Acosta FJ. Psiquiatria.com. 2014; 18:12.
http://hdl.handle.net/10401/6613
Revisión teórica
The treatment of depression
El tratamiento de la depresión
Francisco J. Acosta1*, José L. Hernández2, Judit Herrera3, José Pereira4, Mercedes
Suárez5
Resumen
La depresión es uno de los trastornos psiquiátricos más frecuentes, implica una alta tasa de
recaídas y recurrencias, y es una de las causas principales de discapacidad. Además, la tasa de
suicidio de los pacientes con depresión es 20-40 veces mayor que la de la población general.
Diversas decisiones terapéuticas de la depresión resultan difíciles, como la elección del
tratamiento psicofarmacológico, psicoterapéutico o ambos, la elección del fármaco
antidepresivo, o el tiempo de mantenimiento.
Presentamos una revisión del tratamiento de la depresión, que incluye el manejo clínico, la
elección del fármaco antidepresivo y/o psicoterapia, y las características diferenciales de los
antidepresivos.
El objetivo del tratamiento es la remisión clínica, dado que es un factor clave para la mejora del
pronóstico a largo plazo. Los tratamientos antidepresivos son eficaces para el tratamiento de la
depresión, tanto en la fase aguda como en la prevención de recaídas y recurrencias. Los
antidepresivos de segunda generación son los fármacos de elección y han implicado una mejoría
significativa en la seguridad y tolerabilidad, comparados con los de primera generación. La
elección del antidepresivo debería estar basada en el perfil clínico, efectos adversos, seguridad,
edad, enfermedades físicas, coste y preferencias del paciente. La psicoterapia, sola o en
combinación con antidepresivos, es una opción para el tratamiento de la depresión leve y
moderada, y está recomendada como tratamiento inicial de la depresión leve.
Palabras claves: depresión, antidepresivo, tratamiento, psicoterapia, manejo clínico, efectos
adversos.
Abstract
Depression is one of the most frequent psychiatric disorders, with high relapse and recurrence
rates, and a primary cause of disability. Furthermore, the suicide rate of depressed patients is
20-40-fold higher compared to the general population.
Several therapeutic decisions regarding the treatment of depression are difficult issues, such as
choosing psychopharmacological treatment, psychotherapeutic or both, the choice of the
antidepressant drug, or the maintenance time.
We present a review of the treatment of depression, including clinical management, choice of
the antidepressant drug and/or psychotherapy, and differential characteristics of antidepressant
drugs.
Psiquiatria.com ISSN: 1137-3148
© 2014 Acosta FJ, Hernández JL, Herrera J, Pereira J, Suárez M.
Acosta FJ. Psiquiatria.com. 2014; 18:12 - http://hdl.handle.net/10401/6613
The goal of treatment is clinical remission, since it is a key factor to improve long-term
prognosis. Antidepressant treatments are efficacious to treat depression, for both, the acute
phase and the prevention of relapse and recurrence. Second-generation antidepressants are the
drugs of choice and have involved a significant improvement on safety and tolerability when
compared to first-generation drugs. The choice of the antidepressant should be based on the
basis of the clinical profile, adverse effects, safety, age, patient's medical condition, cost, and
patient's preferences. Psychotherapy, alone or in combination with an antidepressant drug, is an
option for the treatment of mild and moderate depression, and it is recommended as an initial
treatment for mild depression.n this work we present a review of three emerging drugs: 3,4methylenedioxypyrovalerone (MDPV), a synthetic cathinone sold as bath salts, methylone,
another synthetic cathinone with hallucinogenic effects, and 5,6-methylenedioxy-2aminoindane (MDAI), a MDMA analogue. For all the drugs, we describe their pharmacological
characteristics, toxicology, adverse effects as well as the legal status.
Keywords: depression, antidepressant, treatment, psychotherapy, clinical management,
adverse effects.
Recibido: 27/08/2013 Aceptado: 30/08/2013 Publicado: 14/10/2014
* Correspondencia: fjacostaartiles@hotmail.com
1, 2, 4 Service of Mental Health, General Health Care Programs Direction, Canary Health Service; Pérez del
Toro Street s/n, Gran Canaria, Canary Islands, Spain.
3 Department of Psychiatry, Insular University Hospital of Gran Canaria, Avda. Marítima del Sur s/n, Gran
Canaria, Spain.
5 Department of Internal Medicine, Insular University Hospital of Gran Canaria, Avda. Marítima del Sur
s/n, Gran Canaria, Spain.
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Introduction
Depression is one of the most frequent psychiatric disorders and a primary cause of disability
(Gelenberg, 2010; Connolly & Thase, 2011). In the ESEMeD European Epidemiological Study, a
14.7% lifelong prevalence was found for mood disorders (López-Ibor, Alonso, & Haro, 2007).
Depression is a disorder with high relapse and recurrence rates. After a first episode, over 50%
of patients show a recurrence; after two episodes, there is a 70% risk of recurrence and near to
90% if three episodes have occurred (Kupfer, 1991). Furthermore, between one third (Blier,
Ward, Tremblay, Laberge, Hébert, & Bergeron, 2010) and 40-50% (Papakostas, 2009) of
patients do not respond to the initial treatment. Finally, 10-30% of treated patients will not
attain a complete recovery, with persistence of symptoms, and development of disthymia (Katon
& Ciechanowski, 2009). Although mood disorders may appear at any age, the peak onset for
major depression is in the fourth decade of life (Lyness, 2009).
The suicide rate of depressed patients is 20-40-fold higher compared to the general population,
and 6% of patients with a diagnosis of depression will commit suicide. Among unipolar
depression cases, 14-50% attempt suicide (Bousoño, Baca, Álvarez, Eguiluz, Martín, Roca, &
Urretavizcaya, 2008).
Although the antidepressant treatment reduces the suicidal risk (Ludwig, Marcotte, & Norberg,
2009; Mulder, Joyce, Frampton, & Luty, 2008), this effect appears to be different depending on
the age. Thus, in patients older than 65 years old this reduction is clear; in patients of 25-65
years old there is a reduction in the suicidal ideation, but the effect on suicidal behaviours is
neutral; lastly, in patients below 25 years the antidepressants increase the suicidal risk (Stone,
Laughren, Jones, Levenson, Holland, Hughes, & Rochester, 2009). No differences have been
found between the different antidepressants regarding to the suicidal risk (Schneeweiss, Patrick,
Solomon, Mehta, Dormuth, Miller, & Wang, 2010).
Additionally, depression increases the risk of mortality due to other causes; several comorbid
somatic diseases have a worse outcome or a greater risk of occurrence; the condition has a
negative influence on the subject's quality of life, as well as on work, social, and even basic daily
functioning (Lyness, 2009); and generates high financial costs (Gelenberg, 2010; Mauskopf,
Simon, Kalsekar, Nimsch, Dunayevich, & Cameron., 2009).
This article focuses on the treatment of depressive episodes, as defined by the ICD-10 criteria
(ICD-10, 1992).
Key concepts
Response is defined as a clinically significant reduction of symptoms, while remission is the
absence or near absence of depressive symptoms. Recovery implies a prolonged remission
status of at least 4 months. Relapse is defined as the return of the depressive symptoms during
the acute phase treatment (after achieving response) or continuation therapy (after achieving
remission) (Qaseem, Snow, Denberg, Forciea, & Owens, 2008); and recurrence is a new
depressive episode after achieving recovery (Rush, Kraemer, Sackeim, Fava, Trivedi, Frank, &
Schatzberg, 2006a).
The goal of the acute treatment phase is symptom remission in the shortest possible time (APA,
2010) . Acute treatment's duration ranges between a minimum recommended of 6 weeks
(Qaseem et al., 2008) and a maximum of 20 weeks (Rush et al., 2006a).
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Continuation treatment follows the acute phase treatment, and should last the time period
corresponding to the total length of the depressive episode if it had not been treated. Its goal is
to prevent relapses and achieve full remission and recovery (Qaseem et al., 2008; APA, 2010).
The continuation treatment typically ranges between 4 and 9 months (Qaseem et al., 2008;
APA, 2010).
In the maintenance treatment phase, the objectives of the treatment are the consolidation of the
gains made during acute treatment and the prevention of the occurrence of new depressive
episodes (APA, 2010). Its minimum duration is one year (Qaseem et al., 2008) even though it
usually lasts two to three years (Bauer, Bschor, Pfennig, Whybrow, Angst, Versiani, & Möller,
2007) and may be continued indefinitely (ICSI, 2004; APA, 2010). The dose of the
antidepressant drug used to attain remission must remain unchanged (Bauer et al., 2007).
There is consensus in the definition of resistant depression as the one which does not respond
to two different treatments (at least) of different types, at an adequate dose, duration and
compliance (Little, 2009; Malhi, Parker, Crawford, Wilhelm, & Mitchell, 2005).
Effectiveness of psychotherapy
Psychotherapy appears to be as effective as second generation antidepressants in the short-term
treatment of depression, and likely somewhat more effective than second generation
antidepressants in the longer-term management of depressive symptoms (Spielmans, Berman,
& Usitalo, 2011). In general, psychotherapy has a longer lasting treatment effect and carries a
lower risk of relapse following discontinuation than pharmacotherapy (APA, 2010). In
particular, interpersonal psychotherapy and cognitive-behavioral therapy have shown lasting
benefits in maintaining remission (Vittengl, Clark, Dunn, & Jarrett, 2007; Frank, Kupfer,
Buysse, Swartz, Pilkonis, Houck, & Stapf, 2007; Dobson, Hollon, Dimidjian, Schmaling,
Kohlenberg, Gallop, & Jacobson, 2008). The efficacy of primary care psychotherapy is similar
to that of antidepressant drugs, and greater than standard care (Schulberg, Raue, & Rollman,
2002). Receiving psychotherapy in both the acute and continuation phases is the most effective
option (Oestergaard & Møldrup, 2011). Psychotherapy has shown to be an effective treatment to
reduce relapse and recurrence (Beshai, Dobson, Bockting, & Quigley, 2011). Several studies have
shown that acute psychotherapies for major depressive disorder also have maintenance benefits
(APA, 2010). Psychological treatment has also shown to be effective in other specific
populations, such as older adults (Cuijpers, Van Straten, & Smit, 2006), women with
postpartum depression, patients with general medical disorders, inpatients, primary care
patients, patients with chronic depression and subthreshold depression (Cuijpers, Andersson,
Donker, & Van Straten, 2011). However, evidence regarding the effectiveness of psychotherapy
for treatment-resistant depression is limited (Little, 2009).
With the exception of a few investigations, continuation and/or maintenance cognitive therapy
seems to reduce relapse and recurrence rates for major depression. It appears that preventive
cognitive therapy works best for individuals with a history of three or more depressive episodes.
On the other hand, therapy was shown to be less effective in the reduction of recurrent episodes
that are provoked by negative life events (Beshai et al., 2011).
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Although psychotherapy has shown to be effective in the treatment of adults with depression,
there are still some controversial findings. Recently it has been argued that its effect has been
overestimated in meta-analytical studies. They are much smaller than was assumed until now,
even after controlling for the type of control condition used (Cuijpers et al., 2011). The authors
of a systematic review concluded that cognitive therapy might not be an effective intervention
for major depressive disorder compared with `treatment as usual'. The possible treatment effect
is relatively small, and it could be argued that this possible benefit is not clinically relevant.
However, trials with longer follow-up, low risk of bias and low risk of random errors are still
needed (Jakobsen, Lindschou Hansen, Storebø, Simonsen, & Gluud, 2011). Besides, common
factors are associated with outcome and may reduce the apparent benefits of cognitive
behavioural therapy. Unfortunately, to date there is a dearth of research defining and
standardising control conditions (Serfaty, Csipke, Haworth, Murad, & King, 2011).
Effectiveness of antidepressants and treatment settings
Most depressive disorders are to be treated in the primary care setting, unless any of the criteria
for referral to specialized mental health care is fulfilled (Gaynes, Rush, Trivedi, Wisniewski,
Balasubramani, McGrath, & Fava, 2008). Up to 80% of patients with depression are
exclusively treated in the primary care setting (NICE, 2009). Similar remission rates were found
in patients suffering from a depressive episode either treated in primary care clinics or in
specialized mental health units following the same guidelines (Gaynes et al., 2008). Although
referral of a patient to a specialized mental health unit should be individualized and depends on
multiple factors, the following criteria have been suggested: initial treatment failure (due to the
absence of response, intolerance, or lack of adherence to treatment), severe depression with or
without suicidal thoughts, risk of suicide, comorbid mental disorders and/or drug dependence,
patient that could benefit from a psychotherapeutic intervention, and uncertain diagnosis
(Lyness.2009).
Antidepressant drugs are efficacious in the treatment of depression for both, the acute phase
treatment and the prevention of relapse and recurrence (Geddes, Carney, Davies, Furukawa,
Kupfer, Frank, & Goodwin, 2003; Reid & Barbui, 2010). Although the available studies do not
provide evidence for the efficacy of antidepressants in patients with minor depression, these do
not have the power and the methodological quality to exclude efficacy. Antidepressants in minor
depression can be considered in special cases with, for example, suicidality, previous suicide
attempts, family history of affective disorders or previous major depressive episodes (Hegerl,
Schönknecht, & Mergl, 2012).
In real clinical practice conditions (STAR*D Study), a 47% response rate and a 28-33%
remission rate (Trivedi, Rush, Wisniewski, Nierenberg, Warden, Ritz, & Fava, 2006) were
found and, when the four established steps of psychopharmacological strategies had been
completed, a cumulative remission rate of 67% have been found (Rush, Trivedi, Wisniewski,
Nierenberg, Stewart, Warden, & Fava, 2006b). Regarding relapse prevention, despite the lower
level of adherence of patients receiving placebo, a 41% relapse rate was observed in patients
under maintenance therapy with placebo vs. 18% in patients receiving maintenance therapy
with an antidepressant drug (Geddes et al., 2003).
Although some studies questioned the efficacy of antidepressant drugs compared to placebo
(Moncrieff, Wessely, & Hardy, 2004) lower response rates were found with placebo compared to
antidepressant drugs, which efficacy increases with the severity of the depression (Khan A.,
Leventhal, Khan S. R., & Brown, 2002; Fournier, DeRubeis, Hollon, Dimidjian, Amsterdam,
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Shelton, & Fawcett, 2010). Additionally, a number of factors favoring the response to placebo
have been pointed out. Among them, the therapeutic effect of frequent visits in clinical trials
might determine up to 40% of this response (Posternak & Zimmerman, 2007).
Overall principles of clinical magagement
Regardless the chosen treatment option, the ultimate goal should be achieving remission.
Patients on remission have better long-term prognosis compared to those with partial response
(Rush, 2007).
Pychotherapy, alone or in combination with antidepressants, is an option for patients with a
mild to moderate depressive episode (Schulberg et al,. 2002). The NICE and APA guidelines
recommend psychotherapy as an initial therapy for mild depression due to the unfavorable
risk/benefit ratio of antidepressant drugs in this particular case.
A combination therapy with psychotropic agents and psychotherapy would be indicated in
patients with moderate, severe, or recurrent depression (NICE, 2009; Katon & Ciechanowski,
2009; APA, 2010). Poor adherence with pharmacotherapy may also warrant combined
treatment with medications and psychotherapy focused on treatment adherence (APA, 2010).
Pharmacotherapy enhanced with psychotherapy is associated with a higher probability of
remission and a lower risk of relapse, as compared to antidepressants alone for depression
treatment (Oestergaard & Møldrup, 2011). The choice of the treatment regimen also depends on
the type of depression. Thus, although more studies are needed, medication seems to be the best
treatment for dysthymia, whereas combined treatments seem to be more effective in depressed
outpatients, as well as in depressed older adults (Cuijpers, Reynolds, Donker, Li, Andersson, &
Beekman, 2012).
Psychotherapy in the clinical management
Types of psychotherapies and choice
To date, no significant differences in effectiveness among psychotherapies have been found.
Thus, differences between types of psychotherapy are small, and different types of
psychotherapy are efficacious in the treatment of adult depression, including cognitive behavior
therapy, interpersonal psychotherapy, problem-solving therapy, non-directive supportive
therapy, behavioral activation therapy (Cuijpers et al., 2011) and psychodynamic therapy (APA,
2010) . All of them require an appropriate training and about 30-45 minutes per visit (Schulberg
et al., 2002).
The choice of a specific type depends on several factors: appropriate training and expertise in
specific psychotherapeutic approaches, psychosocial context, patient preference, prior positive
response to psychotherapy, the presence of significant psychosocial stressors or interpersonal
difficulties, co-occurring Axis II disorders, or the stage, chronicity, and severity of the major
depressive episode (APA, 2010).
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Initiation
Some factors that suggest the use of psychotherapy include the presence of significant
psychosocial stressors, intrapsychic conflict, interpersonal difficulties, co-occurring axis II
disorder, availability, patient preference, pregnancy, wish to become pregnant, or breastfeeding. The optimal frequency of psychotherapy has not been rigorously studied in controlled
trials (APA, 2010) .
Time to response and non-response
Onset of benefit from psychotherapy tends to be a bit more gradual than that from medication
(APA, 2010). In case of lack of improvement after treatment, several aspects must be addressed
and ruled out: inaccurate diagnosis, inappropriate selection of the therapeutic modality, nonadherence, inadequate duration of treatment, co-occurring medical or psychiatric disorders,
including substance use disorders, complicating psychosocial and psychological factors and poor
"fit" between patient and therapist (Culpepper & Johnson, 2011). Specifically, in psychotherapy
additional factors to be assessed include the frequency of sessions and whether the specific
approach to psychotherapy is adequately addressing the patient's needs (APA, 2010).
If psychotherapy is used alone, the possible need for medications in addition to or instead of
psychotherapy should be assessed (APA, 2010; Katon & Ciechanowski, 2009) if there is no
response after 1-2 months (APA, 2010). For those with partial benefit from a treatment,
augmentation is a reasonable option (Culpepper & Johnson, 2011).
Continuation and maintenance phase
To prevent a relapse of depression in the continuation phase, depression-focused psychotherapy
is recommended, with the best evidence available for cognitive behavioural therapy.
Maintenance treatment should be considered, with a reduced frequency of sessions (APA,
2010).
In the context of delivering high-intensity psychological interventions, for all people with
depression having individual cognitive behavior therapy, interpersonal psychotherapy or
behavioral activation therapy, the duration of treatment should typically be in the range of 16 to
20 sessions over 3 to 4 months (NICE, 2009). Patients with chronic, treatment-resistant
depression may require long-term treatment (APA, 2010).
Termination
Termination is not only the final phase of psychotherapy, but also an important ethical and
clinical responsibility. Besides, a number of circumstances may arise that interfere with the
successful completion and termination of treatment (Vasquez, Bingham, & Barnett, 2008). How
to end psychotherapy is typically dependent on the type of therapy.
Several recommendations have been made in order to achieve an adequate termination:
establishing an expected duration of psychotherapy at the start of treatment; raising the issue of
treatment discontinuation well in advance of the final session (APA, 2010) providing patients
with a complete description of the therapeutic process, including termination, and reminders
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throughout treatment; ensuring that the psychotherapist and client collaboratively agree on the
goals for psychotherapy and the ending of psychotherapy; and helping clients to develop health
and referral plans for posttermination life (Vasquez et al., 2008).
Psychopharmacological treatment in the clinical management
Initiation and time to response
In general, initiation of an antidepressant drug at low doses to minimize the risk of adverse
effects (Katon & Ciechanowski, 2009), and a subsequent progressive dose increase within days
or weeks depending on the subject's tolerability is recommended.
The latency time to response of an antidepressant drug is 2 to 6 weeks, and the time to reach the
greatest response is over 6 weeks (Katon & Ciechanowski, 2009). The careful and frequent
monitoring of the patient's response in the initial period of treatment is particularly important
(APA, 2010). Patients with depression have a higher risk of suicide compared to the general
population (Henkel, Seemüller, Obermeier, Adli, Bauer, Mundt, & Riedel, 2009), and the
earlier response to the treatment has been found to be of prognosis value (Henkel et al., 2009;
Szegedi, Jansen, Van Willigenburg, Van der Meulen, Stassen, & Thase, 2009; Tadi, Helmreich,
Mergl, Hautzinger, Kohnen, Henkel, & Hegerl, 2010). The onitoring should include the
assessment of the response to treatment, clinical condition, emergence of side effects, safety,
and adherence to treatment. Visits should also be frequent enough to monitor and address
suicide risk and to actively promote treatment adherence (APA, 2010).
An early response to treatment, defined as an improvement 20% on the 17-item Hamilton
Depression Rating Scale score within the two first weeks, has shown a high sensibility to predict
the further response and remission (Henkel et al., 2009; Szegedi et al., 2009; Tadi et al., 2010).
Non-response
In case of non-response to psychopharmacological treatment, besides of the previously
mentioned causal factors to be assessed, some specific factors should be taken into
consideration: inadequate dose, pharmacokinetic/pharmacodynamic factors affecting
medication action, and persistent or poorly tolerated side effects (APA, 2010).
If there is no response at all after 1 month, a treatment change would be advised while, if a
partial response is observed, it is recommended to wait until 6 weeks (Gaynes et al., 2008). In
case of partial response after 6-8 weeks the recommended options are: a treatment change
(NICE, 2009; Qaseem et al., 2008; APA, 2010), dose increase (if tolerated) (APA, 2010),
potentiation with an added antidepressant (Shelton, Osuntokun, Heinloth, & Corya, 2010) or
treatment maintenance until 10 weeks and then reassessment (Schulberg et al., 2002). If there
is no response after 8-12 weeks at maximum doses, another antidepressant drug should be
prescribed (within the same class or from a different one) and the patient should be referred to a
psychiatrist. If a patient's depression has failed to respond to two SSRIs, an antidepressant from
another drug class should be used; in case of severe depression, venlafaxine and tricyclic drugs
will be particularly considered (NICE, 2009). Switching, combination, and augmentation are the
pharmacological strategies indicated in the treatment-resistant depression, as well as
electroconvulsive therapy (Bauer et al., 2007; Shelton et al., 2010) In treatment-resistant
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depression, the addition of a cognitive-behavioral therapy to the antidepressant drug should be
considered (NICE, 2009; Bauer et al., 2007; APA, 2010).
Maintenance
After clinical remission, the antidepressant treatment should be continued for at least 6 months
(NICE, 2009) or 1 year in case of elderly patients (NICE, 2004). After this period, it is advisable
to extend treatment duration if residual symptoms and/or psychosocial problems are present
(NICE, 2009; APA, 2010). Therapeutic guidelines recommend a maintenance treatment of at
least 2 years for patients having suffered two depressive episodes and those having suffered
significant functional consequences (NICE, 2004) of at least 3 years for patients with a lifetime
history of three or more depressive episodes and patients showing a high recurrence frequency
(two episodes in five years) (Bauer et al., 2007) but other guidelines recommend an indefinite
maintenance for these patients (ICSI, 2004).
Withdrawal
The withdrawal of an antidepressant drug should be gradual, to avoid the occurrence of a
"withdrawal syndrome" (headache, anorexia, nausea, insomnia, and anxiety) which may be
mistook for an early sign of relapse (Reid & Barbui, 2010; APA, 2010). Paroxetine and
venlafaxine are the antidepressants with greatest risk of withdrawal syndrome (NICE, 2009;
APA, 2010). In general, the period of gradual withdrawal is 4 weeks, although some patients
may require a longer period (NICE, 2009).
To reduce patient's treatment discontinuation, the doctor prescribing the antidepressant drug
should inform the subject on the drug's latency period before onset of action, the possible
adverse effects that might occur during the first treatment days and that usually disappear after
the first week, and the need to maintain the treatment while indicated. In addition, it is
advisable to inform the patient about the availability to attend telephone consultations relative
to adverse effects or other questions (Katon W & Ciechanowski, 2009), and to evaluate the
adverse effects and the subject's clinical status 2 weeks after treatment (Qaseem et al., 2008;
NICE, 2009; APA, 2010).
Choice of the antidepressant drug
First-generation vs. second-generation antidepressants
A basic classification distinguishes first-generation (heterocyclics and MAOIs) from secondgeneration antidepressants (drugs selectively acting on one or more individual
neurotransmitters, such as serotonin, norepinefrine, and dopamine) (Zimmerman, Posternak,
Friedman, Attiullah, Baymiller, Boland, & Singer, 2004).
The use of first-generation antidepressants is currently very limited (Zimmerman et al., 2004).
However, tricyclic antidepressants still are an alternative in the switching or combination
strategies for the treatment of resistant depression (Shelton et al., 2010) and severe depression
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(APA, 2010); and MAOIs are an option for atypical depression (Thase, Trivedi, & Rush, 1995;
APA, 2010).
Although no differences in efficacy or latency to initiation of response have been found
compared to first-generation antidepressant drugs, second-generation antidepressants involve a
significant improvement regarding safety and tolerability (Bauer et al., 2007) and SSRIs are
currently recommended as first-choice antidepressant drugs for the treatment of a depressive
episode (NICE, 2009; Qaseem et al., 2008).
Effectiveness of different second-generation antidepressants
It has been pointed out that no clear differences exist between the different second-generation
antidepressant drugs (Gartlehner, Gaynes, Hansen, Thieda, DeVeaugh-Geiss, Krebs, & Lohr,
2008) or that, when found, these differences would not be clinically relevant (Qaseem et al.,
2008). In this sense, recommendations are that the choice of an antidepressant is made based
on the clinical profile, the adverse effects and safety, the age, the subject's medical condition
(APA, 2010), the cost, and the patient's preferences (Qaseem et al., 2008; APA, 2010). The
adverse effects profile (Hansen, Gartlehner, Lohr, Gaynes, & Carey, 2005; Gartlehner et al.,
2008; Papakostas, 2008), as well as the potential to cause clinically relevant interactions (Spina,
Santoro, & D'Arrigo, 2008), differ among second-generation antidepressant drugs. If an
antidepressant has previously shown to be effective, the use of the same drug is recommended
to treat a recurrence (Katon & Ciechanowski, 2009; APA, 2010).
However, differences in effectiveness have been pointed out by other authors, and an important
controversy exists relative to available evidences in different situations. Thus, a recent metaanalysis comparing twelve antidepressant drugs (bupropion, citalopram, duloxetine,
escitalopram, fluoxetine, fluvoxamine, milnacipram, mirtazapine, paroxetine, reboxetine,
sertraline, and venlafaxine) concluded that escitalopram and sertraline offer advantages related
to their efficacy and acceptability and, when balancing benefit, acceptability, and cost, the
overall benefit is favorable to sertraline. On the other hand, reboxetine indicated to be inferior
than the rest of antidepressant drugs, and has more adverse effect burden than these drugs
(Cipriani, Furukawa, Salanti, Geddes, Higgins, Churchill, & Barbui, 2009a). Furthermore, a
recent meta-analysis concluded advising against its use (Eyding, Lelgemann, Grouven, Härter,
Kromp, Kaiser, & Wieseler, 2010).
Various studies found a greater efficacy of escitalopram compared to citalopram (Montgomery &
Möller, 2009; Sicras-Mainar, Navarro-Artieda, Blanca-Tamayo, Gimeno-de la Fuente, &
Salvatella-Pasant, 2010) even though the clinical significance of this difference might be
questionable (Spina et al., 2008).
Mirtazapine has shown an onset of action similar to that of venlafaxine and quicker than those
of paroxetine, fluoxetine, sertraline, and citalopram (Gartlehner et al., 2008) however, similar
levels of efficacy were found with mirtazapine and SSRI after 6-12 weeks (Watanabe, Omori,
Nakagawa, Cipriani, Barbui, McGuire, & Furukawa, 2008; Croom, Perry, & Plosker, 2009).
Dual-action vs. Single-action antidepressants
Although not all, some studies and meta-analysis have suggested that antidepressant drugs
acting on more than one neurotransmitter have greater efficacy levels (Papakostas, Thase, Fava,
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Nelson, & Shelton, 2007). Although the Number Needed to Treat (NNT) estimated to obtain one
additional responder was 24, far from the NNT = 10 suggested by the United Kingdom's
National Institute of Clinical Excellence, this finding might be of public health relevance given
the large number of depressed patients treated with SSRI / serotonin-norepinephrine reuptake
inhibitor (SNRI) antidepressant drugs (Papakostas et al., 2007).
A recent meta-analysis comparing venlafaxine, SSRI and tricyclic drugs in the treatment of a
depressive episode, resistant depression, and prevention of relapses, concluded the superiority
of venlafaxine in resistant depression and, in the treatment of a depressive episode, its efficacy
was greater when compared to SSRIs, and similar when compared to tricyclic drugs (Bauer,
Tharmanathan, Volz, Moeller, & Freemantle, 2009).
Long-term treatment
The only second-generation antidepressant drugs with available trials on the prevention of
recurrences showing positive results are venlafaxine extended release, in the adult population
(18-65 years), and paroxetine, in subjects over 60 years of age. Thus, these drugs may be
considered the drugs of choice for patients requiring long-term maintenance treatment (Roca,
Baca, Álvarez, Bousoño, Eguiluz, & Martín, 2008).
Elderly and chronic patients
In elderly patients, sertraline has shown negative results in the prevention of recurrent
depressive episodes (Reynolds, Dew, Pollock, Mulsant, Frank, Miller, & Kupfer, 2006).
However, the NICE guideline (2009) considers sertraline, together with citalopram, the drug of
choice for patients with chronic somatic diseases, due to its low level of interactions compared
to other drugs (NICE, 2009). Besides, sertraline has been recommended as the treatment of
choice when initiating treatment in a patient with a recent myocardial infarction or unstable
angina (Cipriani, La Ferla, Furukawa, Signoretti, Nakagawa, Churchill, McGuire, & Barbui,
2009 b; NICE, 2004).
In conclusion, existing evidence does not justify the choice of any second-generation
antidepressant drug over another on the basis of efficacy differences. Currently, SSRIs are firstchoice drugs for the treatment of depression (NICE, 2009), venlafaxine would be indicated in
resistant depression (Bauer et al., 2009), and citalopram and sertraline are the treatment of
choice in elderly and chronic somatic diseases (NICE, 2009).
Differential characteristics of antidepressant drugs
Among SSRIs, there are differences in their receptor selectivity, strength, interaction profile,
and other pharmacokinetic properties, these also determining differences in their profiles.
Fluvoxamine frequently causes gastrointestinal adverse effects. Paroxetine shows a greater
associated anxiolytic effect, while fluoxetine shows an activating profile (Hirsch & Birnbaum,
2009).
Venlafaxine, as well as citalopram, escitalopram, mirtazapine, and reboxetine have a low
potential to cause clinically relevant interactions (Spina et al., 2008).
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Duloxetine has shown its efficacy in the treatment of fibromyalgia's associated pain, regardless
of the presence of depression (Verdu, Decosterd, Buclin, Stiefel, & Berney, 2008). A recent
meta-analysis concluded the efficacy and superiority of duloxetine and paroxetine vs. placebo to
treat depression's associated pain, although no differences were found between both
antidepressant drugs (Krebs, Gaynes, Gartlehner, Hansen, Thieda, Morgan, & Lohr, 2008).
Mirtazapine causes somnolence, thus, it is an option for the treatment of depressed patients
with significant insomnia (Katon & Ciechanowski, 2009). Besides, it is one of the options when
alternative therapy is needed following an inadequate response to initial treatment, for
augmentation / combination treatment (Croom et al., 2009).
The sexual adverse effects caused by Bupropion are significantly lower, similar to those caused
by placebo (Papakostas, 2008) and the drug is not associated to weight gain. It seems to be
particularly efficacious to treat individual depressive symptoms, such as apathy (Katon &
Ciechanowski, 2009). Compared to SSRIs, bupropion has shown greater efficacy to improve
fatigue and somnolence (Papakostas, 2009) but it appeared to be less effective to treat
depression-associated anxiety (Hirsch & Birnbaum, 2009).
Agomelatine has shown efficacy in the restoration of disturbed sleep-wake patterns early in
treatment. There has been no evidence of induced sexual dysfunction, weight gain or
discontinuation-emergent symptoms (Kennedy & Rizvi, 2010; Olié & Kasper, 2007; Lemoine,
Guilleminault, & Alvarez, 2007).
Conclusions
The goal of treatment is clinical remission, a key factor to improve long-term prognosis.
Antidepressant treatment and psychotherapy are efficacious to treat depression, for both, the
acute phase and the prevention of relapse and recurrence.
To reduce the risk of relapse and recurrence after clinical remission, the antidepressant
treatment should continue for a time period of one year minimum, even though it usually lasts
two to three years, 2-3 years, or even indefinitely, depending on the fulfilled established criteria.
Early response to treatment shows a high sensibility to predict the further response and
remission. Poor treatment adherence is a main problem of the treatment of depression.
Strategies must be set up in order to minimize the risk of lack of compliance. Psychotherapy is
also recommended in the maintenance phase to reduce the risk of relapse and recurrence.
Second-generation antidepressants are the drugs of choice and have involved a significant
improvement on safety and tolerability when compared to first-generation drugs. Secondgeneration antidepressants differ in their adverse events profiles and in their potential to cause
clinically relevant interactions. The use of an SSRI is recommended as the first choice treatment
for a depressive episode. A consensus has not been reached on whether all second-generation
antidepressant drugs have the same level of effectiveness. It is recommended to make the choice
of an antidepressant drug on the basis of the following criteria: clinical profile, adverse effects,
safety, age, patient's medical condition, cost, and patient's preferences.
Psychotherapy, alone or in combination with an antidepressant drug, is an option for the
treatment of mild and moderate depression. Psychotherapy is recommended as an initial
treatment for mild depression.
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Cite este artículo de la siguiente forma (estilo de Vancouver):
Acosta FJ, Hernández JL, Herrera J, Pereira J, Suárez M. The treatment of depression.
Psiquiatria.com [Internet]. 2014 [citado 14 Oct 2014];18:12. Disponible en:
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