti-anergic effects, whilst 5HT2C antagonism is associated with anxiolytic and antidepressant effects in animal models; furthermore, 5HT2A would be involved in sleep regulation and cognitive functioning. Altogether, these psychopharmacological effects enhance pre- frontal dopamine levels, and in the case of 5HT2 have led to classify this class of antipsychotics as atypical(45-48). Importantly, there is emerging evidence of involvement of serotonergic receptors in the modulation of glutamatergic and muscarinic system activities whose clinical implications are yet to be determined.(49-51)

Adjuvant antipsychotic therapies have been thoroughly evaluated in several placebo-controlled trials(52-54). Among the most encouraging results, are those described by Bauer et al. One of these studies consisted of a prospective, double-blind, randomized design, with placebo-controlled parallel   groups.   The   study   group   consisted of patients who did not respond to previous antidepressant treatment with the following molecules: amitriptyline, bupropion, duloxetine, citalopram,    fluoxetine,   paroxetine,    sertraline and venlafaxine, all in monotherapy for at least 6  weeks,  with  optimized  dosage.  The  patients were followed-up after six weeks using the MADRS scale (Montgomery-Asberg Depression Rating Scale), and then included in the following randomization: Arm 1: quetiapine XR 150; Arm 2: quetiapine XR 300; Arm 3: placebo associated with the baseline antidepressant. The results reported significant improvements, for both doses of quetiapine when contrasted with placebo. No significant  differences  were  found  in  response and remission rates between the two fixed doses of quetiapine. From a methodological angle, there are two points of interest: 1) the quetiapine loads were quick with 2 days of load at 50 mg to reach 150 mg on the third day; and in the higher dose, 300 mg on the fifth day and 2) the XR formulation presented a middle path which allowed stable noradrenaline  receptors  to  be  recruited  and  at the same time avoided morning somnolence due to the fast-release quetiapine taken in two doses. Bauer reported not only the differences from placebo, but also the differences in the sub-scales of MADRS, informing significant improvements not only in sleeping, which has often been thought to be the role of antipsychotics in low doses in augmentation, but also changes in the following variables: internal tension, sadness, anhedonia, suicidal thoughts, and cognition.(55)

In contrast to the results from Bauer et al., a recent systematic review of randomized, controlled, double-blind studies between 2010-18, including a total of 3466 patients found that seven of eight studies identified were directly funded by the pharmaceutical industry. Another important conclusion was that there was a too wide range of  criteria  to  define non-responsive  depression; as well as discrete differences in the scores of the  MADRS  scale,  revealing  decreased  total scores (2.2 to 3.5 points) for the combination of an antidepressant with an atypical antipsychotic. Of the eight studies reviewed, only Bauer’s report found improvements in other neuropsychiatric symptoms besides sleep quality or rumination; whilst the remaining seven studies were unable to demonstrate a significant improvement in depressive symptoms; consequently, this meta- analysis  suggests  a  small  but  significant effect in this group of drugs, emphasizing the need for long-term follow-up studies.(56)

Patient heterogeneity is likely to be responsible for the inability to correlate these data with observations in clinical practice. This is especially true for patients suffering insomnia, ruminations, more fragile personality structures, irritable depression and altered cognition, in what appears to be the symptomatic profile of the patients who benefit most from enhancement with atypical antipsychotics when the base antidepressant has been optimized.

One of the latest studies concerning augmentation therapy with an atypical antipsychotic is the VAST-D report. In this 12-weeks randomized clinical trial in a predominantly male population (N= 1522) with unipolar depression, who were unresponsive to a first antidepressant treatment (SSRI, SNRI or mirtazapine); three possible strategies for “the next step” decision were designed: a) switch to bupropion, b) to combine the first antidepressant with bupropion and c) augmentation of the first antidepressant with aripiprazole. The augment-aripiprazole group was not significantly better than the combination of the first antidepressant with bupropion in terms of remission rates. However, response rate was significantly higher for the augment-aripiprazole group in comparison with the combination group. An important limitation of this report was the selected study group (patients from the VA system, predominantly male and with frequent comorbid posttraumatic stress disorder).(57)

One of the latest atypical antipsychotics incorporated into this group, which is also approved as an augmentation strategy, is a design drug called brexpiprazole. It is a partial D2 and
5HT1A agonist, similar to aripiprazole, but with important differences for clinical use, as it presents lower intrinsic activity on D2. The greater intrinsic activity on D2 of aripiprazole, combined with the absence of compensatory mechanisms for this effect, mean that, despite its good response in augmentation, this drug can generate agitation, activation and akathisia in some patients(58). At least three action mechanisms on receptors have been associated with the mitigation of akathisia and the extrapyramidal effects associated with D2 blockade in brexpiprazole. These mechanisms are:
1) 5HT2A antagonism, 2) 5HT1A agonism and 3) alpha 1B antagonism(59,60). Although aripiprazole presents action on these three receptors, its effect on each of them is weaker than that of brexpiprazole. In other words, brexpiprazole presents more effective  compensatory  mechanisms  to  reduce the effects of D2 blockade. For this reason, lower rates of akathisia are reported with brexpiprazole (9.4%) than with aripiprazole (21.2%).(58)

Two different studies have provided evidence for brexpiprazole as an augmentation agent in doses of 1, 2 or 3 mg per day, with superior clinical response and remission assessed with MADRS when combined with an antidepressant which had achieved no remission in eight weeks. Responses therein reported were 23.4% upon addition of brexpiprazole vs.    15.7%    with    placebo,    whilst    remission percentages were 14.9% and 9%, respectively. In other  words,  brexpiprazole  in  combination  with an antidepressant showed an equivalent efficacy as compared with aripiprazole or quetiapine (NNT =
11); additionally, brexipiprazole plus antidepressant was associated with less akathisia (compared to aripiprazole) and less somnolence / weight gain (compared to quetiapine).(61-63)

Answering the proposed questions

Based on the results obtained, the initially enunciated questions can be responded as follow:

First question: Is there evidence to clearly recommend combination of antidepressants vs. augmentation with antipsychotics (and the correct moment to do it) in non-responsive unipolar depression, once optimization or switching strategies have failed to obtain remission?

According to our analysis, there is no data available to select one strategy from another in a clear-cut manner. Nevertheless, we suggest favoring a combination or augmentation strategy, based in a “treating to target” approach to profile the patient, considering one or two predominant clinical features that remain active as part of a major depression with partial response. The right moment to take the next step decision into combine or augment should be “as early as possible”, meaning no more than six to eight weeks since the first antidepressant agent was started.

Second   question:   Is   it   possible   to   identify some clinical features to guide the decision of combination of antidepressants vs. augmentation with antipsychotic agents?

Our answer to this question is yes. In Table 1, we select some clinical features with high practical value when the clinician is confronted to choose between a combination or an augmentation strategy (Table   1).  These   recommendations   will   serve as a general clinical guidance but are not fully supported in literature, since “treating to target” approach represents an important heuristic clinical contribution but as a theoretical construct, it still waiting for robust evidence-based data that fully support it , , . The articles that support the content of table 1 can be found in the following references.(67-94)

Table 1. Predominant features in major depressive disorder that should be relevant to consider when deciding between combination vs.  augmentation  strategy.     (++):  Strong clinical recommendation; (+): Moderate clinical recommendation; (-): Not clinically recommended; SNRI: Serotonin and norepinephrine reuptake inhibitor; SSRI: Selective serotonine reuptake inhibitor; NDRI: Norepinephrine dopamine reuptake inhibitor; NRI: Selective norepinephrine reuptake inhibitor; TCA: Tricyclic antidepressant.

Predominant clinical feature	Combination of two antidepressants	Augmentation  with atypical antipsychotic
Rumination	-	++ (almost every atypical antipsychotic could be useful to reduce ruminations)
Insomnia	++ (for agents such as mirtazapine, agomelatine or trazodone)	++ (for agents such as quetiapine, olanzapine or risperidone)
Fatigue	++ (for SNRI, bupropion or reboxetine)	-
Cognitive impairment	++ (for SNRI and multimodal agents such as vortioxetine)	-
Anorexia	++ (for antidepressant which blocks histamine receptors such as mirtazapine)	++ (for agents blocking histamine 1 receptor, alpha 1 adrenergic receptor and muscarinic 1 receptor such as olanzapine, quetiapine. For agents blocking Alpha 1 adrenergic receptors such as risperidone)
Possible “hidden” bipolar disorder	-	++ (for agents approved in bipolar depresión such as: quetiapine, olanzapine or lurasidone)
Possible characteropathy	-	+
Anxiety	++ (for agents such as SSRI, SNRI or agomelatine)	++ (for agents such as quetiapine, olanzapine or risperidone. Off-label indication for treatment resistant-anxiety)
Impulsivity	+ (for SSRI in mild cases)	++ (in more severe cases)
Emotional blunting	++ (for SNRI agents, multimodal agents such as vortioxetine, NDRI agents such as bupropion and NRI agents such as reboxetine)	-
Dysphoria/irritability/internal tension	-	++
Somatic pain	++ (depending on the type of somatic pain, the use of SNRI or TCA could be useful)	- Could be useful in some specific cases, for example in cenesthetic pain in a psychotic depression.
Suicidal ideation	-	+ (could be useful in terms of reducing impulsivity, dysphoria and rumination associated to suicidality)
Psychotic features	-	++
Sexual Dysfunction	++ (for agents such as bupropion, trazodone, mirtazapine, vortioxetine, agomelatine, reboxetine, moclobemide or vilazodone)	-

 

At this point, we think that clinicians must make decisions with the best available evidence, which in psychiatry is far from the level of evidence that support decisions in other fields of medicine. However, we need to give a “step back” and see the whole picture. Medicine still an art based in decisions that are supported by different levels of evidence, but also with important levels of subjectivity. From a phenomenological first- person account, it is simply surprising how psychopharmacologists do not observe the level of inner subjective certainty that emerge at the very moment they are prescribing a specific treatment. Unfortunately, contemporary scientific western tradition tends to oppose objectivity evidence- based knowledge with subjective inner experience, as if the latter one corresponded to an inferior category of knowledge. At this point we are not subscribing  to  any  form  of  “magical  thinking” but only recognizing something that it is well proven by different disciplines such as decision- making theory, or the research program known as “neurophenomenology”.(68)

Strategies in non-responsive unipolar depressions after optimization or switching to another antidepressant,  should  consider  a  combination of antidepressants or augmentation with atypical antipsychotics with partial D2/5HT1A agonism. These strategies should not be relegated to use after several months in which no remission is achieved; on the contrary, they should be started promptly. It is of the utmost importance to assess the patient’s clinical profile continuously, together with family information (e.g. to which agent responded a first degree relative also treated for depression), the residual target symptoms and the potential adverse effects of the strategies used. These clinical elements will be more valuable than the algorithms proposed in clinical guidelines since the latter present great heterogeneity of options and make no distinction between the different clinical sub- types of depression.

Thus, a series of studies that investigate how psychiatrists select a pharmacologic treatment demonstrate that, as in every area of medicine, profiling a patient according to his or her main symptoms and avoiding the most probable side effects as well as considering patient´s preferences are the three main variables for an expert to consider . Besides this, physician´s experience with different molecules or combination of molecules seems to be another relevant variable when  selecting  treatment  options(69,70).   Finally, it is important to recognize that taking the next pharmacological step with a specific patient, is not necessarily related with the best evidence- based data. Thereby, western medicine is slowly taking into account the idea that decision making and creative solutions are not only data driven, but also influenced by intuition which is not an anti- scientific posture, since it is based on analytical and non-analytical reasoning processes in continuous interaction. For more details in decision making theory and the role of intuition in creative thinking and science, refers to the following articles.(71-73)

When is the right moment to use a combination or augmentation strategy? Some complementary thoughts.

Due to the lack of evidence to clearly define “the next step” after antidepressant optimization dose or switch to another antidepressant have failed to induce remission, maybe the right question is not what strategy should be used but when should it be started(74,75). The support for this statement came from a key clinical observation with interesting data to support it: after the initiation of treatment for a unipolar depression episode, rapid sequential attempts of treatment alternatives is an important factor to obtain remission and functional recovery. This observation has its initial support from the concept of “early optimization dose” and “functional recovery”. Thus, shorter duration of the current depressive episode, brief duration of untreated depression as well as early symptomatic and functional improvement, predicts better response and remission rates and increases likelihood of complete functional remission(76-79). Without falling into irrational polypharmacy, it seems important to recognize that rapid sequential attempts benefits patient´s remission and functional recovery. Even though it is not possible to stablish a precise moment  to  start  combination  of  antidepressants or   augmentation   with   atypical   antipsychotics, the following statement represents contemporary knowledge in the field: a clinician should progress to combination or augmentation strategy once a sufficient trial of antidepressant optimization dose or switch has been made. A sufficient trial must be understood as “optimal dose for enough time” of the optimization or switching strategy. Time since the very first attempt at the minimal therapeutical dose of antidepressant, until combination vs. augmentation treatment is initiated, should be approximately six to eight weeks. Waiting too long before taking the next step, has proven to reduce patient´s chances of remission and functional recovery.(80-82)

CONCLUSION

---

We propose that advances in our understanding of the molecular mechanisms at the pshychopharmacological level, will enable the personalization of appropriate synergies, thereby opening hitherto unrecognized therapeutic possibilities for clinicians.

Our  group  believes  that  “deautomatization”  of the prescription, guided by an understanding of the mechanisms of action of different molecules, as well as a “treating to target” approach, should result in a more effective treatment. On this matter, we  agree  with  the  opinion  of  authors  such  as Blier, P, Fountoulakis, K.N. and Stahl, S.M(83,84). Augmentation with atypical antipsychotics and combination of antidepressants are both valid strategies which, with correct patient stratification, will allow better remission rates in the different sub-
populations of unipolar depressives. In the context of non-response or frankly refractory depression, a diagnostic reassessment will always be of central importance, as hidden bipolarity is one of the main differential diagnoses to be considered as was initially and theoretically enunciated by our group and then demonstrated in a longitudinal follow-up by Cheng-Ta Li et al.(85,86)

REFERENCES

---

Paykel, E.S, Ramana, R, Cooper, Z. et al, 1995.
Residual   Symptoms   After   Partial   Remission: An Important Outcome in Depression. Psychol. Med. 25, 1171–1180. https://doi.org/10.1017/ S0033291700033146

Correa, R, Philippi, R, 2019. Optimization versus early Switching in monopolar depression: A comprehensive review of a clinical controversy. Rev. Chil. Neuropsiquiatr. 57, 306–313. https://doi. org/10.4067/S0717-92272019000300306

Rush, A.J, Trivedi, M.H, Stewart, J.W. et al, 2011.
Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and long-term outcomes  of  a  single-blind  randomized  study. Am. J. Psychiatry 168, 689–701. https://doi. org/10.1176/appi.ajp.2011.10111645

Frank    E,    Prien    R.F,    Jarrett    RB,    et    al.: Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Arch Gen Psychiatry 1991; 48:851–855.

Shelton, R.C, Osuntokun, O, Heinloth, A.N, Corya, S.A, 2010. Therapeutic options for treatment- resistant depression. CNS Drugs. https://doi. org/10.2165/11530280-000000000-00000

Thase ME, Rush AJ. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry. 1997;58 Suppl 13:23-29.

McIntyre   RS,   Filteau   MJ,   Martin   L,   et   al.
Treatment-resistant  depression:  definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014;156:1-7. doi:10.1016/j. jad.2013.10.043

Ros,  S,  Aguera,  L,  Gandara,  J,  et  al,  2005.
Potentiation    strategies    for    treatment-resistant depression. Acta Psychiatr. Scand. 112, 14–24. https://doi.org/10.1111/j.1600-0447.2005.00676.x

Fava,  M,  Rush,  A.J,  2006.  Current  Status  of Augmentation and Combination Treatments for Major Depressive Disorder: A Literature Review and a Proposal for a Novel Approach to Improve Practice. Psychother. Psychosom. 75, 139–153. https://doi.org/10.1159/000091771

Fava, M, Rush, A.J, 2006. Current Status of Augmentation and Combination Treatments for Major Depressive Disorder: A Literature Review and a Proposal for a Novel Approach to Improve Practice. Psychother. Psychosom. 75, 139–153. https://doi.org/10.1159/000091771

Cipriani, A,  Pretty,  H,  Hawton,  K,  et  al,  2005.
Lithium  in  the  prevention  of  suicidal  behavior and all-cause mortality in patients with mood disorders: A systematic review of randomized trials. Am. J. Psychiatry. https://doi.org/10.1176/ appi.ajp.162.10.1805

Valerio, M.P, Martino, D.J, 2018. Differential response  to  lithium  between  melancholic  and non-melancholic unipolar depression. Psychiatry Res.          269,    183–184.    https://doi.org/10.1016/j. psychres.2018.08.077

Inoue, T, Abekawa, T, Nakagawa, S, et al, 2011.
Long-term naturalistic follow-up of lithium augmentation: Relevance to bipolarity. J. Affect. Disord. 129, 64–67. https://doi.org/10.1016/j. jad.2010.08.022

Correa, R, Akiskal, H, Gilmer, W, et al, 2010. Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression? J. Affect. Disord. https://doi.org/10.1016/j.jad.2010.06.036

Li,  C.T,  Bai,  Y.M,  Huang,  YL,  et  al,  2012.
Association   between   antidepressant   resistance in  unipolar  depression  and  subsequent  bipolar
disorder: Cohort study. Br. J. Psychiatry 200, 45–
51. https://doi.org/10.1192/bjp.bp.110.086983

Nelson, J.C, Baumann, P, Delucchi, K, et al, 2014.
A systematic review and meta-analysis of lithium augmentation of tricyclic and second-generation antidepressants in major depression. J. Affect. Disord. https://doi.org/10.1016/j.jad.2014.05.053

Nelson   JC,   Mazure,   CM,   Bowers,   MB   Jr, Jatlow P.I. A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry. 1991;48(4):303-307. doi:10.1001/ archpsyc.1991.01810280019002

Leuchter AF, Lesser IM, Trivedi MH, et al. An open pilot study of the combination of escitalopram and bupropion-SR for outpatients with major depressive disorder. J Psychiatr Pract. 2008;14(5):271-280. doi:10.1097/01.pra.0000336754.19566.65

Stewart, JW. Does Dual Antidepressant Therapy as Initial Treatment Hasten and Increase Remission from   Depression?     Journal     of     Psychiatric Practice.2009;15(5): 337-345. doi: 10.1097/01. pra.0000361276.88339.44

Blier,  P,  Ward,  H.E,  Tremblay,  P,  et  al.,  2010.
Combination    of    antidepressant    medications from treatment initiation for major depressive disorder: A double-blind randomized study. Am. J. Psychiatry 167, 281–288. https://doi.org/10.1176/ appi.ajp.2009.09020186

Blier P, Gobbi G, Turcotte JE, et al. Mirtazapine and paroxetine in major depression: a comparison of monotherapy versus their combination from treatment initiation.EurNeuropsychopharmacol.2009;19(7):457-
465. doi:10.1016/j.euroneuro.2009.01.015

Nelson   JC,   Mazure   CM,   Jatlow   PI,   et   al.
Combining  norepinephrine  and  serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study. Biol Psychiatry. 2004;55(3):296-300. doi:10.1016/j. biopsych.2003.08.007

Rush, AJ Trivedi, MH, Stewart, JW, et al, 2011.
Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and long-term outcomes  of  a  single-blind  randomized  study. Am. J. Psychiatry 168, 689–701. https://doi. org/10.1176/appi.ajp.2011.10111645

Rush, AJ,  Trivedi,  MH,  Wisniewski,  SR,  et  al,
2006. Acute and longer-term outcomes in depressed outpatients  requiring  one  or  several  treatment steps:  A  STAR*D   report.  Am.   J.   Psychiatry
163,        1905–1917.        https://doi.org/10.1176/
ajp.2006.163.11.1905

Rush, AJ, Trivedi, MH, Stewart, JW, et al, 2011.
Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and long-term outcomes  of  a  single-blind  randomized  study. Am. J. Psychiatry 168, 689–701. https://doi. org/10.1176/appi.ajp.2011.10111645

Rush, AJ, Trivedi, MH, Stewart, JW, et al, 2011.
Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and long-term outcomes  of  a  single-blind  randomized  study. Am. J. Psychiatry 168, 689–701. https://doi. org/10.1176/appi.ajp.2011.10111645

Bobo, W V, Chen, H, Trivedi, MH, et al, 2011.
Randomized comparison of selective serotonin reuptake   inhibitor   (escitalopram)   monotherapy and antidepressant combination pharmacotherapy for major depressive disorder with melancholic features: A CO-MED report. J. Affect. Disord. 133,
467–476. https://doi.org/10.1016/j.jad.2011.04.032

Blier,  P,  Ward,  H.E,  Tremblay,  et  al.,  2010.
Combination    of    antidepressant    medications from treatment initiation for major depressive disorder: A double-blind randomized study. Am. J. Psychiatry 167, 281–288. https://doi.org/10.1176/ appi.ajp.2009.09020186

Zuilhof, Z, Norris, S, Blondeau, C, et. al, 2018.
Optimized  regimens  of  combined  medications for  the  treatment  of  major  depressive  disorder: A double-blind, randomized-controlled trial. Neuropsychiatr. Dis. Treat. 14, 3209–3218. https:// doi.org/10.2147/NDT.S175203

Stewart  JW,  McGrath  PJ,  Blondeau  C,  et  al.
Combination antidepressant therapy for major depressive    disorder:    speed    and    probability of remission. J Psychiatr Res. 2014;52:7-14. doi:10.1016/j.jpsychires.2013.12.001

Dodd, S, Horgan, D, Malhi GS, Berk M. To combine or not to combine? A literature review of antidepressant combination therapy. J Affect Disord 2005; 89:1–11.

Lam, RW, Wan, DD, Cohen, NL, Kennedy, SH. Combining antidepressants for treatment-resistant
depression:  a  review.  J  Clin  Psychiatry  2002;
63:685–93.

Hannan, N, Hamzah, Z, Akinpeloye, HO, Meagher, D.
Venlafaxine- mirtazapine combination in the treatment of persistent depressive illness. J Psychopharmacol
2007; 21: 161-164 [PMID: 17329295].

Malhi,  GS,  Ng  F,  Berk  M.  Dual-dual  action?
Combining  venlafaxine  and  mirtazapine  in  the
treatment of depression. Aust N Z J Psychiatry
2008;   42:   346-349   [PMID:   18330778   DOI:
10.1080/000 48670701881587]

Ricken,  R,  Ulrich,  S,  Schlattmann,  P, Adli,  M.
Tranylcypromine   in   mind   (Part   II):   Review of   clinical   pharmacology   and   meta-analysis of controlled studies in depression. European Neuropsychopharmacology.2017;27:714-731.

McGrath   PJ,   Stewart   JW,   Fava   M,   et   al.
Tranylcypromine versus venlafaxine plus mirtazapine following three failed antide- pressant medication trials for depression: a STAR*D report. Am J Psychiatry 2006; 163: 1531-141; quiz 1666 [PMID: 16946177].

Ashton, AK, Rosen, RC, 1998. Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual dysfunction. J. Clin. Psychiatry 59, 112–
115. https://doi.org/10.4088/JCP.v59n0304

Young, SJ, 1996. Panic associated with combining
fluoxetine and bupropion. J. Clin. Psychiatry 57 (4),
177–178. https://pubmed.ncbi.nlm.nih.gov/8601558/

Carpenter,  LL,  Jocic,  Z,  Hall,  JM,  et  al,  1999.
Mirtazapine  Augmentation  in  the  Treatment  of
Refractory Depression. J. Clin. Psychiatry 60, 45–
49. https://doi.org/10.4088/JCP.v60n0110

Warden,  D,  Trivedi,  M.H,  Carmody,  T,  et  al.,
2014. Adherence to Antidepressant Combinations and Monotherapy for Major Depressive Disorder. J. Psychiatr. Pract. 20, 118–132. https://doi. org/10.1097/01.pra.0000445246.46424.fe

García-Muñoz,   E,   Licona-Galicia,   DG,   2018.
Usos potenciales de la mirtazapina en cuidados paliativos más allá de su efecto antidepresivo. Rev. la Soc. Española del Dolor 25, 37–44. https://doi. org/10.20986/RESED.2017.3575/2017

Bhatara, VS, Magnus, RD, Paul, KL, Preskorn, SH,
1998. Serotonin Syndrome Induced by Venlafaxine and Fluoxetine: A Case Study in Polypharmacy and Potential Pharmacodynamic and Pharmacokinetic Mechanisms. Ann. Pharmacother. 32, 432–436. https://doi.org/10.1345/aph.17041

Mulder, R, Hamilton, A, Irwin, L, et al., 2018. Treating depression with adjunctive antipsychotics. Bipolar Disord. 20, 17–24. https://doi.org/10.1111/bdi.12701

Zhou,  X,  Ravindran,  AV,  Qin,  B,  et  al,  2015.
Comparative Efficacy, Acceptability, and Tolerability of Augmentation Agents in Treatment- Resistant Depression: Systematic Review and Network  Meta-Analysis.  J  Clin  Psychiatry  76,
487–498. https://doi.org/10.4088/JCP.14r09204

Prieto, E, Micó, JA, Meana, JJ, Majadas, S, 2010.
Neurobiological bases of quetiapine antidepresant effect in the bipolar disorder, Actas Esp Psiquiatr. https://pubmed.ncbi.nlm.nih.gov/20931407/

Kapur, S, Zipursky, R, Jones, C, et al., 2000. A positron emission tomography study of quetiapine in schizophrenia: A preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch. Gen. Psychiatry 57, 553–559. https://doi.org/10.1001/ archpsyc.57.6.553

Dekeyne, A, Mannoury La Cour, C, Gobert, A, et al, 2008. S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models. Psychopharmacology (Berl). 199, 549–568. https:// doi.org/10.1007/s00213-008-1177-9

Bauer, M, El-Khalili, N, Datto, C, et al., 2010.
A pooled analysis of two randomised, placebo- controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder. J. Affect. Disord. https://doi.org/10.1016/j.jad.2010.08.032

Drago,  A,  Crisafulli,  C,  Sidoti,  A,  Serretti,  A,
2011. The molecular interaction between the glutamatergic,      noradrenergic,      dopaminergic and serotoninergic systems informs a detailed genetic perspective on depressive phenotypes. Prog. Neurobiol. https://doi.org/10.1016/j. pneurobio.2011.05.009

Schmitt, A, May, B, Müller, B, et al, 2004. Die wirkung von antipsychotika auf glutamaterge neurotransmission im tiermodell. Nervenarzt. https://doi.org/10.1007/s00115-003-1593-3

Zhang, W, Bymaster, F.P, 1999. The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D1, D2, D3, 5HT(2A) and muscarinic receptors. Psychopharmacology (Berl). 141, 267–278. https:// doi.org/10.1007/s002130050834zhou

Kamijima, K, Higuchi, T, Ishigooka, J, et al., 2013.
Aripiprazole augmentation to antidepressant therapy in Japanese patients with major depressive disorder: A randomized, double-blind, placebo-controlled study (ADMIRE study). J. Affect. Disord. 151, 899–
905. https://doi.org/10.1016/j.jad.2013.07.035

Mahmoud,   R.A,   Pandina,   G.J,  Turkoz,   I,   et al., 2007. Risperidone for treatment-refractory major depressive disorder: A randomized trial. Ann. Intern. Med. 147, 593–602. https://doi. org/10.7326/0003-4819-147-9-200711060-00003

Weisler, R.H, Montgomery, S.A, Earley, WR, et al,, 2012. Efficacy of extended release quetiapine fumarate monotherapy in patients with major depressive disorder. Int. Clin. Psychopharmacol.
27,             27–39.             https://doi.org/10.1097/
YIC.0b013e32834d6f91

Bauer, M, El-Khalili, N, Datto, C, Szamosi, J, Eriksson, H, 2010. A pooled analysis of two randomised, placebo-controlled     studies     of extended  release  quetiapine  fumarate  adjunctive to antidepressant therapy in patients with major depressive disorder. J. Affect. Disord. https://doi. org/10.1016/j.jad.2010.08.032

Mulder, R, Hamilton, A, Irwin, L, et al., 2018. Treating depression with adjunctive antipsychotics. Bipolar Disord. 20, 17–24. https://doi.org/10.1111/bdi.12701

Mohamed S, Johnson GR, Chen P, et al. Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder                 Unresponsive      to     Antidepressant Treatment: The VAST-D Randomized Clinical Trial. JAMA. 2017;318(2):132-145. doi:10.1001/ jama.2017.8036

Stahl,  S.M,  2016.  Mechanism  of  action  of brexpiprazole:   comparison    with    aripiprazole. cambridge.org. https://doi.org/10.1017/ S1092852915000954

Citrome, L, 2015. The ABC’s of dopamine receptor partial   agonists   -   Aripiprazole,   brexpiprazole and  cariprazine:  The  15-min  challenge  to  sort these  agents  out.  Int.  J.  Clin.  Pract.  https://doi. org/10.1111/ijcp.12752

Citrome, L, Ota, A, Nagamizu, K, et al., 2016.
The    effect    of    brexpiprazole    (OPC-34712) and aripiprazole in adult patients with acute schizophrenia: Results from a randomized, exploratory  study.  Int.  Clin. Psychopharmacol. 31,           192–201.           https://doi.org/10.1097/
YIC.0000000000000123

Thase,  ME,  Youakim,  JM,  Skuban,  A,  et  al.,
2015(a). Efficacy and Safety of Adjunctive Brexpiprazole 2 mg in Major Depressive Disorder: A   Phase   3,   Randomized,   Placebo-Controlled Study in Patients With Inadequate Response to Antidepressants. J Clin Psychiatry 76, 1224–1231. https://doi.org/10.4088/JCP.14m09688

Thase,  ME,  Youakim,  JM,  Skuban,  A,  et.  al.,
2015(b). Adjunctive  Brexpiprazole  1  and  3  mg for Patients With Major Depressive Disorder Following Inadequate Response to Antidepressants: A  Phase  3,  Randomized,  Double-Blind  Study. J Clin Psychiatry 76. https://doi.org/10.4088/ JCP.14m09689

Aftab, A, Gao, K, 2017. The preclinical discovery and development of brexpiprazole for the treatment of major depressive disorder. Expert Opin. Drug Discov. https://doi.org/10.1080/17460441.2017.1354849

Singh, MK, and Gotlib IH. The Neuroscience of Depression: Implications for Assessment and Intervention. Behav Res Ther. 2014; 62: 60–73. doi:10.1016/j.brat.2014.08.008

Demyttenaere,     K,     De     Fruyt,     J,     Stahl, SM  The  many  faces  of  fatigue  in  major depressive disorder. International Journal of Neuropsychopharmacology.2005; 8:93–105. DOI:
10.1017/S1461145704004729

McIntyre,  RS,  Lee, Y,  Mansur,  RB Treating  to target in major depressive disorder: response to remission  to  functional  recovery.  CNS  Spectr.
2015 Dec;20 Suppl 1:20-30; quiz 31. doi: 10.1017/
S1092852915000826.

Stahl, SM, Zhang, L, Damatarca, C, Grady, M.
Brain  circuits  determine  destiny  in  depression: a novel approach to the psychopharmacology of wakefulness,  fatigue,  and  executive  dysfunction in major  depressive  disorder.  J  Clin  Psychiatry.
2003;64 Suppl 14:6-17.

Varela,   F.   (1996).   Neurophenomenology:   A methodological  remedy  for  the  hard  problem. Journal of Consciousness Studies, 3(4), 330-349.

Rajendran, S, Sajbel, TA, Hartman, TJ. Factores involucrados en la toma de decisiones para recetar medicamentos para trastornos psiquiátricos por psiquiatras: un estudio de encuesta. Psiquiatría Q
2012; 83: 271–280.

Zimmerman, M, Posternak, M, Friedman, M, et al. Which factors influence psychiatrists’ selection of,   antidepressants?   Am   J   Psychiatry   2004
Jul;161(7):1285-9.

Dingledine, R. Why Is It so Hard to Do Good
Science? eNeuro 2018; 5(5).

Van den Brink, N, Holbrechts, B, Brand, PLP, et al. Role of intuitive knowledge in the diagnostic reasoning of hospital specialists: a focus group study. BMJ Open 2019; 9(1), e022724.

Undorf, M, Zander, T. Intuition and metacognition: The effect of semantic coherence on judgments of learning. Psychon Bull Rev 2017;24(4): 1217-1224.

Stahl,      SM.      Combining      Antidepressant Therapies From the Initiation of Treatment: A Paradigm Shift for Major Depression. J Clin Psychiatry.2009;70(11):1493-1494.

Stahl, SM. Enhancing Outcomes from major Depression: Using Antidepressant Combination Therapies with Multifunctional Pharmacologic Mechanisms from the Initiation of Treatment. CNS Spectr.2010;15(2): 677-692.

Habert  J,  Katzman  MA,  Oloruntoba  OJ,  et  al.
Functional Recovery in Major Depressive Disorder: Focus on Early Optimized Treatment. Prim Care Companion CNS Disord. 2016;18(5):10.4088/ PCC.15r01926. Publicado el 1 de septiembre de
2016. doi:10.4088/PCC.15r01926

Greer, TL, Kurian BT y Trivedi, MH. Definir y medir la recuperación funcional de la depresión. Medicamentos del SNC. 2010 Abr;24(4):267-84. doi: 10.2165/11530230-000000000-00000.

Sheehan,  DV.  Restauración  de  la  función  en el trastorno depresivo mayor: una revisión sistemática. J Afecto Disord. 2017; 215:299-313. doi: 10.1016/j.jad.2017.02.029.

Oloruntoba   OJ,   Katzman   MA,   Habert   J,   et al. Functional Recovery in Major Depressive Disorder: Providing Early Optimal Treatment for the Individual Patient. Int J Neuropsicofarmacio.
2018;21(2):128-144. doi:10.1093/ijnp/pyx081

Habert  J,  Katzman  MA,  Oloruntoba  OJ,  et  al.
Functional Recovery in Major Depressive Disorder: Focus on Early Optimized Treatment. Prim Care Companion CNS Disord. 2016;18(5):10.4088/ PCC.15r01926. Published 2016 Sep 1. doi:10.4088/ PCC.15r01926.

Sheehan,  DV.  Restoring  function  in  major depressive disorder: A systematic review. J Affect Disord.  2017;    215:299-313.    doi:    10.1016/j. jad.2017.02.029.

Oloruntoba  OJ,  Katzman  MA,  Habert  J,  et  al.
Functional Recovery in Major Depressive Disorder: Providing Early Optimal Treatment for the Individual Patient. Int J Neuropsychopharmacol.
2018;21(2):128-144. doi:10.1093/ijnp/pyx081

Blier,   P.   Neurobiology   of   depression   and mechanism  of  action  of  depression  treatments. J  Clin  Psychiatry.  2016  Mar;77(3):e319.  doi:
10.4088/JCP.13097tx3c.

Fountoulakis,  KN,  Stahl,  SM.  Precision  and personalized  assessment,  diagnosis  and  treatment in  psychiatry.  CNS  Spectr.  2020  Mar  31;1-7.doi:
10.1017/S1092852920000139. Online ahead of print.

Correa, R, Akiskal, H, Gilmer, W, et al, 2010. Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression? J. Affect. Disord. https://doi.org/10.1016/j.jad.2010.06.036

Li,  CT,  Bai,  YM,  Huang,  YL,  et  al,  2012.
Association   between   antidepressant   resistance in unipolar depression and subsequent bipolar disorder: Cohort study. Br. J. Psychiatry 200, 45– 51. https://doi.org/10.1192/bjp.bp.110.086983