GERIATRIC DISORDERS (DC STEFFENS, SECTION EDITOR)
Treatment of Depression in Older Adults
Cássio M. C. Bottino & Ricardo Barcelos-Ferreira &
Salma R. I. Ribeiz
#Springer Science+Business Media, LLC 2012
Abstract Depression is the most frequent mental disorder
in older people, often causing emotional distress and re-
duced quality of life. Despite its clinical significance, de-
pression remains underdiagnosed and inadequately treated
in older patients. Regarding prognosis, data suggest that
almost 70% of patients, treated long enough and with ap-
propriate doses, recover from an index episode of depres-
sion. Antidepressants are efficient for treating depressed
outpatients with several comorbid physical diseases as well
as hospitalized patients, with selective serotonin reuptake
inhibitors being the antidepressants of choice for older
patients. Available data can guide pharmacological treat-
ment in both the acute and maintenance stages, but further
research is required to guide clinical strategies when remis-
sion is not achieved. Approaches for the management of
resistance to treatment are summarized, including optimiza-
tion strategies, drug changes, algorithms, and combined and
augmentation pharmacological treatments. Finally, addition-
al therapeutic choices such as electroconvulsive therapy,
transcranial magnetic stimulation, and integrated psycho-
therapy are presented.
Among the mental disorders that affect older people,
depression is the most frequent cause of emotional
distress and reduced quality of life and is recognized
as a serious public health problem . There is ongoing
debate as to whether the prevalence of depression
increases or decreases with age . Formal diagnoses
of depression are less common in older people; the
frequencies of such diagnoses are considerably lower
than those in younger populations [3, 4]. However,
when broader measures are used, including those that
do not exclude a diagnosis of depression in the presence
of conditions that are more common in older people,
such as bereavement or dementia, prevalence rates of
between 6 and 20 % have been reported in community-
dwelling populations [5, 6], of up to 50 % in older
people living in residential care  and of 48 % in a
hospital sample .
Despite its clinical significance, depression remains
underdiagnosed and inadequately treated in approximately
70 % of cases. According to surveys of patients being
assisted at primary healthcare facilities in the United States,
only 22.7 % of patients with depression were prescribed
antidepressants, and only 13.7 % of those patients were
receiving the proper dose .
The aim of this paper is to review the literature on
pharmacological and nonpharmacological interventions for
the treatment of late-life depression and to suggest
approaches that combine evidence-based data and clinical
C. M. C. Bottino (*):R. Barcelos-Ferreira:S. R. I. Ribeiz
Old Age Research Group (PROTER), Institute of Psychiatry,
University of São Paulo Medical School,
Rua Dr. Ovídio Pires de Campos, 785, Cerqueira César,
São Paulo, SP, Brazil CEP 05403-010
Curr Psychiatry Rep
Pharmacokinetic Considerations in the Elderly
Owing to changes in the efficiency of hepatic, renal, and
gastrointestinal function with aging, the pharmacokinetic
parameters of drugs are altered in the elderly, which can affect
how these drugs should be administered. In particular, the
efficiency of psychotropic drug metabolism declines with
age, leading to prolonged elimination half-life, reduced clear-
ance, and elevated plasma levels. Therefore, compared with
younger patients, elderly patients may be exposed to a higher
risk of side effects at a given dose of antidepressant. This can
are possiblyrelated toincreases inreceptorsensitivity. Elderly
patients become more susceptible to a number of drug side-
effects, particularly to those concerning the central and auto-
nomic nervous systems . Elderly patients seem more
susceptible to common antidepressant side-effects, such as
sedation, anticholinergic effects, extrapyramidal effects and
orthostatic hypertension. These side-effects can occur even at
modest plasma drug levels . Sedation is of particular
concern in the elderly because of falls, which can cause
fractures in patients who potentially have osteoporosis.
It is important to consider the side-effect profile of anti-
depressant drugs when making prescriptions for the elderly
(Table 1). Tricyclic antidepressants (TCAs) are generally
poorly tolerated in this respect, with the exception of desi-
pramine and nortriptyline. Selective serotonin reuptake
inhibitors (SSRIs) are better tolerated and do not have the
potentially serious cardiovascular side-effects of TCAs;
SSRIs do have gastrointestinal side-effects and can precip-
itate a serotonin withdrawal syndrome. Serotonin and nor-
epinephrine reuptake inhibitors (SNRIs) and bupropion are
generally well tolerated .
Efficacy of Antidepressants in the Elderly
Studies assessing the prognosis of depression in the elderly
long enough and with appropriate doses, recover from the
index episode of depression. Nevertheless, the recommenda-
tion is to maintain at least 6 weeks of treatment for antide-
pressants to attain their optimal effect, and efficacy must be
questioned when there isno response inthe first 4 weeks .
With regard to the pharmacological treatment of depres-
sion in the elderly, a review of controlled clinical trials
showed that all three classes of antidepressants (TCAs,
SSRIs, and monoamine oxidase inhibitors [MAOIs]) are
efficient for treating outpatients with several physical dis-
eases and hospitalized patients .
Selective serotonin reuptake inhibitors are currently the
antidepressants of choice for elderly patients. The most
commonly observed adverse effects are nausea, diarrhea,
and weight changes; increased risk of bone fractures (falls);
sexual dysfunction; hyponatremia (especially in women with
low body massindex or who use diuretics); and increased risk
of gastrointestinal bleeding (especially in patients using non-
steroidal anti-inflammatory drugs or warfarin) .
Among tricyclic antidepressants (TCAs), nortriptyline is
the best tolerated and has received considerable attention in
the treatment of the elderly. Adverse events reported with
nortriptyline include tachycardia, dry mouth, constipation,
and taste abnormalities.
The efficacy and tolerability of TCAs, SSRIs, and
MAOIs for the treatment of depressed elderly are relatively
well studied, although the MAOIs may be an exception. In
another literature review, Salzman et al.  noted that
MAOIs have been demonstrated to be safe and effective
for depressed elderly in a small number of studies. The
authors concluded that more research with MAOIs is re-
quired in patients with severe medical disorders and in
Other antidepressants, such as bupropion, duloxetine, mir-
tazapine, and venlafaxine, are considered to be effective and
safefor thetreatmentofdepressed elderly patients,butthereis
little evidence regarding their use in this population .
The advantages of bupropion include activation, which
may be indicated in elderly patients with anergic depression
or significant psychomotor retardation, and a lack of cardio-
vascular, anticholinergic or cognitive adverse effects.
Bupropion does not cause sedation, but it may interfere with
sleep . Its extended release formulation showed efficacy
similar to that of paroxetine and a lower frequency of some
adverse effects in the elderly .
Duloxetine was assessed in two multicenter placebo-
controlled trials that included depressed patients who were
at least 55 years old. Duloxetine was significantly better
than the placebo on the Hamilton depression scale, and the
estimated probability of remission for patients treated with
duloxetine (44.1 %) was significantly higher than for the
placebo group (16.1 %). Generalized and lumbar pain also
improved in the duloxetine group .
Mirtazapine is an effective and safe antidepressant in the
elderly, with anxiolytic and sedative properties that also
make it useful as a hypnotic agent. Mirtazapine is not
associated with drug interactions or enzymatic inhibition,
and its most important adverse effect is weight gain . In
two randomized clinical trials performed with elderly
patients, mirtazapine was compared with amitriptyline (n0
115) and paroxetine (n0246), and it exhibited efficacy sim-
ilar to the former  and higher than the latter .
The pharmacological profile of venlafaxine makes it an
interesting alternative for elderly patients because of the
unlikelihood of interactions with other drugs, the weak
inhibition of cytochrome P450 and the low level of binding
to serum proteins. The results of three double-blind and four
Curr Psychiatry Rep
open clinical trials confirmed the efficacy and safety of
venlafaxine in depressed elderly patients . The tolerable
adverse effects included insomnia, agitation and dry mouth
at the onset of treatment, whereas more severe adverse
effects, such as falls or heart rhythm disorders, appeared to
be rare. Hypertension occurred in a fraction of elderly
patients and usually with doses higher than 150 mg per
day. Additional data suggest that venlafaxine may also be
effective in the treatment of other conditions, such as anx-
iety and neuropathic pain .
The goal for acute or short-term treatment always must be
the full remission of symptoms. However, additional studies
are required to examine not only the efficacy of the drugs in
treating depressive symptoms and the tolerability of the
newer antidepressants in elderly patients. These studies
should also apply auxiliary indicators of functional indepen-
dence and self-perceived well-being to help clinicians
choose the best treatment option for each patient.
The goal of long-term treatment is the prevention of recur-
rence. Getting well is important, but staying well is what
counts . However, the overall prognosis for elderly
depressed patients is poor. In a meta-analysis of 12 natural
history studies that followed up on elderly patients with
depression in community or primary care, Cole et al. 
investigated the patients’ long-term outcomes. The pooled
data from these studies showed that after 24 months, 33 %
of patients had recovered, 33 % were still depressed, and
21 % had died. Physical illness, disability, cognitive impair-
ment, and more severe depression were associated with
worse outcomes; the extent of social support may also have
been an important determinant of the outcome .
The increased risk of recurrence of depressive episodes in
the elderly makes most of these patients appropriate candi-
dates for maintenance therapy with antidepressants. The
utility of such treatment in preventing recurrence has been
established for nortriptyline, particularly in association with
interpersonal psychotherapy . This maintenance treat-
ment has also been shown to prevent declines in social
adjustment in elderly depressed patients .
Only a few controlled studies have been conducted on the
efficacy of maintenance antidepressant medication. Most
experts recommend 6–12 months of pharmacotherapy after
a first episode of depression in old age. The efficacy of an
SSRI in maintenance treatment of depression was tested in a
2-year maintenance treatment with paroxetine and monthly
interpersonal therapy. Patients experiencing their first epi-
sodes also benefited from the 2-year maintenance treatment,
which challenges the conventional wisdom and practice of
limiting continuation treatment to 6–12 months following
remission from acute treatment .
Resistance to Treatment
The notion of resistance to treatment is traditionally applied
to nonresponse (patients who do not exhibit at least a 50 %
reduction of symptoms). However, the absence of remission
of symptoms has also been considered to be an
Table 1 Side-effects of antide-
0: none; 0/+: unusual; +: mild; +
+: moderate; +++: strong; ++++:
aExcept for dry mouth. Adapted
from Alexopoulos and Salzman
 and Small and Salzman 
Sedation Hypotension Anticholinergic
rhythm and rate
Curr Psychiatry Rep
inappropriate response to treatment . Because a signifi-
cant fraction of patients do not attain remission in spite of
appropriate treatment with antidepressants , depression
poses a challenge to clinicians. Achieving remission of
depression in elderly patients is even more difficult in the
primary healthcare setting because of the clinical complex-
ity exhibited by this population and the limitations of pri-
mary healthcare .
The next section describes possible strategies to manage
resistance to treatment of depression in the elderly.
Initial Strategy for the Management of Resistance
When a patient presents with treatment-resistant depression,
the primary diagnosis must always be reassessed while
considering clinical and psychiatric comorbidities as the
possible cause of treatment failure . The following
measures must be instituted before changing medication in
1. Improving compliance with treatment
2. Ensuring that the patient is using the proper dose
3. Ensuring that the duration of treatment is appropriate
Concomitant medical conditions are common in the elderly
and may significantly impact on or be impacted by
Nonresponse because of inappropriate treatment is known
as pseudo-resistance . When remission does not occur
after an appropriate duration of treatment, the dose is usually
gradually adjusted until one of the following occurs:
1. Symptoms enter remission
2. Side-effects appear that preclude any further increase
3. The maximum dose limit is reached
The optimization of the dose and the duration of treat-
ment allow clinicians to distinguish between pseudo and
true treatment resistance. Another issue to note is that elder-
ly patients with depression and cognitive impairment are at
risk of noncompliance with treatment because of difficulties
organizing and planning the intake of medication .
To promote compliance with treatment, clinicians must
take into account patients’ cultural and social contexts when
making therapeutic decisions for depression . Psycho-
educational interventions are a possible strategy to improve
compliance and the self-management of depression .
Strategies for Medication Changes
Mulsant et al.  performed a study on the treatment of
depression in the elderly in the primary healthcare setting
based on PROSPECT guidelines. The guidelines indicate that
medication should be changed for patients who do not re-
spond after 6 weeks oftreatmentand thatitshouldbechanged
after 12 weeks in partial responders. This recommendation is
consistent with observations reporting that depressed elderly
patients improve, but improvement usually takes longer than
normal to develop and requires perseverance .
Experts agree  that when patients do not respond to
treatment and the drug dose is low, clinicians should wait 2–
4 weeks before increasing the dose and the length of the
treatment course. When patients do not respond and the
dose is appropriate, a change of medication is advisable.
Similarly, when patients are partial responders, clinicians
must increase the dose and wait 3–5 weeks before changing
medication. When patients are using high doses of drugs,
longer initial courses are recommended (3–6 weeks when
little or no response is observed, or 4–7 weeks when a
partial response is observed). Several clinical factors influ-
ence the decision to augment or change medication, but
there is no consensus to serve as a guide .
The most frequent clinical situation when augmentation or
a combination of medication is suggested is when a patient
exhibits a partial response to an antidepressant and the clini-
cian does not want to jeopardize the improvement by discon-
tinuing the drug. However, there isnoevidenceto support this
concern that changes of medication lead to a loss of clinical
improvement.Therefore, a change of antidepressant isrecom-
mended in these cases to attain remission .
In the final instance, the use of three or four courses of
antidepressants is associated with positive responses in 80–
90 % of patients . In some cases, for remission to be
attained, patients and clinicians must work together and
persevere through several attempts and several drugs.
Studies using algorithms to model the pharmacological
treatment of depression have been performed to improve
remission and response rates by optimizing antidepressant
use in terms of therapeutic doses, duration of treatment and
the rational use of antidepressant monotherapy or combined
therapy. Treatments based on algorithms have resulted in
better outcomes and fewer medication changes than conven-
tional treatments .
Studies that use algorithms for the treatment of depres-
sion in the elderly [30, 32] suggest that this strategy may
benefit a significant fraction of the population. Steffens 
designed the Duke Somatic Treatment Algorithm for
Curr Psychiatry Rep
Geriatric Depression (STAGED), which uses five stages that
are based on the patient’s history of previous treatment and
was tested on 228 elderly patients with depression. In the
course of 18 months of treatment, 88.6 % of the patients
responded and 65.4 % attained full remission of symptoms.
Combined Pharmacological Therapy
Combined antidepressant therapy is defined as the prescrip-
tion of two drugs that exhibit different mechanisms of action
. Approximately half of patients with major depression
who are treated with augmentation or change of medication
respond to treatment . However, it should be stressed
that a combination of drugs may increase the risk of side-
effects because of pharmacodynamic interactions . Ad-
ditionally, changes of medication may be as effective as
augmentation by adding a second drug and may decrease
the risk of falls and side-effects .
Because of the possibility of drug interactions and addi-
tional undesirable side-effects, it is important to assess the
efficacy of the combination of psychotherapy for depression
and pharmacotherapy for attaining partial or total responses
. The most frequently used antidepressant combinations
are described in the next section.
SSRIs and Heterocyclic Agents
Most studies on the effects of the combination of SSRIs with
heterocyclic agents in refractory depression are small clini-
cal trials with young adults.
Studies performed with fluoxetine, imipramine, and desi-
mipramine reveal that SSRIs interfere with the metabolism
of tricyclic antidepressants and increase serum levels [29••].
Despite these promising results, additional data are required
to support a combined therapy with SSRIs and tricyclic
antidepressants  in adults.
This combination therapy approach requires extra care
for the elderly because of the unique characteristics of their
metabolism and the frequent simultaneous use of many
drugs, which increases the risk of side-effects and diminu-
tion of drug effects.
SSRIs and Bupropion
Combining SSRIs with bupropion is a commonly used
strategy, although most data are obtained from case-reports
and small open clinical trials . There is some evidence of
a reduction of side-effects when bupropion is added to SSRI
treatment . Weight gain has been observed in long-term
treatment with some SSRIs, whereas weight loss has been
observed in long-term treatment with bupropion .
Double-blind controlled trials with bupropion as an aug-
mentation agent in the treatment of refractory depression in
young adults and the elderly are required to confirm the
positive results of the open trials.
Serotonin and Norepinephrine Reuptake Inhibitors
A retrospective study of patients with refractory depression
showed a 30% remission ratewhen patientswere treatedwith
a combination of bupropion and duloxetine . Controlled
studies are required to better assess the use of bupropion as an
augmentation strategy in adults  and in the elderly.
The abovementioned combination therapies and their
corresponding evidence are summarized in Table 2.
Augmentation Pharmacological Treatment
Augmentation pharmacological treatment is commonly de-
. In patients who do not respond to first-line pharmaco-
logical therapy, the use of augmentation strategies showed a
50 % response rate. In the elderly, this strategy is reserved for
cases of major depression that are difficult to treat .
Some studies suggest possible predictors of the response to
augmentation therapy . Clinically significant anxiety and
high medical stress are predictors of longer recovery times
duringaugmentation pharmacological therapy .Addition-
ally, high levels of anxiety symptoms and longer recovery
times at initial treatment are predictors of recurrence .
A literature review  assessed the risk of relapse when
lithium is discontinued as an augmentation agent in the
treatment of unipolar depression in elderly patients. The
overall relapse rate could not be established in three studies,
but a 50 % increase in the relapse rate during the first
6 months of follow-up could be inferred. Therefore, there
seems to be a risk of relapse when augmentation treatment
with lithium is discontinued in the elderly.
Thyroid hormones have been used for more than 20 years
as augmentation agents in the treatment of unipolar depres-
sion . Although thyroid disorders may occur in a small
fraction of patients with depression, augmentation with thy-
roid hormones may be effective in patients with depression
and normal thyroid function . However, controlled stud-
ies with older patients could not be found.
Atypical antipsychotics have been assessed as augmen-
tation agents in the treatment of refractory depression; how-
ever, most of the studies were retrospective or small clinical
trials. Adjuvant therapy with atypical antipsychotics has
shown higher response rates compared with antidepressant
monotherapy and placebos, but also resulted in more
Curr Psychiatry Rep
dropouts because of side-effects . The chronic use of
antipsychotics as augmentation agents in major depression
must be carefully assessed, as these drugs are frequently
associated with metabolic disorders, sedation, extrapyrami-
dal effects, and hyperprolactinemia . These side-effects
may be particularly harmful in older patients.
Little is known about the effect of central nervous system
stimulants on patients with refractory depression . De-
spite there being little empirical support for it, the use of a
combination of SSRIs and methylphenidate or dextroam-
phetamine is common in clinical practice . In a small
open study performed with older patients with depression,
methylphenidate showed positive effects on augmenting the
action of citalopram .
Electroconvulsive therapy (ECT) in the depressed elderly
may be an alternative to treatment with antidepressants. A
Cochrane systematic review of the efficacy and safety of
ECT (compared with simulated ECT or antidepressants)
 in depressed elderly patients found that randomized
evidence is sparse. Only three trials could be included, and
they had major methodological shortcomings; the data were
mostly lacking in essential information to perform a quanti-
tative analysis. Randomized evidence on the efficacy and
safety of ECT in depressed elderly with concomitant de-
mentia, cerebrovascular disorders or Parkinson's disease is
completely absent. Possible side-effects could not be ade-
quately examined because of the lack of randomized evi-
dence and the methodological shortcomings. Reviewers
concluded that none of the objectives of this review could
be adequately tested because of the lack of firm evidence.
Given the specific problems in the treatment of depressed
elderly, a well-designed randomized controlled trial is re-
quired to compare the efficacy of ECT with one or more
antidepressants  Furthermore, additional studies are re-
quired on continuation pharmacotherapy and continuation
ECT after a successful ECT course .
Transcranial Magnetic Stimulation
Transcranial magnetic stimulation (TMS) was approved by
the FDA in 2008 as a treatment for depression that is
resistant to pharmacotherapy [20••]. A high-frequency pulse
repetitive TMS (rTMS) is applied to the left dorsolateral
prefrontal cortex. The treatment appears to be better tolerat-
ed than ECT [20••].
A 2-week open study  examined the antidepressant
efficacy of rTMS in vascular depression. The authors found
that 5 out of 11 treatment-resistant patients with late-onset
vascular depression were responders. There was a clinically
meaningful improvement in HDRS scores. Two small con-
trolled studies [45, 46] failed to show a significant effect with
active rTMS. Nevertheless, another controlled trial 
revealed efficacy of rTMS among geriatric patients with vas-
culardepression. Theyobservedresponserates of6.9 % inthe
sham group and 39.4 % in the active-stimulation group; the
remissionrates were 3.5 %and 27.3% respectively. Olderage
and smaller frontal gray matter volumes were associated with
a poorer response to rTMS.
These data suggest that additional studies are required to
further assess the efficacy and safety of rTMS as a treatment
option for depressed elderly patients.
Although antidepressant medication is the first-line treatment
for moderateand severedepression), 30–40% ofpatients
do not respond sufficiently to an adequately prescribed drug
. The limited success of pharmacological strategies has
initiated a change in focus toward a more holistic and person-
ing, components of psychiatric management and general
“psychotherapeutic support” should always be initiated and
continued throughout the treatment .
The National Institute for Health and Clinical Excellence
 recommends that patients with severe, treatment-
resistant or recurrent depression should receive a combina-
tion of antidepressant medication and individual cognitive-
behavioral therapy (CBT). Keller et al.  reported that the
most frequently used psychotherapeutic techniques were
Table 2 Most frequently used antidepressant combinations
Combination strategiesEvidence of efficacy
SSRIs and heterocyclic agents Small clinical trials with young
Despite promising results,
more information is required .
Fewer side-effects are present when
bupropion is added to treatment
with SSRIs .
Controlled trials are required.
One retrospective study: 30 %
of patients attained remission
when treated with bupropion
and duloxetine .
Controlled studies are required
in adults  and in the elderly.
Controlled studies are required
to establish their indication.
SSRIs and bupropion
SNRIs and bupropion
Mirtazapine and venlafaxine
SSRIs 0 selective serotonin reuptake inhibitors
Curr Psychiatry Rep
cognitive therapy (CBT), interpersonal therapy (IPT), a
cognitive behavioral analysis system of psychotherapy, and
mindfulness-based cognitive therapy. Patients with chronic
or recurrent depression, adolescents, geriatric patients, and
patients with moderate and severe depression benefit most
from combined treatments.
A meta-analysis of 20 studies showed that combined ther-
apy is associated with a small benefit in attaining remission
. However, combined psychotherapy and pharmacothera-
py showed a moderate effect in reducing relapse rates com-
pared with medication alone. The largest effect of combined
treatment, compared with medication alone, was found in
patients who were discontinuing medication.
The effect of CBT seems to continue over long-term
follow-up regardless of whether CBTis delivered in the acute
trials showed that patients who received combined treatment
improved significantly compared with those who received
drug treatment alone . Studies lasting for longer than
12 weeks showed a significant advantage of combined treat-
dropouts compared with nonresponders.
and pharmacotherapy integration design, such as concurrent
The simultaneous administration of pharmacotherapy and
psychotherapy in the acute phase only resulted in a modest
improvement; however, a sequential strategy that used phar-
macotherapy in the acute phase and cognitive therapy for
residual symptoms was beneficial in preventing relapse and
recurrence. Importantly, this sequential model introduces a
conceptual shift in therapeutic practice and may represent a
method of enhancing long-term depression recovery [55••].
Medical and psychiatric comorbidities, polypharmacy, previ-
ous response to treatment, the profile of adverse effects and
the potential interactionsof antidepressants mustbetaken into
account when selecting the most appropriate antidepressant
for individual older patients with depression. The currently
available data can guide pharmacological treatment in the
acute and maintenance stages, but further research is required
to guide clinical strategies when remission is not achieved.
Some possible augmentation and combination strategies
are reported for instances when remission is not achieved.
However, none of these strategies has been rigorously stud-
ied in older patients with depression. Additional controlled
studies are required to compare therapeutic options, aid the
selection of medication according to patients’ individual
clinical characteristics and determine the duration of com-
bination or augmentation therapy.
In addition, it is of importance to conduct well-designed
randomized controlled trials to further evaluate the efficacy
of ECT (in comparison to one or more antidepressants) and
rTMS as treatment options for older depressed patients.
Psychotherapy combined with pharmacotherapy may
help to achieve remission in the acute phase treatment and
should be considered for enhancing long-term depression
recovery, helping to prevent relapse and recurrence in older
The goal of acute, or short-term, treatment of depression
in older patients is the full remission of symptoms. Howev-
er, additional studies are needed that apply auxiliary indica-
tors of functional independence and self-perceived well-
being to help the clinician to choose the best treatment
option for each patient.
received payment for the development of educational presentations
from Pfizer and Janssen-Cilag, and has had travel/accommodation
expenses reimbursed by Janssen-Cilag.
Drs Barcelos-Ferreira and Ribeiz reported no potential conflicts of
interest relevant to this article.
Dr Bottino has served as a board member of Pfizer, has
Papers of particular interest, published recently, have been
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