174 Central Nervous System Agents in Medicinal Chemistry, 2011, 11, 174-183

Duloxetine in the Treatment of Depression: An Overview

Francesco Monteleone, Mariella Caputo, Mario Felice Tecce and Anna Capasso*

Department of Pharmaceutical and Biomedical Sciences, University of Salerno, 84084-Fisciano, Italy

Abstract: Depression is a disorder that can be classified in the categories of non-organic psychiatric disorders and mood
disorders. Mood tone is an important psychic function involved in the adaptation to both our internal and external world.
It is flexible, that is, it goes up when we are in positive and favorable conditions, but it goes down when we are in nega-
tive and unpleasant states. We can define depression as a condition when mood tone loses its flexibility, it goes down and
it’s no longer influenced by favorable external events. In fact, depression is characterized by changes in the way how the
affected individual thinks, feels and acts. Even if this change occurs gradually, a depressed subject is not the same as be-
fore. For example, a brilliant student could be persuaded to be not able to finish his studies; an affectionate mother could
start to neglect her sons; an enterprising worker could lose every interest for his activity. Moreover, a depressed person
doesn’t care of his aspect or of himself. The surviving instinct could leave place to the desire to stop his own life. The
most evident characteristic of depression in the adulthood is a sad mood, a gloomy solitary and apathetic attitude. A de-
pressed subject could cry also with no apparent reason, he could have difficulty falling asleep or he could wake up very
early in the morning and no longer returns to sleep. Or, instead, he could sleep more than usually and he could feel tired
persistently. He could lose appetite and weight, or, in some cases, he could eat much more than usually and he could gain
weight. Typically, a depressed person feels himself in a extremely negative way, he could think to be hopeless and help-
less and he often condemns himself for small guilty. A depressed subject is pessimistic about himself and his own future;
he loses interest in all what happens around him and he gets no satisfaction from the activities that before were pleasant.
Some persons can be depressed also if they don’t show evident signs of depression, but they complain for physical symp-
toms or they abuse of alcohol or other substances. It has been estimated that in the industrialized Western world one to six
persons has a depressive episode at least once during his life; at present, the incidence of depression in the general popula-
tion is around 5% with clear cut prevalence in the female sex. This leads to high social costs: behind the short-term inabil-
ity, we have to consider also the long term inability (it has been estimated that, in 2020, depression will represent the sec-
ond most frequent cause of permanent inability) as well as the suicide risk, the proved major susceptibility of depressed
subjects to various non-psychiatric pathologies and the increased rate of premature deaths of depressed individuals as
compared to the general population. The present work not only evaluates the drugs used for the treatment of depression,
but it focuses also on those studies that investigated the efficacy of a second generation drug: Duloxetine that has a higher
selectivity of action and a better tolerability profile as compared to first generation medications. These characteristics
make Duloxetine the most effective therapeutic choice to improve both psychological and somatic symptoms of depres-
sion in order to get higher rates of symptomatic remission on depressive episodes.
Keyword: Depression, duloxetine, SNRI.

INTRODUCTION • Loss of interests and affects: reduction of interest for

both working and no working activities; inability to
Depression
prove pleasure and affective involvement in the activi-
1. Symptomatology ties that were previously considered pleasurable and re-
warding. The patient often complains to be not able to
Depression symptomatology includes psychological, be- feel sentiments for his dear ones and to feel hardened.
havioral and somatic manifestations. The core symptoms of
depression are: • Ideal-motor slowing: poor and slow ideation, difficulty
to concentrate and to make decisions, attention and
• A decrease of the mood tone: the patient is sad, pessi- memory difficulties.
mistic and hopeless. Also when not clearly expressed,
depressed mood is revealed by various signs: the tone of • Excitement and anxiety with motor restlessness, in-
the voice is low, the speech is slow and the style of dress crease motor activity, continuous complaints.
is shabby. • Alterations of thought: prevailing ideas of negative
evaluations of himself are frequent, low self-esteem, in-
adequacy, unworthiness and guilty preoccupations over
*Address correspondence to this author at the Department of Pharmaceuti- presumed past mistakes generally appear when there is a
cal and Biomedical Sciences, University of Salerno, Via Ponte don Melillo,
84084 Fisciano (Salerno) Italy; Tel +39 089969744; Fax +39 089969602; worsening in the clinical picture and they can lead to
E-mail: annacap@unisa.it frequent ideas of death and suicide. About 1% of the se-
rious depressed individuals kills themselves, but at least

1871-5249/11 $58.00+.00 © 2011 Bentham Science Publishers

Duloxetine in the Treatment of Depression Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 3 175

80% of suicides occurs in the course of a depressive epi- known to induce depressive syndromes especially in vulner-
sode. able individuals. Among the most widely used drugs there
are antihypertensive and cardio-vascular drugs (digitalis,
Somatic and autonomic manifestations are always pre-
beta-blockers and diuretics), some NSAIDs, cortisonic and
sent in the depressive outline:
antibiotics; other drugs less used are the oral anticonceptive.
• Asthenia and loss of physical energy, which is often
Depression can be induced also by substances of abuse or
premature and preponderant.
as consequence of their abrupt withdrawal (abstinence).
• Precocious and frequent alterations in the sleep-wake Among these the drugs most frequently related to depression
rhythm, with prevailing central and terminal insomnia, are alcohol, anxiolitics, opioid drugs. As for depression risk
but also with hypersomnia and frequent desire of sleep. related to abrupt discontinuation, we remember cocaine, am-
• Alteration of appetite, more often a decrease, with con- phetamines and amphetamine-like drugs used as adjuvant
sequent weight loss. In many cases there is bulimia, es- during dieting.
pecially in women. Depressive episode in the post-partum. In the post-
• Reduction in the sexual desire partum a slight mood variation toward a depressive state,
lasting 1-4 days after partum, physiologically occurs in about
• Different and unspecific pain symptoms (headache, low 80% of the puerperas. These conditions do not need a spe-
back pain, cervicalgias, muscular pains) cific treatment because a complete resolution happens spon-
taneously within a few days.
Etiology of Depression
About 10-15% of the women present, after partum, a
Inheritability. Genetic studies of depressive disorders non-recurrent depressive disorder that has no symptoma-
disclose a strong involvement of hereditary factors. In fact, tological peculiarity with respect to nonpuerperal depressive
there is a higher concordance rate for monozygotic twins disorders. These conditions generally start from two weeks
than for dizygotic twins and concordance rates are similar to twelve months after partum, with the highest frequency in
independently from the fact that twins have grown together the first 6 months, and are more frequent in persons with
or separately. Adoptions studies strength the inheritability previous depressive episodes.
hypothesis.
The period immediately following the delivery is actually
Depression induced by a medical condition. It is possi- a very critical period from an emotional point of view. These
ble to find depressive symptoms in 15-40% of patients with a are moments in which bivalent sentiments alternate: on one
medical disease. hand, the euphoria deriving from the first contacts with the
It is important to underline that there are at least two mo- baby, on the other hand a sense of inadequacy for the new
dalities through which a physical disease may induce depres- role of mother, worries for the future, changes of the life
sion. style, etc.

The first way is that a patient who becomes aware of having Alarming signs are: easy irritability against relatives,
a severe medical disease (heart pathologies, cancer, degen- unstable mood, exhaustion, sense of inadequacy, insomnia or
erative disorders) doesn’t accept to be sick and becomes de- drowsiness, loss of appetite, negative thoughts of sickness or
pressed. In this situation the medical condition is a stressful death, behaviors of neglect or, on the contrary, of hyperpro-
event which the patient isn’t able to cope with. tection toward the baby, fear to be alone.

The second way occurs when depression is not a psycho- Changes in the blood brain flow. PET shows an in-
logical consequence of the medical disease, but it’s possible creasing blood flow in the frontal cortex in depressed pa-
to identify a direct patho-physiological relationship between tients as compared to healthy subject. Blood flow is in-
the medical disease and depression. creased in amigdala too, whereas it is decreased in parietal
and posterior temporal cortex, brain areas involved in the
Some diseases of the Central Nervous System (tumors, language and attention processing.
Parkinson’s disease and cranial traumas), endocrine disease
(hypothyroidism, Cushing syndrome), infectious (AIDS) and Neurochemical hypotheses of depression. There are
auto-immune diseases (Lupus, rheumatoid arthritis) are able many theories in this field:
to cause a depressive symptomatology similar to a “primary” • Monoaminergic hypothesis of depression: depression
depressive disorder. should be related to a decreasing in noradrenergic and
In Cushing syndrome there are high cortisol levels be- serotoninergic synaptic connections. This decrease af-
cause of pituitary tumors producing high ACTH levels, or fects especially the hypotalamus and the limbic system.
tumors of the surrenal glands. In Parkinson disease, the most To this are associated:
modern researches suggest that patients have anatomical - Deficit of GABA transmission (anxiety)
lesions involving neurons of the dorsal rafe nucleus contain-
- Deficit of opioid system activity (lack of reward)
ing high levels of serotonin. Therefore, the decreased levels
of serotonin in the celebrospinal fluid of depessive patients Monoaminergic hypothesis is supported by the fact that
would play an important role in the etiology of depression. reserpine may induce depression through the decrease of NA
and 5-HT stores [1].
Substance or drug-induced depression. There are drugs
usually used in the treatment of chronic diseases that are
176 Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 3 Monteleone et al.

• Deranged regulation hypothesis of depression: on the Dysthimia often starts in the early adulthood and has a
basis of this theory, depression would arise from the cunning course that can lead to chronicity. It differs from a
failure of a regulatory system modulating neurotransmit- major depressive episode especially for intensity and for
ter activities; so derangements of the regulation system length of symptomatology. Females have twice the risk to
would lead to neurotransmitters responding to the envi- develop dysthimia than males.
ronmental needs in an aberrant way;
The symptom most usually reported by the patient con-
• The hypothalamus-pituitary-adrenal axis hypothesis of sists of depressed mood almost every day for many months
depression: studies in Cushing syndrome showed that an or even forever. Other symptoms are sleep disorders, feeding
enhanced release of ACTH by the anterior pituitary was changes (anorexia or iperphagia), low self-esteem, difficulty
associated with depression. A possible mechanism could of concentration, asthenia and hopelessness. To make the
be represented by the abnormal excitation of pituitary diagnosis of dysthimia, the above symptomatology has to
cells in depressed patients driven by limbic system that last almost for two years. Patient can have periods where
would lead, as already told, to an enhanced release of there is no symptom, but these periods are no longer than
ACTH. two consecutive months at least. Also during the day short
wellness periods can occur. Differently from major depres-
It should be remembered that other hormonal studies
showed a relationship between high growth hormone levels sion, the clinical picture seems to be influenced quite clearly
by external events. Anyway in dysthimia symptoms are
and depression and between hyper/hypothyroidism and emo-
clearly responsible for a clear impairment of social, working
tional changes.
and interpersonal functioning. Sometimes, depression can
• The seasonal hypothesis of depression: there are indi- lead to complications such as alcohol or drug abuse.
viduals who undergo depression in the winter period; for
some of these individuals winter depression switches to Reactive depression. This diagnosis is used for depres-
sive disorders with an onset strictly linked to events of great
summer mania. This syndrome is told as SAD (seasonal
emotional impact, which can clearly generate depressed
affective disorder), and it seems to depend from changes
mood. According to the classical definition, this event has to
in the duration of the photoperiod. In fact, several ex-
precede of 3-6 months the onset of depression and a casual
perimental studies showed that bright light has a signifi-
relationship between this event and depressive episode must
cant anti-depressant effect that is reverted when light
exposure is stopped. to be evident. From a symptomatological point of view, pe-
culiar aspects are emotional liability, somatic anxiety, initial
This antidepressant effect of light seems to be driven by insomnia, ideation mainly polarized on the causing event, the
some neurochemical intermediaries such as 5-HT, which absence of motor inhibition and delusions, the ability to
follows a marked seasonal rhythm in man, with lower values modulate mood reactions in response to environmental
in winter than in summer or autumn. changes. The episode has often a prolonged duration, in rela-
tion with the persistence of stress events and it can improve
1.2. Depressive Subtypes and sometimes resolve with the modification of the external
Depression is included in the category of the mood dis- conditions.
orders, which includes disorders characterized by recurrent Bipolar disorders are characterized by recurrent epi-
phases of depression only (unipolar disorders) and disorders sodes of pathologic variation of mood tone, toward either a
in which phases of depression alternate with mania phases, decrease (depressive phase) or an increase.
that is, pathological increase of mood tone (bipolar disor-
ders). According to the DSM-IV, (Diagnostic and statistical The pathological increase of mood is typical of a manic
manual of mental disorders, IV edition) the main clinical episode. Manic episode is characterized by a pathological
forms of depression are: euphoria, which easily flows in irritability and hostility; a
marked emotional instability coexists. The course of thinking
Major depression, also known as unipolar depression, is is accelerated, with the feeling that ideas succeed rapidly
a severe recurrent depressive disorder that every year affects (running away of ideas); there is logorrhea with speedy lan-
about 5% of the adult population. Differently from a normal guage; associative links are instable and often strange. The
feeling of sadness or of a loss or from a transient status of increasing interest for several activities often occurs in an
bad mood, major depression has enduring characteristics and afinalistic and chaotic way. Thought content is characterized
can severely interfere on the individual’s way of thinking, by an excessive self-esteem and sometimes there are brilliant
behavior, mood, activities and his physical wellness. A car- ideas of grandiosity and megalomania (exaggerated talent,
dinal symptom, depressed mood and loss of interests and richness, noble origins). The behavior can be intrusive, in-
affects, and at least other five symptoms among sleep and discreet and arrogant; patients have often the tendence to put
appetite changes, motor agitation or slow, asthenia, difficulty themselves in evidence with eccentric and exhibitionistic
of concentration, thinking alteration, thoughts of death behaviors.
should be present for at least two weeks. Major depression is
the most frequent cause of disability in many developed The neuro-vegetative system is interested too. There are a
countries. Women are affected by major depression twice psychomotor acceleration with increased sense of wellness, a
than men. Major depression occurs in every age of life in the tendence to iperphagia with excessive consumption of alco-
childhood as well as in the youth or in the adulthood. All holic drinks and also drug abuse. The need of sleep is re-
ethnic, racial or social groups can be affected by depression. duced and often a shifty onset of insomnia is predictor to the
imminent recurrence of a manic phase. According to DSM-
Duloxetine in the Treatment of Depression Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 3 177

IV, maniac episode is defined as a period of pathologically discrete areas of the head. Electric stimulation causes a short
expanded mood lasting at least a week, accompanied by at brain block (lasting about 30 seconds). A person during ECT
least three symptoms with a marked impairment of the social doesn’t experience electric impulses. The treatment consists
functioning. A less severe and shorter duration condition of several ECT sessions, on average thrice a week. Anyway,
with less impairment of social functioning is defined hypo- it is not allowed when there are lesions of the central nervous
mania. Clinical subtypes of bipolar disorders are: system (CNS) associated to increased intra-brain pressure,
cardio-vascular problems and when antihypertensive and
• Type I bipolar disorder: manic episodes alternating with
antidepressive drugs are used.
episodes of major depression. Usually, it begins with a
depressive episode, and its course is characterized by at In the last years, ECT has been substantially improved:
least a manic episode. The depressive phase can precede before the treatment, a muscle relaxant drug is administered;
or immediately follow a manic phase, or depression and so, the treatment is delivered under a light anesthesia.
mania can be separated by months or years.
2.2. Pharmacologic Therapy
• Type II bipolar disorder: depressive episodes alternate
with hypomania episodes. During hypomania the mood Different antidepressant drugs are available for the treat-
increases, sleep need decreases and psychomotor activ- ment of depressive disorders. Sometimes physicians pre-
ity increases above the patient’s usual level. Most of the scribe different antidepressant drugs before finding the drug
patients who experiment a pleasant increase of mood, or the drug combination more effective for a given patient.
usually after a depression, don’t report it if they are not Sometimes, the dose needs to be increased to be effective.
asked. Both bipolar subtypes start mainly in the youth Even though there is some symptom improvement in the first
without sex prevalence. Their incidence is about 2-4%. weeks of treatment, antidepressant drugs need to be taken
regularly for 3 or 4 weeks (sometimes, 8 weeks too) before a
• Cyclothymic disorder: with regularly alternating mild
full therapeutic effect can arise.
depressive and manic phases of insufficient severity to
satisfy criteria for major depression or manic episode. Often patients would stop pharmacologic treatment too
soon. They feel better and think they don’t need drugs any-
Treatment more. Or they think drug isn’t helping them. It’s important to
take the drug for an adequate period of time even if side ef-
2.1. Psychotherapy fects appear before the onset of therapeutic effects. Once
Many types of psychotherapy, including some short patient feels better, it’s important that he continues to take
forms (10-12 weeks) can be useful for depressed patients. the drug for 4-9 months, to prevent a possible relapse of the
Psychotherapies help the patient to become aware of the na- depressive episode. Some drugs need to be stopped gradu-
ture of his/her problems and to get strategies to cope with ally, to allow the body to adapt to the new condition. It’s
them by a verbal exchange with the therapist, sometimes advisable to not stop antidepressant treatment without con-
with the addition of “homework” assigned at the end of each sulting a physician about the discontinuation modalities. For
session. Behavioral therapists teach patients how to get re- persons affected by bipolar disorders or by chronic major or
ward and satisfaction from their behaviors and how dismiss recurrent depression, pharmacologic treatment could be
those behaviors that contribute to the maintenance of depres- maintained for indefinite time.
sion or are the consequence of depression. Antidepressant drugs don’t induce tolerance. Anyway, as
Scientific research showed that two types of short psy- in all the cases in which drugs are prescribed for many days,
chotherapy, interpersonal and cognitive-behavioral therapy, antidepressant drugs have to be carefully monitored to verify
are useful for the treatment of some forms of depression. if adequate doses have been prescribed; physicians will
Interpersonal therapist focalizes on the patient’s personal check the dose and its efficacy regularly.
deranged relationships, which cause and increase depression. Since major depression is likely due to serotonin hypoac-
Cognitive-behavioral therapists help patients to modify nega- tivity, antidepressant drugs enhance serotonin transmission.
tive thought styles and behaviors often associated with de-
pression. Anyway antidepressants represent a symptomatic therapy
because they improve the serotonin lack but they don’t affect
Psychodynamic therapies that sometimes are used for the the process causing this lack.
treatment of depression focalize on the resolution of the pa-
tients’ conflictual feelings. Often, these therapies are not Pharmacologic treatment of depression induces a consid-
used until depressive symptoms do not decrease signifi- erable increase in the extra-cellular serotonin concentration;
cantly. this represents the key event of the antidepressant treatment
and causes, as a consequence, the down-regulation of pre-
Electro-Convulsive Therapy (ECT) synaptic 5-HT1 receptors.

Electro-convulsive therapy is particularly useful for those Antidepressant drugs can be classified in tri-cyclics (imi-
patients who do not respond to antidepressant drugs or pramine, desipramine, clomipramine, amitriptiline, doxepine,
whose depression is so severe to affect seriously their health. amoxapine, maprotiline), MAO inhibitors (isocarboxazide,
ECT is often effective in those cases in which antidepressant tranilcipromine, fenelzine, iproniazide, monclobemide,
drugs don’t improve symptoms enough. This therapy con- toloxatone, selegiline), selective serotonin reuptake inhibi-
sists in the induction of seizures lasting 25-30 seconds by tors (SSRI) (fluoxetine, fluvoxamine, paroxetine, sertraline,
means of electric impulses delivered by electrodes placed in citalopram, escitalopram), noradrenaline reuptake inhibitors
178 Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 3 Monteleone et al.

(maprotiline, viloxazine, reboxetine, desipramine), NASSA they should be considered useful but not first choice drugs.
(mirtazapine), noradrenaline and serotonin reuptake inhibi- With MAOI the commonest side effects are postural hy-
tors NSRI (venlafaxine, duloxetine and milnacipram), atypi- potension and dizziness. Other MAOI frequent side effects
cal antidepressant drugs (ademehtionine, amisulpride, amin- are erectile dysfunctions (less common with tranil-
eptine, maprotiline, mianserine, minaprine, nefazodone, tra- cipromine), anxiety, nausea, dizziness, insomnia, peripheral
zodone, viloxazine) and mood stabilizers (lithium). edemas and weight increase. Liver toxicity (reason for which
the first MAOI, iproniazide, was abandoned) is rarer with the
Tri-cyclic antidepressant drugs act by acutely blocking
use of present MAOI. The ingestion of food containing
serotonin, noradrenaline and to a lesser extent adrenaline
tiramine (cheeses, products containing yeasts, bier, wine)
reuptake in presynaptic terminals through competitive bind-
together with MAOI treatment can cause letal hypertensive
ing to the monoamine transporter proteins. Chronically (after
weeks or months), the blockade of monoamine reuptake re- reactions. Sometimes, if patient is resistant to treatment with
a single drug, it is possible to combine antidepressant drugs.
sults in the decrease of the number and sensitivity (down-
However, the association of MAO inhibitors must be
regulation) of brain -adrenoreceptors and 5-HT2 receptors.
avoided.
So, these drugs raise the mood tone, increase physical activ-
ity and reduce preocupations about being sick in depressed The only MAOI marketed in Italy is Parmodalin that is
patients, but don’t modify mood tone in healthy subjects. often prescribed in combination with a neuroleptic drug.
The antidepressant effect starts slowly, it takes 2-3 weeks Serotonin reuptake inhibitors: have antidepressant ef-
at least to arise. fects quite similar to tricyclic drugs in terms of efficacy and
times of occurrence but they are less cardiotoxic and have
Although tricyclic antidepressant drugs are very effective
less anticolinergic effects than tricyclics. They block SERT
molecules, they should be considered second choice drugs.
The reason for this is in the frequency of their side effects in serotonin nervous terminals.
that often are very uncomfortable. The most common side It seems that 5-HT2 receptors are up-regulated in de-
effects of these drugs are due to their antimuscarinic and
- pressed patients, probably because of a modified signal
blocking action. So, the majority of these drugs is not indi- transduction once receptor is activated. The blockade of
cated in patients with heart diseases. Also low doses can SERT by SSRIs induces a down-regulation of 5-HT2 recep-
cause tachycardia and chinidine-like effects on heart conduc- tors.
tion. Because tricyclic drugs could cause postural hypoten-
These drugs are used in major depression, in obsessive-
sion, they are not indicated in patients with osteoporosis,
compulsive disorder, in bulimia and anorexia nervosa and in
brain arterosclerosis or ischemic heart disease. Others side
the pain associated with diabetic neuropathy.
effects include blurred vision, tachycardia, constipation,
urine retention, late ejaculation and decreased libido, weight Side effects are caused by a 5-HT excess in some brain
increase and perspiration. circuits and the consequent stimulation of 5-HT2a, 5-HT2c
and 5-HT3 postsynaptic receptors.
A behavioral toxicity (excitement, confusion, hallucina-
tions or excessive sedation) is high probable particularly in The commonest adverse effects are: loss of libido, in-
older patients with organic brain disease. somnia or frequent night awakenings and/or excitement, se-
dation or tiredness, headache, dizziness, tremor, nausea and
In over-dosage these drugs can cause suicide, provoke vomiting due to the stimulation of 5-HT3 receptors, and in-
excitement, delirium, convulsions, coma and respiratory de-
testinal cramps, diarrhea and anorexia. Moreover, SSRIs
pression [2].
inhibit orgasm in a variable percentage of patients. Actually,
Because of their anticholinergic action they shouldn’t be such effect is utilized for the treatment of praecox ejacula-
used in patients with prostatic diseases or glaucoma. tion.
Mono-amino-oxidase Inhibitors (MAOI): are drugs In association with MAOI and TCA they may provoke
with a phenil-etil-amino structure similar to the endogenous “serotonin syndrome” characterized by tremors, hyperther-
substrates of MAO causing a fast and sustained increase in mia and collapse and in some cases death.
brain 5-HT, noradrenaline and dopamine which results in
NASSA: mirtazapine. Mirtazapine blocks
2-auto-
increased motor activity, euphoria and excitement. They are
receptors of the pre-synaptic noradrenergic terminals in-
able to inhibit irreversibly or reversibly MAO increasing creasing noradrenaline release in the synaptic cleft. Moreo-
intracellular stores of catecholamines in neurons.
ver it blocks
2 receptors localized on pre-synaptic serotonin
Irreversible inhibitors (tranilcipromine, phenelzine, ipro- terminals increasing 5-HT release, and blocks post-synaptic
niazide) block MAOA and MAOB. 5-HT2 and 5-HT3 receptors.
Reversible MAOI (moclobemide and tolaxotone) block Noradrenalin reuptake inhibitors. Noradrenaline reup-
only MAOA, which preferentially catabolizes 5-HT. take inhibitors induce a selective block of the noradrenaline
transporter (NET). They are used in depressive disorders
MAO inhibitors (MAOI) are used for the treatment of
characterized by a psychomotor retardation, apathy, and lack
atypical depression, phobic disorders and treatment resistant
of motivational stimuli.
depression.
In some cases, MAO inhibitors are very effective. How- The commonest side effects are constipation, dry mouth,
difficulty in bladder emptying, perspiration and difficulty to
ever, because of their relevant side effects, their frequent
get sleep.
interactions with other drugs and their low therapeutic index,
Duloxetine in the Treatment of Depression Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 3 179

Noradrenaline and serotonin reuptake inhibitors noradrenaline reuptake, makes Duloxetine a drug of superior
(SNRI). Noradrenaline and serotonin reuptake inhibitors, in efficacy as compared to both SSRI, acting only on serotonin,
relation to the dose, can block the reuptake of all the mono and the other antidepressant drug of the same therapeutic
amines. In fact, at low doses, they block the reuptake of sero- class, venlafaxine which has a non balanced effect on sero-
tonin only, at middle doses, they block serotonin and tonin and noradrenaline reuptake resulting mainly in sero-
noradrenaline reuptake; at high doses, they block serotonin, tonin effects. Furthermore, venlafaxine needs titration to
noradrenalin and dopamine reuptake. reach its therapeutic effect [10, 11].
Their use is not advised in patients with agitation, anxi- The optimum safety and tolerability profile, similar to
ety-panic, insomnia and arterial hypertension. that of SSRI, the rapidity of action, the daily monoadminis-
Principal side effects are cephalea, nausea, sleep disor- tration (60 mg) without need to titrate, improve the patient
adherence to Duloxetine therapy.
ders, tremors, irritability, anorexia and loss of libido.
Duloxetine is indicated in the treatment of both depres-
In association with MAOI they increase the risk of hyper-
sion [12] and neuropathic diabetic pain in which pain is
tensive reactions [3, 4].
commonly described as burning, cutting, pungent, shooting
Atypical antidepressant drugs: ademetionine (Samyr), as an electric shake. Drug response must be evaluated after
amisulpride (Deniban), amineptine (Survector), maprotiline two months of treatment.
(Ludiomil), mianserine (Lantanon), minaprine (Cantor), ne-
fazodone (Reseril), trazodone (Trittico), viloxazine (Vicilan). 3.1. Pharmaco-Dynamic Properties
Mood stabilizers (lithium). Lithium is considered the Duloxetine is a dual inhibitor of the reuptake of serotonin
first choice drug for the treatment and relapse prevention of (5-HT) and noradrenaline. In fact, it increases dose-
bipolar disorders. dependently extra-cellular levels of serotonin and noradrena-
line in several animal brain areas [13] and it weakly inhibits
It acts inhibiting the Ca2+ dependent extracellular
dopamine reuptake with no significant affinity for hista-
noradrenaline and dopamine release by noradrenergic nerve
minergic, dopaminergic, cholinergic and adrenergic recep-
terminals, and by increasing 5-HT release and IP3 concentra-
tion. tors. A similar selectivity of action contributes to a favorable
profile of tolerability.
Main side effects are nausea, polyuria, weight gain,
Duloxetine normalizes pain threshold in different pre-
edema, kidney toxicity, neural toxicity, confusion and con-
clinical models of neural and inflammatory pain and it at-
vulsions.
tenuates the attitude towards pain in a persistent model of
Lithium therapy must always be accompanied by the pain. The pain inhibitory action of Duloxetine is due to the
monitoring of blood lithium levels. inhibition of ascendant pain pathways in the central nervous
Then there are some bench drugs or natural origin sub- system.
stances that are commonly used as antidepressants. Among For the treatment of major depressive episodes, Du-
these drugs, the most known is the ipericum extract. loxetine has been studied in a clinical trial including 3518
Ipericum trade success has to be researched in the fact that patients responding to DSM-IV criteria for major depression
it’s a natural extract, in the common belief it’s considered an [14]. Duloxetine efficacy at recommended dose of 60 mg
effective drug, relatively harmless and without side effects. once a day has been demonstrated in three acute, fixed doses,
On this regard, some important considerations need to be randomized, double blind and placebo controlled clinical
done. Ipericum might have an antidepressant effect but its studies carried out on adult out patients with major depres-
efficacy is absolutely less proved than other antidepressant sion. Duloxetine efficacy at daily doses ranging from 60 mg
drugs. The common idea that it is without side effects and to 120 mg has been demonstrated in five out of seven acute,
toxicity, because of its natural origin, must be discarded. In fixed dose, randomized, double blind and placebo-controlled
fact, serious cases of allergic reactions and photo-sensitivity clinical studies carried out on adult out patients with major
have been reported. Moreover, ipericum can interact with depression [15].
many others drugs interfering markedly with their metabo-
Duloxetine showed a statistical superiority with respect
lism (for example, it facilitates the metabolism of oral con-
traceptive drugs and changes the kinetic of oral anti- to placebo as measured as improvement of the 17 item Ham-
ilton Depression Rating Scale (HDRS) total score (that in-
coagulant drugs).
cludes both somatic and psychopathological symptoms of
depression).
Duloxetine
Also response and remission rates were statistically and
Among the most interesting and promising alternative
significantly higher with Duloxetine than placebo. Only a
therapeutics there is without doubt Duloxetine, belonging to small part of patients included in clinical studies had a severe
the class of SNRI [5-7].
depression at baseline (HDRS score >25).
In fact, this molecule is able to selectively inhibit sero-
In a relapse prevention study, patients who responded to
tonin and noradrenaline reuptake, with poor affinity for oth-
a 12 week open-label acute treatment with Duloxetine at the
ers neurotransmitters systems [8, 9].
dose of 60 mg once a day were randomized to receive both
The peculiar mechanism of action, characterized by a 60 mg/day Duloxetine or placebo for further six months.
combined and balanced inhibition of serotonin and
180 Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 3 Monteleone et al.

Duloxetine 60 mg once a day demonstrated a statistically (average, 12 hours). After an intravenous dose, the plasma
significant superiority versus placebo (p=0.004) with regard clearance of Duloxetine varies from 22 L/ hour to 46 L/ hour
to the primary outcome, depressive relapse prevention, (average 36 L/ hour).
measured as the time to relapse. Relapse incidence over the
After an oral dose, the apparent plasma clearance varies
six months, double blind, follow-up period, was 17% and from 33 L/ hour to 26 L/ hour (average 10 L/ hour).
29% for Duloxetine and placebo, respectively [16, 17].
Pharmacokinetic differences depend from:
The efficacy of Duloxetine 60 mg once a day in geriatric
depressed patients (
65 years) has been specifically verified Sex. Pharmacokinetic differences have been identified in
in a study that showed a statistically significant difference in women as compared to men (the apparent plasma clearance
the decrease of the 17 item HDRS total score in patients is about 50% lower in women). Due to the variability of the
treated with Duloxetine compared to those treated with pla- clearance, sex-related pharmacokinetic differences don’t
cebo. The tolerability of Duloxetine 60 mg once a day in old justify the general recommendation to use a lower dose in
patients is comparable to that observed in young adults. female patients.
Anyway, data on old patients treated with the maximal dose Age. Pharmacokinetic differences have been observed in
(120 mg a day) are limited, so caution is recommend in the young women as compared to old ones (
65 years) (in old
treatment of this patient population. patients, the AUC increases of about 25% and the half life is
In another double blind, randomized study, Duloxetine about 25% longer), although the range of these variations is
has been evaluated at the doses of 40 mg/day (20 mg twice a not enough to justify adjustments in the dose. As general
day) and of 80 mg/day (40 mg twice a day) versus placebo recommendation, we have to be cautious in the treatment of
and Fluoxetine 20 mg/day in depressed outpatients. Both old patients.
Duloxetine 80 mg/day (3,62 points; p=0.002), and Duloxet- Kidney insufficiency. Patients with terminal kidney dis-
ine 40mg/day (2,43 points; p=0.034) resulted superior to ease who undergo dialysis have Cmax and AUC values of
placebo in reducing the 17-item HDRS total score scale, Duloxetine twice higher than healthy persons. In patients
whereas Fluoxetine did not significantly differ from placebo with light or mild kidney insufficiency pharmacokinetic data
(1,51 points). Duloxetine 80 mg/day was superior to Fluoxet- about Duloxetine are limited.
ine on either the 17-item HDRS total score (2,39 points;
p=0.037) and remission rate (57% for Duloxetine versus Alterations of liver functionality. Mild liver disease (B
34% for Fluoxetine; p=0.022). class according to Child-Puhg classification) affects Du-
loxetine pharmacokinetic properties. In patients with appar-
The incidence of insomnia, a side effect, was higher with ent mild liver disease, plasmatic clearance is lower than
Duloxetine (19,8%) than Fluoxetine (8%) (p=0.031). 79%, terminal half-life is 2,3 times longer than in healthy
subjects. The pharmacokinetic of Duloxetine and its metabo-
3.2. Pharmacokinetic Properties
lites hasn’t been studied in patients with liver insufficiency
Duloxetine is administered as single enantiomer and is of mild or severe degree.
widely metabolized by enzymatic oxidative systems
(CYP1A2 and the polymorph CYP2D6), followed by conju- 3.3. Preclinical Safety Data
gation. Duloxetine pharmacokinetic shows a wide inter- Duloxetine has not shown genotoxic properties in a series
patient variability (generally 50-60%), in part due to sex, of standard tests and has not displayed carcinogenic activity
age, smoking and CYP2D6 metabolic activity. in the rat. In rat carcinogenic studies, multi-nucleated cells
Duloxetine is well absorbed after oral administration with have been observed in the liver in absence of other histopa-
a Cmax reached 6 hours after the ingestion; its oral bioavail- thologic modifications. The mechanism of these effects and
ability ranges from 32% to 80% (average 50%). Food slows their clinical relevance are unknown. Female mice receiving
from 6 to 10 hours the time to reach the maximum concen- Duloxetine for 2 years have presented an increased incidence
tration and decreases marginally the absorbed amount (about of adenomas and carcinomas in liver cells only with the
11%); but these variations have no clinical relevance. Du- highest dose (144 mg/kg/day).
loxetine is binded to human plasma proteins for about 96%, The relevance of these mouse data for man is unknown.
it binds to both albumin and -1-acid glycoprotein and this Female rats treated with Duloxetine (45 mg/kg/day) before
binding isn’t influenced by alterations of liver or kidney and after reproduction and during the early phases of preg-
functionality. nancy showed a decreased food consumption and body
Duloxetine is largely metabolized and its metabolites are weight, an interruption of the oestrus cycle, a decrease in
eliminated mainly in the urine. Both CYP450-2D6 and 1A2 vitality indexes of the new born and a reduced survival and a
catalyze the synthesis of the two main metabolites, the glu- late growth of the off-spring for levels of systemic exposi-
coronide conjugated 4-hydroxy-Duloxetine and the sulphate- tion retained to be almost equal to the levels of maximal
conjugated 5-hydroxy-6-methoxy-Duloxetine. In vitro stud- clinical exposure.
ies suggest that, circulating Duloxetine metabolites are In a theratogenic study in the rabbit, higher incidence of
pharmacologically inactived. Duloxetine pharmacokinetic in cardiovascular and bone malformations has been observed
patients with a reduced metabolic activity of CYP2D6 has for levels of systemic exposure below the maximal clinical
not been studied specifically. Limited data suggest that in exposure. In another study performed to test a higher dose of
these patients plasma levels of Duloxetine are higher. The a different salt formulation of Duloxetine, no malformation
half-life of Duloxetine elimination ranges from 8 to 17 hours has been observed. In prenatal and postnatal studies of toxic-
Duloxetine in the Treatment of Depression Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 3 181

ity in the rat, Duloxetine induced behavioral adverse effects with caution in patients treated with other drugs, which have
in the offspring for levels of systemic exposure below the the potential to induce hepatic damage.
maximal clinical exposure.
3.5. Interactions with Other Drugs
3.4. Particular Warnings and Use Cautions
CNS drugs. Caution is recommended when Duloxetine
Use in children and teenagers. Duloxetine must not be is assumed with other drugs and other substances that act
used in the treatment of children and teenagers. Suicide- centrally, including alcohol and sedative drugs (for example,
related behaviors (suicide attempts and suicide thoughts) and benzodiazepines, morphine-like substances antipsychotics,
hostile behaviors (especially aggressiveness, menace and Phenobarbital, antihistaminic sedatives).
anger) have been observed more frequently in clinical stud-
Serotonin syndrome. In rare cases, in patients who as-
ies in children and teenagers treated with antidepressant
sume SSRI in association with serotonergic drugs the sero-
drugs as compared to those treated with placebo. Anyway, if,
tonin syndrome has been reported. This is characterized by
on the base of clinical needs, the decision to treat is taken,
tremors, hyperthermia, collapse and death too. Therefore,
patients must be carefully monitored for the emerging of
caution is recommended if Duloxetine is used in combina-
suicide symptoms [18]. Furthermore in children and teenag- tion with serotonin antidepressant drugs as SSRI, tricyclics
ers there are no data about long term safety with respect to
as Clomipramine or Amitriptiline, Saint John’s worth (hy-
growth, maturity and cognitive and behavioral development.
pericum perforatum), Venlafaxine or triplanes, tramadole,
Mania and convulsions. Duloxetine must be used care- petidine and tryptophan.
fully in patients with a long history of mania or a diagnosis
Monoamine oxydase inhibitors (MAOI). Because of
of bipolar disorder and/or convulsions. the risk to develop serotonin syndrome, Duloxetine must not
Mydriasis. Mydriasis has been reported in association be used in association with non selective and irreversible
with Duloxetine, therefore it must be used carefully in pa- MAOI, and over 14 days after the discontinuation of a
tients with increased intra-ocular pressure, or in those at risk MAOI treatment. Based on Duloxetine halflife, we must wait
of acute closed corner glaucoma. at least 5 days after its suspension before starting treatment
Blood pressure. In some patients, Duloxetine use has with MAOI.
been associated with an increase of blood pressure. This ef- CYP1A2 inhibitors. Since CYP1A2 is involved in the
fect is essentially linked to the noradrenergic action of the metabolism of Duloxetine, it is likely that the use of Du-
drug. Therefore, in patients with an established hypertension loxetine in combination with potent CYP1A2 inhibitors
and/or other heart pathology an adequate monitoring of leads to higher Duloxetine concentrations. Therefore, Du-
blood pressure, especially during the first month of treat- loxetine must not be administrated in association with potent
ment, is recommended CYP1A2 inhibitors.
Suicide. Because improvement doesn’t occur during the CYP1A2 inductors. Population pharmacokinetic studies
first weeks of treatment, patients must be strictly controlled showed that smokers display plasma concentrations of Du-
until that improvement is observed. It is a general clinical loxetine almost 50% lower than non-smokers.
experience with all antidepressant therapies that suicide risk
can increase during the first phases of the recovery. During 3.6. Pregnancy and Feeding
treatment with Duloxetine or immediately after its discon- Pregnancy. There are no data about the use of Duloxet-
tinuation, cases with suicide thoughts and behaviors have ine in pregnant women. Studies performed in animals
been reported. A strict supervision of patients with high sui- showed teratogenic effects for exposure to systemic concen-
cide risk must accompany pharmacologic therapy [19]. trations of Duloxetine lower than clinical maximal exposure.
Coagulation alterations. With SSRI haemorrhagic skin Potential risk for humans is unknown. As other serotonin-
manifestations like bruises and purpura have been signaled. like drugs, withdrawal symptoms can occur in the baby after
Caution is recommended in patients treated with anticoagu- maternal use of Duloxetine before delivery. Duloxetine
lants and/or with drugs known to have effects on platelet should be used in pregnancy only if the potential benefit jus-
function as well as in patients with ascertained vulnerability tifies the potential risk for the foetus. Women have to be
to haemorrages. informed to refer to their physician the start of pregnancy or
the intention to start a pregnancy during the therapy.
Sucrose. Rigid gastroresistent capsules of Cymbalta con-
tain sucrose. Patients with rare hereditary problems of intol- Feeding. Duloxetine and/or its metabolites are eliminated
erance to fructose, or with malabsorption of glucose- in rat milk during breast-feeding. Behavioral adverse effects
galactose or with kidney insufficiency of saccarose- have been observed in the offspring in a study on pre- and
isomaltase enzyme cannot assume this drug. post-natal toxicity in rats. Duloxetine and/or its metabolites
elimination in human milk hasn’t studied. Its use during
Hepatitis. Cases of hepatic injuries, including marked
breast feeding is not recommended.
increases of hepatic enzyme values (>10 times above the
normal upper limit), hepatitis and jaundice have been re- 3.7. Effects on the Ability to Drive Cars and on Machines
ported with Duloxetine. The most of cases occurred during Use
the first months of treatment. The type of hepatic damage has
been essentially hepatocellular. Duloxetine must be used Although in controlled studies Duloxetine didn’t demon-
strate to alter psychomotor performance, cognitive functions
182 Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 3 Monteleone et al.

or memory, its assumption can be associated with a sedative in 1139 patients treated with Duloxetine and 777 patients
effect. Therefore, patients must be informed about Duloxet- treated with placebo during 8-week clinical studies on major
ine possible effects on their ability to drive cars and to use depressive disorder, and in 528 patients treated with Du-
dangerous machines. loxetine and 205 patients treated with placebo during 13-
weeks clinical studies on neuropathic diabetic pain. In Du-
3.8. Side Effects loxetine treated patients the QT interval was not different
In depressed patients treated with Duloxetine the most from that observed in placebo treated patients. Duloxetine
commonly reported adverse reactions have been nausea, treated patients did not differ from placebo treated ones in
mouth dryness and constipation. Anyway, the majority of the measures of QT, PR, QRS or QTcB.
common adverse reactions has been of light or mild inten- FDA (Food and Drug Administration) received different
sity, generally they started early during treatment and most reports of liver damage after treatment with Duloxetine. Re-
of them tended to resolve with prosecution of the therapy ports included abdominal pain, hepatomegaly and increase of
[20]. transaminase levels with or without jaundice. Cholestatic
In patients with diabetic neuropathic pain treated with jaundice with minimal increase of transaminase levels has
Duloxetine the most commonly reported adverse reactions also been reported.
have been: nausea, sleepiness, dizziness, constipation and Duloxetine may also aggravate a subthreshold hepatic
fatigue. disease. The risk/benefit ratio of Duloxetine use in patients
The abrupt discontinuation of Duloxetine treatment is assuming alcohol, or who present a chronic hepatic disease
commonly followed by withdrawal symptoms. The most or have evidence of hepatic insufficiency has to be evaluated
commonly reported reactions are dizziness, sensitive disor- carefully.
ders (including parestesy), sleep disorders (including insom- Signs and symptoms of hepatic damage are: itch, dark
nia and vivid dreams), agitation or anxiety, nausea and/or urines, jaundice, pain at palpation at the level of the right
vomit, tremors and headache. hypocondrium, or presence of unexplained flu-like symp-
Generally, these symptoms are of variable intensity rang- toms.
ing from light to mild severity; anyway, in some patients
3.9. Overdose
they can be very intense. Usually, these symptoms appear in
the first days after treatment discontinuation, but there have There is limited clinical experience concerning Duloxet-
been very rare reports of such symptoms in patients who ine overdose in man. In marketing clinical studies, cases of
involuntarily forgotten to take a single dose. Generally these letal overdose with Duloxetine have not been reported.
symptoms are self-sustained and usually resolved within two A specific antidote for Duloxetine is unknown. It is rec-
weeks, even if in some patients they can last longer (2-3
ommended to monitor vital and heart signs, together with
months or more). Therefore, it is advisable to gradually re-
appropriate symptomatic measures of support.
duce Duloxetine over a period not shorter than two weeks
before the full discontinuation of the treatment according to Duloxetine has a wide volume of distribution and it is
patient’s needs. unlikely that forced diuresis, blood perfusion and exchange
perfusion may be of benefit.
In clinical studies, treatment with Duloxetine has been
associated with increased level of ALT, AST, alkaline phos- Today depression is a social problem. Physical exam
phatase and creatinine phosphokynase numerically signifi- made by a physician is the first step to start an appropriate
cant but not clinically relevant; transient abnormal values of treatment.
these enzymes have been infrequently observed in patients Some drugs as well as some medical conditions, may
treated with Duloxetine, versus those treated with placebo. cause depression-like symptoms; thus physicians, through an
Duloxetine influence on urethral resistance it’s known. In accurate clinical assessment, a clinical interview and labora-
clinical studies controlled with placebo, the difficulty to start tory analyses, should exclude these possibilities. Once or-
to urine has been rarely (<1%) reported in males. If during ganic causes have been excluded, a psychological assess-
treatment with Duloxetine symptoms related to difficulty to ment by psychiatrist or a psychologist should be done in or-
urine, appear, the possibility that these symptoms could be der to start soon an antidepressant therapy, choosing at first
related to the drug should be taken into consideration. In the best drug for the patient and for the type of depression.
clinical studies with Duloxetine in patients with diabetic neu- Treatment has to be continued until the full remission of
ropathy, a light but statistically significant increase of blood depressive symptoms, followed by a maintenance period (2-
glucose has been observed in patients treated with Duloxet- 3 months) and then gradually reduced till discontinuation.
ine as compared to patients treated with placebo at 12 and 52
weeks. The increase was similar at both observation times A key role is played by patient’s relatives and friends. In
and it was not judged clinically relevant. As compared to fact, they should provide a moral and emotional support.
placebo or routine treatment, mean values of HbA1c were The patient’s feeling should not be undervalued and his
stable, no increase in mean body weight was observed, mean comments about suicide thoughts should be not neglected
concentrations of lipids (cholesterol, LDL, HDL, triglyc- and the participation to previously pleasant activities such as
erids) were stable, and no differences were observed in the hobbies, sport, religion and cultural activities should be en-
incidence of severe and not severe diabetes related adverse couraged without ever forcing the patient to do too much or
reactions. Electrocardiographic assessments have been made too soon. The depressed subject needs recreations and
Duloxetine in the Treatment of Depression Central Nervous System Agents in Medicinal Chemistry, 2011, Vol. 11, No. 3 183

friends, but too many requests could generate feelings of [2] Almási, J.; Rihmer, Z. Review of antidepressants from the TCAs to
failure and ineffectiveness. Also psychotherapeutic interven- the third generation drugs, Neuropsychopharmacol. Hung., 2004,
6(4), 185-194.
tions and in particular, cognitive-behavioral therapy (CBT), [3] Dell'Osso, B.; Nestadt, G.; Allen, A.; Hollander, E. Serotonin-
that has been shown to be extremely efficacious in the treat- norepinephrine reuptake inhibitors in the treatment of obsessive-
ment of depression, are very important. compulsive disorder: A critical review. J. Clin. Psychiatry, 2006,
67(4), 600-610.
CBT is a discipline whose efficacy has been proved by [4] Stahl, S.M.; Grady, M.M.; Moret, C.; Briley, M. SNRIs: their
several clinical studies and, as suggested by the name, it pharmacology, clinical efficacy, and tolerability in comparison
combines behavioral and cognitive psychotherapy. Behav- with other classes of antidepressants.CNS Spectr., 2005, 10(9),
732-747.
ioral psychotherapy helps the patient to learn new strategies [5] Hunziker, M.E.; Suehs, B.T.; Bettinger, T.L.; Crismon, M.L. Du-
to cope with daily difficulties; cognitive psychotherapy helps loxetine hydrochloride: a new dual-acting medication for the treat-
to identify negative recurrent thoughts, to correct them and ment of major depressive disorder. Clin. Ther., 2005, 27(8), 1126-
to integrate them with others more objective and functional 1243.
to the individual wellbeing. It differ from other types of in- [6] Mallinckrodt, C.H.; Prakash, A.; Andorn, A.C.; Watkin, J.G.;
Wohlreich, M.M. Duloxetine for the treatment of major depressive
tervention as psychoanalysis, because it is based on the pre- disorder: a closer look at efficacy and safety data across the ap-
sent life and aims to suggest practical solutions, giving less proved dose range. J. Psychiatr. Res., 2006, 40(4), 337-348.
weight to what happened in the childhood or to how much [7] Norman, T.R. Prospects for the treatment of depression. Aust. N. Z.
past events could influence the present. This therapy has J. Psychiatry, 2006, 40(5), 394-401.
[8] Bauer, M.; Möller, H.J.; Schneider, E. Duloxetine: a new selective
been shown to be very effective in the prevention of relapses, and dual-acting antidepressant. Expert Opin. Pharmacother., 2006,
which are extremely frequent in major depression. Because 7(4), 421-417.
of the demonstration that one year after antidepressant with- [9] Cobb, C.; Crichlow, R. Duloexetine (Cymbalta) for treatment of
drawal half of the patients relapse in the disease, psychia- major depressive disorder. Am. Fam. Physician, 2005, 72(6), 1099-
trists are used to make prescriptions for longer and longer 1101.
[10] Lee, S.I.; Keltner, N.L. Biological perspectives. Serotonin and
periods, also if the percentage of relapses is the same inde- norepinephrine reuptake inhibitors (SNRIs): venlafaxine and du-
pendently from the duration of pharmacological treatment. loxetine. Perspect. Psychiatr. Care, 2006, 42(2), 144-148.
[11] Vis, P.M.; van Baardewijk, M.; Einarson, T.R. Duloxetine and
It seems likely that combined treatment of drugs and psy- venlafaxine-XR in the treatment of major depressive disorder: a
chotherapy, represents actually the most effective cure to get meta-analysis of randomized clinical trials. Ann. Pharmacother.,
recovery from depression and to offer a patient a new and 2005, 39 (11), 1798-1807.
different way to cope with life problems. In fact, from the [12] Crippa, J.A.; Zuardi, A.W. Duloxetine in the treatment of panic
disorder. Int. J. Neuropsychopharmacol., 2006, 9(5), 633-644.
Toronto Rotman Research Institute came brain images ob- [13] Takano, A.; Suzuki, K.; Kosaka, J.; Ota, M.; Nozaki, S.; Ikoma, Y.;
tained by PET (positrons emission tomography), showing Tanada, S.; Suhara, T. A dose-finding study of duloxetine based on
that psychotherapy and drugs have different mode of actions. serotonin transporter occupancy. Psychopharmacology (Berl).
Both therapies have effects on brain structures modulating 2006, 185(3), 395-399.
the functioning of some brain regions, but they follow two [14] Bailey, R.K; Mallinckrodt, C.H.; Wohlreich, M.M.; Watkin, J.G.;
Plewes, J.M. Duloxetine in the treatment of major depressive dis-
opposite ways. Drugs modify the biochemical equilibrium of order: comparisons of safety and efficacy. J. Natl. Med. Assoc.,
neurotransmitters in brain areas involved in the regulation of 2006, 98(3), 437-447.
emotions, psychotherapy instead changes the way in which a [15] Hirschfeld, R.M.; Mallinckrodt, C.; Lee, T.C.; Detke, M.J. Time
person interprets stimuli coming from the external world. course of depression-symptom improvement during treatment with
duloxetine. Depress Anxiety, 2005, 21(4), 170-177.
But research goes on, and from the University of Pitts- [16] Delgado, P.L.; Brannan, S.K.; Mallinckrodt, C.H.; Tran, P.V.;
burg comes the notice of the individuation of 19 chromoso- McNamara, R.K.; Wang, F.; Watkin, J.G.; Detke, M.J. Sexual
functioning assessed in 4 double-blind placebo- and paroxetine-
mal regions that could be involved in the pathogenesis of controlled trials of duloxetine for major depressive disorder. J.
depression. The comprehension of the genetic bases of the Clin. Psychiatry, 2005, 66(6), 686-692.
disease could open the way, in the future, to individualized [17] Perahia, D.G.; Kajdasz, D.K.; Walker, D.J.; Raskin, J.; Tylee, A.
therapies: a tailored treatment for each patient, without pro- Duloxetine 60 mg once daily in the treatment of milder major de-
ceeding by attempts as it happens today. pressive disorder. Int. J. Clin. Pract., 2006, 60(5), 613-620.
[18] Lenzer, J. FDA accepts weakened antidepressant warning. BMJ,
2005, 330, 620-625.
REFERENCES [19] Deneys, M.L.; Ahearn, E.P. Exacerbation of PTSD symptoms with
use of duloxetine. J. Clin. Psychiatry., 2006 67(3), 496-497.
[1] Neubauer, H.A.; Hansen, C.G.; Wiborg, O. Dissection of an allos-
[20] Wernicke, J.F.; Gahimer, J.; Yalcin, I.; Wulster-Radcliffe, M.;
teric mechanism on the serotonin transporter: a cross-species study. Viktrup, L. Safety and adverse event profile of duloxetine. Expert
Mol. Pharmacol., 2006, 69(4), 1242-1250.
Opin. Drug Saf., 2005, 4(6), 987-993.

Received: June 13, 2011 Revised: July 19, 2011 Accepted: July 22, 2011