Dialogues in Clinical Neuroscience

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Core symptoms of major depressive disorder:

relevance to diagnosis and treatment

Sidney H. Kennedy

To cite this article: Sidney H. Kennedy (2008) Core symptoms of major depressive disorder:
relevance to diagnosis and treatment, Dialogues in Clinical Neuroscience, 10:3, 271-277, DOI:
10.31887/DCNS.2008.10.3/shkennedy

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State of the art
Core symptoms of major depressive disorder:
relevance to diagnosis and treatment
Sidney H. Kennedy, MD, FRCPC

Core and associated symptoms within the

diagnosis of major depressive disorder

T he current polythetic approach to diagnostic clas-

sification of “Major Depressive Disorder (MDD)” in the
Diagnostic and Statistical Manual of Mental Disorders. 4th
ed. (DSM-IV)1 or “Recurrent Depressive Episodes” in
The construct of major depressive disorder makes no eti- The ICD-10 Classification of Mental and Behavioral
ological assumptions about populations with diverse Disorders: Clinical descriptions and diagnostic guidelines.
symptom clusters. “Depressed mood” and “loss of inter- (ICD-10)2 is devoid of implications about etiopathology
est or pleasure in nearly all activities” are core features of or treatment response. Only “depressed mood” (mood)
a major depressive episode, though a strong case can be or “loss of interest or pleasure in nearly all activities”
made to pay increasing attention to symptoms of fatigue, (anhedonia) are considered to be essential requirements
sleep disturbance, anxiety, and neurocognitive and sexual for the diagnosis of a Major Depressive Episode (MDE)
dysfunction in the diagnosis and evaluation of treatment in DSM-IV. When these two “core symptoms” were used
outcome. Mood, guilt, work, and interest, as well as psy- to screen for MDD using a 2-item version of the Patient
chic anxiety, are consistently identified across validated Health Questionnaire (PHQ-2), they displayed a sensi-
subscales of the Hamilton Depression Rating Scale as tivity of 83% and a specificity of 92% for “caseness”
prevalent and sensitive to change with existing treat- based on a Structured Clinical Interview for DSM-IV
ments. A major limitation of these antidepressant thera- (SCID)3 and comparable results were obtained in a sub-
pies is their narrow spectrum of action. While the core sequent European replication.4
“mood and interest” symptoms have been the main focus Confirmatory diagnosis of an MDE, according to DSM-
of attention, the associated symptoms listed above are IV, requires a minimum of five symptoms (at least one
often unaffected or exacerbated by current treatments.
Careful clinical evaluation should address all of these Keywords: major depressive disorder; anxiety; sleep; fatigue; cognitive symptom
dimensions, recognizing that improvement may occur
sooner in some symptoms (eg, mood) compared with oth- Author affiliations: Department of Psychiatry, University Health Network,
University of Toronto, Ontario, Canada
ers (eg, sleep disturbance).
© 2008, LLS SAS Dialogues Clin Neurosci. 2008;10:271-277. Address for correspondence: Sidney Kennedy, MD, FRCPC, Department of
Psychiatry, University Health Network, University of Toronto, 200 Elizabeth
Street, 8EN-222, Toronto, Ontario M5G 2C4, Canada
(e-mail: [email protected])

Copyright © 2008 LLS SAS. All rights reserved 271 www.dialogues-cns.org

State of the art
Selected abbreviations and acronyms Major depressive episode subtypes
MDD Major Depressive Disorder
HAM-D Hamilton Rating Scale for Depression Specifiers may be added to imply greater homogeneity
MDE Major Depressive Episode within a subpopulation. For example, “with melancholic
DSM Diagnostic and Statistical Manual of Mental features” requires at least three of the following symp-
Disorders toms: complete loss of pleasure, lack of reactivity, psy-
ICD International Classification of Diseases chomotor retardation, significant weight loss, excessive
guilt, or distinct quality of depressed mood. Some authors
being mood or anhedonia) for a minimum of 2 weeks (see have emphasized the presence of psychomotor retarda-
Table I for DSM-IV). It is easy to see how the multiple tion as a core feature of melancholic depression.5 The
permutations and combinations of these symptoms con- presence of “atypical features” requires two or more of
tribute to substantial intraclass heterogeneity. the following symptoms: overeating/weight gain, hyper-
somnia, leaden paralysis, preservation of mood reactivity,
or interpersonal rejection sensitivity. These latter two
Five (or more) of the following symptoms have been present symptoms (preservation of mood reactivity and interper-
during the same 2-week period and represent a change from sonal rejection sensitivity) have been criticized on the
previous functioning; at least one of the symptoms is either: basis of poor reliability, and some authors have recom-
(1) Depressed mood or mended that only the reverse vegetative symptoms,
(2) Loss of interest or pleasure hypersomnia, and overeating as well as leaden paralysis
Note: Do not include symptoms that are clearly due to a general form the core of atypical depression.6
medical condition, or mood-incongruent delusions or There have been attempts to dichotomize these two
hallucinations. depression subtypes on both treatment responsiveness
(1) Depressed mood most of the day, nearly every day, as indicated and psychobiology. Historically, tricyclic antidepressants
by either subjective report (eg, feels sad or empty) or observation and electroconvulsive therapy were recommended for the
made by others (eg, appears tearful). Note: In children and melancholic patient,7 while patients with atypical features
adolescents, can be irritable mood appeared to respond better to classical monoamine oxi-
(2) Markedly diminished interest or pleasure in all, or almost all,
dase inhibitors8,9 than to tricyclic antidepressants. These
activities most of the day, nearly every day (as indicated by either
distinctions have been less apparent with the current gen-
subjective account or observation made by others)
eration of selective serotonin reuptake inhibitor (SSRI)
(3) Significant weight loss when not dieting or weight gain (eg,
and serotonin-norepinephrine reuptake inhibitors (SNRI)
a change of more than 5% of body weight in a month), or
antidepressants, and no currently available antidepressant
decrease or increase in appetite nearly every day.
carries a specific indication for either melancholic or atyp-
Note: In children, consider failure to make expected weight gains
ical symptoms. In fact, Parker’s group recently acknowl-
(4) Insomnia or hypersomnia nearly every day
edged that symptom profiles within the “melancholia”
(5) Psychomotor agitation or retardation nearly every day
population may vary with age. Hypersomnia was noted to
(observable by others, not merely subjective feelings of restlessness
be more common in the younger age group, while late
or being slowed down)
insomnia became the dominant sleep disturbance of older
(6) Fatigue or loss of energy nearly every day
patients.10
(7) Feelings of worthlessness or excessive or inappropriate guilt
(which may be delusional) nearly every day (not merely s
Evidence of core symptoms from rating scales
elf-reproach or guilt about being sick)
(8) Diminished ability to think or concentrate, or indecisiveness,
It is common to evaluate the severity of a depressive
nearly every day (either by subjective account or as observed by
episode using classic rating scales, particularly the
others)
Hamilton Rating Scale for Depression (HAMD-17)11 or
(9) Recurrent thoughts of death (not just fear of dying), recurrent
the Montgomery Asberg Depression Rating Scale
suicidal ideation without a specific plan, or a suicide attempt or
(MADRS).12 Differences in medication type and in the
a specific plan for committing suicide
symptom profiles of the population being evaluated may
Table I. DSM-IV criteria for Major Depressive Episode. influence outcomes on a rating scale. Among individual

272
Core symptoms of major depressive disorder - Kennedy Dialogues in Clinical Neuroscience - Vol 10 . No. 3 . 2008

items, the core “depressed mood” item on either the of depressed patients meet criteria for a comorbid anxi-
HAMD-17 or the MADRS was more sensitive to drug- ety disorder.19,20 This lack of syndrome independence on
placebo separation and to establishing optimal dosing, Axis I is a major limitation to the current concept of
compared with the full scales in several controlled tri- comorbidity. Comorbid disorders should only exist at a
als.13,14 level expected by chance, yet in the case of MDD, comor-
The sensitivity of some items to differentiate between bidity is the rule and not the exception.21
active drug and placebo can be compromised when a drug A recent proposal for mood and anxiety spectrum disor-
has an unfavorable effect on certain items. For example, ders, to be considered in DSM-V, has been advanced by
increased anxiety may occur during the early weeks of Watson22 who proposes three subclasses of emotional dis-
SSRI therapy, and activating antidepressants may disrupt orders: “bipolar disorders,” “distress disorders,” (MDD,
some aspects of sleep.15 The net result is that prevalent dysthymic disorder, generalized anxiety disorder, and
items may not emerge on rating scales that are designed post-traumatic stress disorder) and “fear disorders” (panic
to detect improvements during antidepressant therapy. disorder, agoraphobia, social phobia and specific phobia).
When symptom prevalence and sensitivity to change have This reflects a pendulum swing to the unitary position of
been evaluated in large data sets using item analysis or Mapother23 and Lewis24 who viewed states of anxiety
factor analysis, several core symptoms emerge with along a continuum with depressive disorders, in contrast
greater sensitivity to change and less distortion by treat- to the progressive separation of mood and anxiety disor-
ment emergent side effects than with the full versions of ders initiated more than three decades ago.25,26 It is likely
the scale. that the inconsistent impact of some antidepressants on
Three such scales derived from the HAMD-17 are the anxiety has distorted measurement of anxiety symptoms
“Bech 6,”16 “Maier subscale,”17 and “HAMD-7”18 (Table during treatment.
II). Four items are common to each of these scales: mood, What is less in dispute is the impact of anxiety comorbid-
guilt, anhedonia, and psychic anxiety. In HAMD-7 and ity on response to the treatment of depression. Patients
Bech 6, loss of energy (fatigue) was also present, as was without anxiety symptoms at the time of remission are sig-
psychomotor retardation in Bech 6 and Maier 6, while the nificantly more likely to remain well than those patients
HAMD-7 included somatic anxiety and suicidal ideation. with residual anxiety.27 There is also consistent evidence of
All three scales include anxiety symptoms, in contrast to lower response rates and higher relapse in comorbidly
current diagnostic systems. anxious depressed patients.Although there is a strong jus-
tification to consider “anxious depression” as a depressive
The prominence of anxiety symptoms subtype,28 a case can be made to maintain the separation
and syndromes of Generalized Anxiety Disorder (GAD) from MDD.29

Surprisingly, anxiety is not considered as a core or associ- Sleep disturbance, apathy, and fatigue
ated symptom of depression according to either DSM-IV
or ICD-10 criteria. Neither is “with anxious features” a Sleep disturbance
specifier within DSM-IV, yet up to 90% of patients have
co-occurring anxiety symptoms, and approximately 50% The relationship between sleep and depression is com-
plex. Insomnia is a frequent symptom of depression, and
MAIER-6 HAMD-7 BECH-6 there is evidence to suggest that sleep disturbances are
Mood Mood Mood often a prodrome to a MDE.30 Paradoxically, sleep depri-
Guilt Guilt Guilt vation has been advocated as an antidepressant therapy31
Work and interest Work and interest Work and interest while several antidepressant agents actually worsen
Psychic anxiety Psychic anxiety Psychic anxiety sleep.15 Sleep disturbance also lends itself to objective
Agitation Energy Energy evaluation through polysomnography. Disturbances in the
Retardation Somatic anxiety Retardation ratio of rapid eye movement (REM) sleep to non-REM
Suicide sleep, decreased slow-wave sleep, and impaired sleep con-
Table II. Core symptoms from three scales derived from the Hamilton tinuity are among the most robust markers for MDD.
Depression Rating Scale. Whether reductions in slow-wave sleep and REM latency

273
State of the art
are trait or state abnormalities is a controversial issue,32 etine it is less likely to have been a treatment-emergent
and attempts to establish robust diagnostic electroen- adverse event. The persistence of insomnia is a particular
cephalographic markers for MDD have been confounded concern, given the propensity for residual sleep distur-
by the effects of age and gender.33 bance to predict relapse.36
Among the symptoms of depression, sleep disturbance is Persistent sleep disturbances in SSRI “responders”
a prominent symptom that is frequently unresponsive to include prolonged sleep latency (beyond 1 hour), reduced
current antidepressants, or is overtreated with consequent total sleep time, and multiple awakenings. Although
daytime somnolence. In a family practice evaluation of coprescription of a hypnotic may have a beneficial effect,37
physician diagnosis and patient self-report of depressive concerns about long-term hypnotic use limit this recom-
symptoms, “insomnia or hypersomnia” along with mendation. Elsewhere, advantages beyond sleep restora-
“depressed mood” were the symptoms most frequently tion were demonstrated when eszopiclone and fluoxetine
elicited by physicians, although only “suicidal ideation” were combined in the acute treatment of MDD.38 Given
and “insomnia or hypersomnia” were associated with a the role of sleep disruption in predicting relapse, there is
statistically significant likelihood of depression diagno- a strong argument to consider sleep disturbance as a core
sis.34 Middle (71%), early (62%), and late (55%) insom- symptom in depression, and to emphasize the importance
nia were frequently reported items from the HAMD-17 of sleep restoration early in the treatment of an MDE.
in a sample of almost 300 depressed clinic patients.18 The daytime effects of persistent sleep disruption should
However, underscoring the limited effectiveness of cur- not be underestimated in depressed patients.
rent antidepressants to improve sleep, none of these three
sleep items were among the seven with greatest sensitiv- Fatigue and apathy
ity to change during treatment (Table III). In fact, middle
insomnia emerged as the eighth most sensitive item to Particularly in primary care settings, depressed patients
reflect antidepressant change.18 are likely to present with complaints of exhaustion or
inability to carry out physical or mental work. In fact,
Symptom from Percent endorsement Change score fatigue was the commonest depressive symptom in a sur-
HAMD-17 Cohen’s d vey of family practice settings.39 In the large European col-
M F All laborative study of almost 2000 depressed patients across
Work & interest 99 98 99 1.84 6 countries (DEPRES II), 73% of patients “felt tired”;
Depressed mood 98 98 98 1.81 this symptom was associated with severity of the episode
Anxiety-somatic 86 92 90 1.03 and was more prevalent in women.40 Although “fatigue or
Suicide 77 72 73 0.88 loss of energy nearly every day” is not considered an
Energy 98 94 95 0.88 essential depressive symptom according to DSM-IV, it is
Guilt 86 85 85 0.86 emphasized within the atypical symptom cluster, with
Anxiety-psychaitric 59 90 79 0.83 “leaden paralysis” as the extreme variant. However,
reduced energy is considered a “core feature” in the def-
Table III. HAMD-7: A brief measure of remission. HAMD, Hamilton
Rating Scale for Depression inition of depressive episode according to ICD-10,
Adapted from ref 20: McIntyre R, Kennedy S, Bagby RM, et al. Assessing emphasizing that marked tiredness may occur after only
full remission. J Psychiatry Neurosci. 2002;27:235-239. Copyright © slight effort.41 It is a reasonable assumption that sleep dis-
Canadian Medical Association 2002
turbance and daytime fatigue are related (as previously
The importance of sleep disturbance as a residual symp- reviewed—over 40% of remitters to fluoxetine had sleep
tom in MDD has also been highlighted by Nierenberg disturbance and just under 40% had fatigue), although
and colleagues,35 who examined threshold and subthresh- there are no data to confirm this relationship.
old symptoms among patients who achieved remission Similarly, apathy may overlap with diminished interest,
(HAMD-17″ 7) after 8 weeks of antidepressant treatment loss of energy, and even indecisiveness, but this construct
with fluoxetine. The three most prevalent residual symp- is too nonspecific to be considered a core symptom. In
toms were disturbances in sleep (44%), fatigue (38%), fact, apathy has been reported more frequently as a side
and anhedonia (27%). Since the majority of these patients effect in up to 20% of patients who receive SSRI antide-
reported sleep disturbance prior to treatment with fluox- pressants.42

274
Core symptoms of major depressive disorder - Kennedy Dialogues in Clinical Neuroscience - Vol 10 . No. 3 . 2008

Cognitive dysfunction Nevertheless, low libido may contribute to deteriorating

interpersonal/marital relations and further exacerbate
Subjective neurocognitive disturbance in depression is depression. In the case of SSRI antidepressants, up to
represented by “diminished ability to think or concen- 60% of patients report treatment-emergent sexual func-
trate” in DSM-IV, although broader neurocognitive dis- tion.55,56 Antidepressants that do not stimulate serotonin
turbances can be measured using standardized neu- release are less likely to induce or exacerbate sexual dys-
ropsychological test batteries. Neuropsychological deficits function.53,57,58 This has implications for treatment adher-
have most often been detected in older individuals and ence, as sexual dysfunction remains one of the common-
include disturbances in psychomotor speed,43 memory,44 est reasons for treatment discontinuation.53
verbal fluency,45 attention,45 executive function,45 and pro-
cessing speed.48 Whether restoration of cognitive function Future directions
occurs with symptom remission in MDD has been a topic
of considerable interest in recent years. Mostly in elderly Both DSM-IV and ICD-10 represent descriptive systems
patients, the data suggest enduring deficits in both mem- of classification. With DSM-V in mind, several authors
ory and executive function.49 Links between recurrent have advocated a role for phenotypic characteristics,
depressive episodes, reduced hippocampal volume and genetic data, as well as cognitive or other biological mark-
memory deficits have also been reported.50 Although it is ers.59,60 Endophenotypes reflect the gap between the gene
premature to endorse any specific neurocognitive deficit and the expression of the disease process. In depression,
as a core symptom of depression, residual memory dis- putative biological candidates include disruptions in cir-
turbance has major implications for functional recovery cadian rhythm, immune function, neurotransmitter-recep-
and deserves ongoing attention in clinical management. tor signaling pathways, and neuroendocrine axes, as well
as brain structure and function. Studies exploring the
Sexual dysfunction influence of gene-environment interactions (involving
polymorphisms of the serotonin transporter) on symptom
Sexual dysfunction is also a complex issue among patients presentation and treatment response in depression have
with depression. Common complaints include reduction in attracted considerable attention.59,60 Reduction in hip-
desire or libido, diminished arousal, a decline in the fre- pocampal volume has been consistently reported in
quency of intercourse, or an undesirable delay in achieving MDD63 and linked to duration of untreated depression,64
orgasm. The prevalence of sexual dysfunction in the com- as well as deficits in neurocognition.50 There are also pre-
munity is high;51 it is even higher in untreated depressed liminary reports on potential markers for treatment resis-
patients52 and may be further exacerbated by antidepres- tance. Lower serotonin transporter binding in the mid-
sants.53 In a large European study designed to evaluate sex- brain, medulla, and anterior cingulate cortex was
ual function in both treated and untreated depressed associated with nonremission,65 while hypermetabolism in
patients, more than two thirds of men and women reported the ventral anterior cingulate area brain region was a pre-
decreased libido and the prevalence increased with sever- dictor of nonresponse to both cognitive therapy and ven-
ity and duration of the depressive episode.54 lafaxine.66 Though provocative, these interesting findings
The reluctance among many patients to spontaneously are unlikely to influence diagnostic or treatment selection
report sexual dysfunction as a disturbing symptom of practices in the near future. In the meantime, a re-exam-
depression has resulted in a relatively low and misleading ination of core symptoms in depressed patients and care-
prevalence rate. The true importance of sexual dysfunc- ful clinical attention to their response to disparate anti-
tion as a depressive symptom has not been recognized depressant strategies will remain the cornerstone of good
either in diagnosis or during antidepressant therapy. clinical practice. ❏

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275
State of the art
Síntomas centrales del trastorno depresivo Symptômes essentiels des troubles
mayor: relevancia para el diagnóstico y el dépressifs majeurs : importance pour le
tratamiento diagnostic et le traitement

El constructo trastorno depresivo mayor no asume La constitution des troubles dépressifs majeurs ne
etiologías para las poblaciones con diversas agru- présuppose pas d’origine étiologique chez des
paciones sintomáticas. El “ánimo depresivo” y la patients aux symptômes variés. « L’humeur dépres-
“pérdida de interés o placer en casi todas las acti- sive » et « la perte d’intérêt ou de plaisir dans
vidades” son características centrales de un episo- presque toutes les activités » sont des critères essen-
dio depresivo mayor, aunque han existido buenos tiels d’un épisode dépressif majeur, bien qu’il y ait
argumentos para prestar atención creciente a sín- beaucoup à dire sur l’intérêt croissant que suscitent
tomas como fatiga, alteraciones del sueño, ansie- les symptômes de fatigue, les perturbations du som-
dad, y disfunciones neurocognitivas y sexuales para meil, l’anxiété et les dysfonctions sexuelles et cogni-
el diagnóstico y la evaluación de los resultados del tives dans le diagnostic et l’évaluation du traite-
tratamiento. El ánimo, la culpa, el trabajo y el inte- ment. Des sous-échelles validées de l’HAMD
rés como también la ansiedad psíquica son identi- (Hamilton Depression Rating Scale) montrent régu-
ficados consistentemente a través de subescalas lièrement que l’humeur, la culpabilité, le travail et
validadas de la escala de depresión de Hamilton l’intérêt comme l’anxiété psychique sont des symp-
como prevalentes y sensibles de cambiar con los tra- tômes prévalents et susceptibles de variations avec
tamientos disponibles. Una limitación importante les traitements existants. Ces traitements antidé-
de estas terapias antidepresivas es su limitado presseurs sont très limités par leur spectre d’action
espectro de acción. Mientras que los síntomas cen- étroit. Alors que l’attention s’est majoritairement
trales “ánimo e interés” han sido el principal foco focalisée sur les symptômes majeurs « humeur et
de atención, los síntomas asociados antes señalados intérêt », les symptômes associés cités ci-dessus sont
a menudo no son afectados o exacerbados por los souvent inchangés ou exacerbés par les traitements
tratamientos actuales. La evaluación clínica debe actuels. Toutes ces questions devraient faire l’objet
ser cuidadosa y orientarse a todas estas dimensio- d’une évaluation clinique soigneuse, certains symp-
nes, reconociendo que la mejoría puede ocurrir más tômes (par ex, l’humeur) pouvant être améliorés
rápido en algunos síntomas (como el ánimo) en avant d’autres (par ex, troubles du sommeil).
comparación con otros (como las alteraciones del
sueño).

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277
IDI-1270
Mental Illnesses Article
Topic Major depressive disorder
Stephenie Esther Aybar Peguero Matrícula:100671831 Sec:02
final conclusion
Core symptoms of major depressive disorder: relevance to diagnosis and treatment

Nowadays it is unquestionable that the large number of patients who come to the clinic
doctors suffer from some type of mental illness or underlying mental disorder. About All
patients with symptoms associated with major depressive disorder. The loss of interest
inactivities, a low mood, sleep disturbances, persistent fatigue or Anxiety are central
symptoms of a major depressive disorder that naturally involves a diagnosis and a clinical
evaluation for a possible treatment. Clinical evaluation must necessarily contain these
symptoms that are requirements essential for a diagnosis. Requiring at least a minimum of
five symptoms during approximately 2 weeks.

In major depressive disorder there are also subtypes of episodes that generate a better
classification, guaranteeing better treatment. One of these characteristics is "melancholy"
whose central symptoms are excessive weight loss, loss of interest or psychomotor
retardation. Both patients with these symptoms and those with atypical characteristics have
been treated with antidepressants and inhibitors, however none are specific for each case.
Although it seems surprising, Anxiety is not considered a subtype or episode of major
depression by DSM-IV or ICD despite Anxiety being one of the most common symptoms in
major depressive disorder, and there is also a high rate that indicates that comorbidly anxious
depressed patients tend to relapse more

Sleep disorders, apathy and fatigue even using the Hamilton Depression Rating Scales
(HAMD-17) or the Montgomery Asberg Depression Rating Scale (MADRS) help in
prescribing better treatments during therapy, continuing its relationship with MDD and its
possible treatment is complex. Sleep loss and fatigue are central symptoms of depression that,
accompanied by cognitive dysfunction or sexual dysfunction, affect the real life of patients.
Actually, every day there are more studies and research on this topic and the search for more
effective methods, better therapies and less harmful medications, all in order to obtain better
results for patients and ensure good mental health.
Reference

Sidney H. Kennedy (2008) Core symptoms of major depressive disorder:

relevance to diagnosis and treatment, Dialogues in Clinical Neuroscience, 10:3, 271-277, DOI:
10.31887/DCNS.2008.10.3/shkennedy
https://www.tandfonline.com/doi/epdf/10.31887/DCNS.2008.10.3/shkennedy?needAccess=true