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T O P I C R E V I E W

The relationships between depression and brain tumors

N. Scott Litofsky Æ Andrew G. Resnick

Received: 14 October 2008 / Accepted: 23 February 2009 / Published online: 5 March 2009

� Springer Science+Business Media, LLC. 2009

Abstract Depression is a common complication/

co-morbidity in patients with brain tumors. Better under-

standing of the relationships between brain tumors and

depression should lead to improvement in patient care. This

paper reviews these relationships in order to direct further

study to improve patient care, and hopefully, outcome. Both

anatomic and physiological perturbations in the brain are

likely involved in the associations between depression and

brain tumors. Tumor treatments are also associated with

depression. Depression has a significant negative impact on

outcome in brain tumor patients. The role of treatment of

depression in brain tumor patients has been scantly studied.

Further investigation directed to these areas of knowledge

deficit should benefit depressed patients with brain tumors.

Keywords Depression � Brain tumors � Anatomy � Neuro-oncology � Incidence � Review

Introduction

Brain tumors may be accompanied by a number of

co-morbidities. While brain tumors may directly affect

patients’ cognition, mobility, communication, perception,

and other neurological functions, these co-morbidities may

also significantly effect patients’ quality of life. Among

these other co-morbidities—which include deep venous

thrombosis, infections, seizures, and adverse drug reac-

tions—depression is the most common [1]. Despite the

frequent presence of depression in patients with brain

tumors, the relationships between these two disease pro-

cesses remain incompletely studied and understood.

The objective of the paper is to create better under-

standing of the issue of depression in the population of

patients with brain tumors. This objective is significant

because depression is such a common co-morbidity

or complication in patients with brain tumors. Neurosur-

geons, neurologists, neuro-oncologists, medical oncolo-

gists, radiation oncologists, and other physicians and

health care professionals who treat patients with brain

tumors must be more vigilant with regard to assessment

of their patients for the possibility of depression. Psy-

chiatrists also need to be aware of these issues when they

are asked to consult on these patients. Many of the

characteristics of brain tumors—tumor size, location, and

histopathology—are explored for their impact on depres-

sion in these patients. Methodologies for making the

diagnosis of depression and the subsequent defined inci-

dence of depression in patients with brain tumors are also

discussed. The effect of depression on survival and other

outcome measures, such as quality of life, are reviewed.

Issues related to treatment of depression in this chal-

lenging group of patients receive scrutiny. Lastly,

questions for additional study are posed. Hopefully,

identifying the most significant features of the relation-

ships between brain tumors and depression will stimulate

additional research to answer many of the remaining

questions, particularly with regard to the optimal treat-

ment and efficacy of such treatments.

N. S. Litofsky (&) Division of Neurological Surgery, University of Missouri-

Columbia School of Medicine, One Hospital Drive, N502,

Columbia, MO 65212, USA

e-mail: [email protected]

A. G. Resnick

Department of Psychiatry, University of Missouri-Columbia

School of Medicine, Columbia, MO, USA

123

J Neurooncol (2009) 94:153–161

DOI 10.1007/s11060-009-9825-4

Symptoms of depression

Brain tumor patients who are depressed may have a variety

of symptoms in addition their neurological deficits. They

may have dysphoric mood, helplessness, worthlessness,

guilt, loss of self-esteem, concentration difficulties and

suicidal ideation [2]. Many of these symptoms are the same

criteria used in the DSM-IV to make a diagnosis of

depression [3]. A consideration key to making the diag-

nosis of depression is to distinguish it from apathy. In

depression, patients tend to feel an emotional pain, while in

apathy they feel a lack of feeling, emotion, interest or

concern [4]. This distinction is especially important in

determining the incidence of depression, as well deter-

mining what types of treatments should best be considered.

Patients with brain tumor patients may initially present

with psychiatric symptoms. In addition to depression, these

symptoms may include personality change, abulia, apathy,

either auditory or visual hallucinations, mania, panic

attacks and amnesia [5]. These symptoms may be indis-

tinguishable from such symptoms in psychiatric patients

without brain tumors. Obviously, the presence of any one

of these particular symptoms does not mean that a psy-

chiatric patient has a brain tumor. Other clues may be

present. Psychiatric symptoms developing after the age of

40 should increase the index of suspicion for the presence

of a brain tumor. Neurological symptoms or signs, head-

ache, seizure, and memory loss in concert with psychiatric

symptoms suggest the possibility that a brain tumor or

structural brain mass is present. A change in the patient’s

symptoms from his/her usual psychiatric symptoms also is

suggestive of the possibility of a brain tumor. Patients who

respond poorly to treatment and those with an absence of a

family history of psychiatric illness should raise concerns

for a brain tumor. Any of these unusual features of psy-

chiatric disease warrant investigation with neurodiagnostic

imaging [5–7], preferably magnetic resonance imaging

(MRI) of the brain without and with contrast; computed

tomography (CT) scan without and with contrast is a sat-

isfactory substitute if MRI is unavailable.

Suicide ideation and/or death by suicide are important

and common symptoms in psychiatric patients with

depression. In patients with brain tumors, however, these

particular symptoms have not been well quantified. In other

medical illnesses with associated depression, patients are

much less likely to have suicidal thoughts and commit

suicide than psychiatric depression patients; the suicide

rate was only 10% medically ill depressed patient sample

versus a 45% suicide rate in a psychiatrically ill group [8].

Suicide appears to be an uncommon cause of death of

patients with most types of brain tumors (personal expe-

rience). Methodological difficulties have prevented

investigators from concluding that suicide is increased in

brain tumor patients compared to the general population

[9]. On the other hand, however, pituitary tumors were

found in autopsies of 47.7% of suicide patients compared

to 18.3% of patients who died from non-suicidal causes,

suggesting the pituitary tumors may be a risk factor for

suicide [10].

Mechanisms of depression

The reasons why depression occurs in brain tumor patients

are not well understood. A number of mechanisms may

contribute to the development of depression. Reactions of

the patient to the cancer diagnosis may contribute. Patients

experience shock and disbelief, dysphoria, despair, anger

and anxiety, impaired concentration, impaired activities of

daily living, and intrusive thoughts about their diagnoses

[11]. These issues may cause an adjustment disorder to the

situation rather than primary depression. Adjustment dis-

orders, if persistent, can then go on to become a bona fide

major depressive episode [12, 13]. On the other hand,

awareness of prognosis was not associated mood disorders

in one study examining this relationship [14]. A number of

co-morbid psychosocial problems are also present. Patients

experience a sense of helplessness, hopelessness, and loss.

They worry about existential issues, that they are going to

die, and what is going to happen as they leave their loved

ones. They have decreasing levels of social and occupa-

tional functioning. Patients become withdrawn and reduce

interaction with others. Fatigue and cognitive deficits also

play a role. Steroids, used in treatment of cerebral edema,

may also be a factor [15], as will be discussed in more

detail below. Anatomic factors likely also play a role, as is

also discussed below.

Evaluation and determination of depression

The gold-standard evaluation method of evaluating a

patient with a brain tumor suspected of having depression

is for a psychiatrist to see the patient and apply DSM-IV

criteria to make the diagnosis. Such an evaluation is not

always possible. Many patients refuse psychiatric evalua-

tion. Patients frequently deny that they may be depressed;

they claim that they are just dealing with a bad situation.

Therefore, other physicians may need to be able to make a

diagnosis of depression on many occasions; DSM-IV

criteria are the preferable methodology.

A variety of questionnaires or other self-assessment

tools have been developed to assist in the determination of

depression or to quantify depression and quality of life. The

SF-36, primarily a quality of life scale, is frequently used in

many medical disorders, including brain tumors [1, 16].

154 J Neurooncol (2009) 94:153–161

123

The patient answers 36 questions related to the patient’s

feelings, functioning, and sense of well-being, among other

issues. A mental health scale is contained within the overall

score—it has been used to make a determination of

depression [17]. The form must be scored with some

interpretation. Some authors have suggested asking a

number of questions as a screening test [18]. The numerical

values on the Self-rating Depression Scale suggest a

diagnosis of depression [19]. Probably the most commonly

used scales in the literature include the Hospital Anxiety

and Depression Scale (HADS) [16, 20–24] and the Beck

Depression Inventory [4, 15, 25–27]. Recently, Armstrong,

et al. have developed the M.D. Anderson Symptom

Inventory Brain Tumor Module (MDASI-BT), a self-

reporting scale which includes assessment of affective

symptoms, in addition to others; this scale has been vali-

dated to be able to follow symptoms such as depression

throughout the course of the patient’s disease, and assess

the impact of these symptoms on patient’s quality of life

[28]. Many other scales (Table 1) have also been used to

varying degrees.

Incidence of depression in brain tumor patients

The incidence of depression in patients with brain tumors

has been reported with a large range, depending on the

study and the methodology used. In some studies, the

incidence has been fairly low, less than 10% [19, 29]. In

other studies, as many as 50% of patients [30–32] and

perhaps over 80% of patients [1, 20, 33] with brain tumors

may be depressed. Unfortunately, the studies reporting the

incidence of depression have used a hodge-podge of

methods to determine the presence of depression. Some

studies have grouped different tumor types together [4, 15,

19]; others have focused on a single tumor type [27, 29,

31]. The true incidence of depression in brain tumor

patients, therefore, is uncertain.

The Glioma Outcomes Project was one of the largest

studies to look at the incidence of depression in brain tumor

patients, specifically focused on high-grade glioma. The

Glioma Outcomes Project was North American multi-

center (51 sites) observational cohort study. Seven hundred

eighty-eight total patients were enrolled; data from 578

patients were analyzed for depression-related issues. The

database was designed to look at practice patterns of

physicians in the care with patients with high-grade glioma.

One of the questions being investigated was depression and

the use of anti-depressant medications. Data was collected

prospectively as the patients were recruited into the data-

base. Physicians used DSM-IV criteria as part of their

evaluation process and completed questionnaires. Patients

self-reported their symptoms on their own questionnaires

and answered the filled out the SF-36. One definition of

depression used was a mental health score on the SF-36 of

61 or less; this score had been validated in patients with

other illnesses as being consistent with depression. Patients

were also asked three specific questions, which have also

been used in other studies. The patient was supposed to

respond yes or not to ‘‘I have been sad for 2 weeks or

more,’’ ‘‘I have been sad for much of the year,’’ or ‘‘I feel

sad.’’ Patients were assessed post operatively and at every

3-month intervals for up to 24 months. In the post opera-

tive evaluation, physicians diagnosed depression about

15% of the time, whereas patients self-reported depression

much more frequently. Over time, at 3 months and

6 months, the incidence of physician diagnosed depression

increased to about 22%; over 90% of patients self-reported

symptoms of depression using SF-36 mental health scores

less than 61. Using the three questions, the incidence was

not quite as high (about 70%) but still exceeded physician-

reported incidence [1].

Depression may pre-exist the diagnosis of the brain

tumor, so a percentage of patients being treated for

depression will subsequently be diagnosed with a brain

tumor. This brain tumor incidence in patients with

depression is poorly described. Benson [34] reported that

1–4% of mentally ill patients were found to have brain

tumors on autopsy. A South African study found that 27

out of 200 (13.5%) of patients hospitalized in psychiatric

institutions have brain tumors [35]. Numerous anecdotal

reports of patients with psychiatric illnesses harboring

brain tumors have been published [5, 36–40], but these

Table 1 Evaluation methods for determining depression in brain tumor patients

Instrument Reference

DSM-IV [31]

SF-36 (\61 on Mental health scale) [1] Self-rating depression scale (C50) [19]

Hospital anxiety and depression scale

Unknown cut-off [20, 22]

C13 [16, 21]

C10 [23, 24]

Functional living index-cancer [19, 52]

Hamilton rating scale [12, 46]

Beck depression inventory ([10) [4, 25–27, 43] Profiles of mood—Short form (B50) [31, 33, 52]

Edmonton symptom assessment scale [50]

Freiburg questionnaire of coping [48]

Mood assessment scale ([11) [27] Primary care evaluation of mental disorders [32]

Focused questions [1]

J Neurooncol (2009) 94:153–161 155

123

reports add little to understanding how often brain tumors

are present in depressed patients.

Impact of depression on clinical outcomes

Depression may have a significant impact on survival in

patients with brain tumors. In low-grade glioma patients,

survival is shorter if patients are depressed [4]. In glio-

blastoma patients participating in clinical trials, depression

was not associated with shorter progression-free survival; if

the mental health scores declined, however, then survival

also declined [41]. In the Glioma Outcomes Project, glio-

blastoma patients with depression had shorter survival,

34 weeks median if depressed compared to 41 weeks if not

depressed [1]. High-grade glioma patients with a pre-

operative diagnosis of depression (defined by taking anti-

depressant medications had a significantly reduced survival

[42]; At 12 months, 15% of depressed patients were alive

compared to 41% of non-depressed patients, and no

depressed patients survived 20 months, while 21% of non-

depressed patients were still alive.

Depression is also associated with patients’ clinical

status. The Karnofsky Performance Score (KPS) is fre-

quently used in brain tumor patients to measure functional

performance. Some studies have shown that performance is

not influenced by depression independent of age [30].

Other studies have shown that a poorer performance status

is associated with a greater incidence of depression;

depression is present in 50% of patients with KPS less than

or equal to 70, while only 14% of patients with KPS greater

than 70 are depressed [4]. In the Glioma Outcomes Project,

depression was associated with both worse neurological

function and lower performance status [1]. Whether the

relationship is causative or an epiphenomenon can not

really be determined at this point.

The Glioma Outcomes Project data also examined the

association of depression on complications. Patients diag-

nosed by physicians with depression had significantly more

other medical complications such as deep venous throm-

bosis, seizure, systemic infection, and adverse drug

reactions. Post-operative intracerebral hemorrhage was

more common in depressed patients, though not to a sta-

tistically significant level [1]. Again, cause and effect data

are lacking.

Depression can also have an impact on interpersonal

relationships of patients with brain tumors. Married brain

tumor patients are more likely to have problems with

depression. They are also more likely to have problems

with depression if they had previous negative life events.

Factors influencing depression are different in married than

in single patients with brain tumors. Those who are married

experience difficulties with their sexual relationships,

inactivity, and finances; marital difficulties themselves do

not appear to be a major issue. Single patients, on the other

hand, are more concerned with bodily deterioration, cog-

nitive difficulties, finances, reduction of social activity [2].

A number of studies have shown that depression is the

major factor reducing quality of life in patients with brain

tumors [15, 20, 25]. Other studies indicate that while

depression may not be the major factor reducing quality of

life, it is an important factor [30, 43].

Recent work has examined the importance clustering of

symptoms together in brain tumor patients, such as

depression, fatigue, sleep disturbance, cognitive impair-

ment and pain. With further study, these symptom clusters

may be shown to affect treatment response, quality of life,

and overall survival in patients with brain tumors, as they

have been shown to do in patients with other cancers [44].

For instance, in a study of symptom clusters in long-term

surviving glioma patients, Fox, et al. found that depression,

fatigue, sleep disturbance, and cognitive impairment are

significantly intercorrelated. Depression is responsible for

26% of the variance in patient quality of life and for 56%

of the variance in patient functional status, exhibiting a far

greater impact on these outcomes than other symptoms in

the cluster [20]. Biological mechanisms, such as tumor

location, elevated intracranial pressure, and biochemical

changes may underlie the pathogenesis of these symptom

clusters [44].

Impact of tumor location on depression

Tumor location appears to have a relationship to depres-

sion. Anterior frontal tumors may be related to symptoms

of depression. Dorsolateral tumors may cause difficulties

with organization and planning. Orbito-frontal tumors may

cause disinhibition and medial frontal tumors may cause

apathy and abulia [7, 11, 31]. For instance, patients with

large planum sphenoidale meningiomas become so apa-

thetic that they stop doing their regular chores. The patient

frequently complains that his/her previous excellent

housekeeper skills have deteriorated; over a few years he/

she has stopped being so meticulous. Once the tumor is

removed, the patient’s housekeeping improved. Personality

change may also be observed with frontal tumors [7].

Diencephalic and pituitary lesions may be associated with

vegetative symptoms [11]. Diencephalic lesions are also

thought to be associated with hypersomnic hyperphagic

variants of depressive disorders [38]. Frontal, temporal and

diencephalic lesions can cause depression with delusions,

hallucinations, mania and catatonia [40]. Temporo-limbic

lesions are often associated with auditory and visual

hallucinations, panic attacks and amnesia [7]. Left hemi-

spheric lesions seem to be more associated with depression

156 J Neurooncol (2009) 94:153–161

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than right hemispheric lesions, but this relationship may be

more related to verbal impairment and communication

difficulties than actually being causative of depression [23,

45, 46]. Other studies, including the Glioma Outcome

Project, found that tumor location did not really impact the

incidence of depression [1, 15, 41].

Multi-focal tumor sites and tumors greater than 4 cm in

diameter, however, do have a relationship to increased

incidence of depression [1]. How these factors affect

depression is not completely characterized at this point.

One possibility is that cortical interconnections to limbic

structures may be more important than location [4].

Tumors with multiple foci or larger size may be more

likely to disrupt limbic interconnections by infiltration or

mass effect. Frontal or limbic deficits or disinhibition

related to disconnection of various areas may occur. Het-

eromodal ventral frontal and temporo-parietal association

cortical interconnections to limbic areas are felt to be

particular important in the development of affective dis-

orders [46]. Another possibility is that tumors may exert

effects on the hypothalamic-pituitary-adrenal axis. Tumors

may change biochemical levels locally in the brain. Fatty

acids and phospholipid metabolism may be affected.

Serotonergic systems near tumor sites may also be altered

[26]. More work needs to be done to sort out these factors.

Impact of tumor type on depression

The incidence of depression may vary depending on the

type of tumor that a patient has. Pituitary tumors are fre-

quently associated with depression. In patients with

Cushing’s Disease from adreno-cortico-tropin (ACTH)

secreting pituitary tumors, (or hypercortisolemia from

other causes), the incidence of depression is about 63% of

patients [47]. Symptoms may include lethargy, sleepiness,

cyclic mood instability, cognitive deficits (in the form of

memory and concentration difficulties), and personality

change [48]. When cortisol levels drop towards normal as a

result of treatment, depression improves [47]. Acromegaly,

or gigantism, from excessive growth hormone secretion, is

associated with depression about 75% of cases. These

patients often have personality change, anger, decreased

willingness to socialize, and desire for seclusion [48].

Hyperprolactinemia is associated more with anxiety rather

than depression. Depression does not appear to factor

determining quality of life in this group of patients, how-

ever [21, 48].

Hormonal hyperfunction may not be the only significant

factor. Craniopharyngioma, which is located in the same

general location as pituitary tumors, is not associated with

hormonal hyperfunction; these tumors do not seem to have

an increased incidence of depression compared to normal

controls unless visual impairment is also present [16]. Two

different factors may be involved in determining these

relationships. The first is that visual impairment, being a

physical disability, may be associated with more adjust-

ment-types of difficulties. The second issue that a

craniopharyngioma associated with visual impairment is

probably a larger tumor with a greater likelihood of com-

pressing hypothalamic and other diencephalic structures to

a greater degree. Spence, et al. [38] felt that such dience-

phalic compromise was the key anatomic issue in tumors in

this location. The proximity of the diencephalon to limbic

structures and interconnections should not be forgotten.

With pituitary tumors, patients’ symptoms require the

differentiation of depression from ‘‘fatigue and apathy

syndrome’’ and from the secondary effects of hormone

dysfunction. Many depressive symptoms may be related to

fatigue and the overlapping constructs may confuse the

diagnosis. One important reason to distinguish between the

entities is that fatigue and hormonal dysfunction generally

do not respond to antidepressant medications [48]. If the

patient’s problem is really apathy and fatigue and not

depression, then treatment with antidepressants is probably

not best; other medications need to be instituted. If the

symptoms are related to hormonal dysfunction—either

from hyposecretion of thyroid stimulating hormone (TSH)

causing hypothyroidism, or hyposecretion of ACTH caus-

ing hypocortisolemia, or hypersecretion as discussed

above, then hormonal replacement or surgical correction of

the endocrinopathy is needed.

Several anatomic relationships are involved in fatigue

and apathy. Neoplasms can affect patients’ attention control.

Frontal anatomic areas are involved in selecting competing

stimuli. Posterior parietal areas are involved in shifting focus

spatially to the various stimuli and the reticular formation is

involved with maintaining alertness and wakefulness. Other

structures that are involved with fatigue and apathy include

the medial dorsal nucleus of the thalamus, the caudate

nucleus, nucleus accumbens and the globus pallidus. The

involvement of these structures suggests that there is a

cortical-striatal-thalamic-cortical circuit involved. The

pituitary gland provides afferents to the medial-dorsal

thalamus; therefore the fatigue and apathy syndrome occurs

in patients with large pituitary tumors [48].

Hormonal effects, particular in Cushing’s Disease, are

associated with cerebral atrophy and decreased hippo-

campal volume. Increasing cortisol levels cause decreased

dopamine synthesis and turnover in the nucleus accum-

bens, further linking it to the anatomic pathways that have

been identified with fatigue [22]. Because norepinephrine

systems are linked to attention, one of the medications

shown to be helpful in patients who have apathy and fati-

gue syndrome is methylphenidate, which helps with

increasing concentration [48].

J Neurooncol (2009) 94:153–161 157

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Meningiomas are also associated with a high incidence

of depression. Pringle [23] suggested that the more com-

mon female gender in meningioma patients caused

increased depression relative to other tumor types. Mainio

[2] also found a higher incidence of depression in menin-

gioma patients (29.8%) relative to low-grade glioma

(20.8%), high-grade glioma (19.5%), vestibular schwan-

noma (15.6%) and other tumor types; gender was not

defined as a factor. However, female patients did have

worse quality of life than male patients, and depression was

the major factor involved in that reduced quality of life

[25].

High-grade gliomas are also associated with depression

fairly frequently, ranging from about 8% to over 50% of

patients [1, 15, 19, 23, 29–32, 49]. When patient self-

reporting methodologies are used, even more patients are

noted to have depression [1, 31]. Among tumor types,

depressive coping is most commonly observed in high-

grade tumors. Patients often pity themselves and withdraw

from others [50]. These depressive coping strategies in

patients with brain tumors may not differ from such coping

in other neurological disorders, such as multiple sclerosis

and stroke.

Risk factors for depression in glioma patients have been

identified. One risk factor is a history of depression prior to

the brain tumor diagnosis [4, 32]. A family psychiatric

history is also a risk factor [31]. Pre-operative screening is

helpful to elucidate these facts. Unfortunately, patients do

not always share this information with their physicians.

Additional risk factors include female gender, less than

high school education, and pre-existing medical conditions

[32].

Impact of tumor treatments on depression

Tumor treatments also affect depression. Some studies

have shown that extent of surgery has no relationship to

depression [15, 23]. Others have shown that less depression

occurs with gross total resection of tumor [4]. Quality of

life also improves with gross total resection [41]. In the

Glioma Outcomes Project, patients were more likely to be

depressed if the patient had a stereotactic biopsy instead of

a gross total resection [1]. Depression improved after sur-

gical resection [23]. Several factors may be involved with

this relationship. Aggressive surgery may decompress

tumor that is disrupting or compromising limbic pathways

that are involved. Those pathways may function better after

surgery. Patients who have had only a stereotactic biopsy

may have more of a sense of hopelessness than if they had

been offered an aggressive operation. Another explanation

is that stereotactic biopsies are reserved for tumors that are

in difficult-to-resect locations. These are locations that are

in proximity to limbic structures, and hence, are more

likely to be associated with depression.

Radiation therapy, which is an important part of treat-

ment of patients with brain tumors, does not to appear to

have an affect on depression in either primary brain tumors

[1, 51] or metastases [52]. It also does not appear to have a

negative impact on quality of life [53, 54].

Probably the major brain tumor treatment associated

with depression is glucocorticosteroids, used to reduce

cerebral edema. Patients who are on glucocorticosteroids

often will have dysphoria with negative or nihilistic

thoughts. They may have anxiety with psychomotor agi-

tation and racing thoughts [11, 31]. These features also

contribute to the depressive symptomatology. In the Gli-

oma Outcomes Project, steroid use immediately after

surgery and at 3 months was not associated to depression,

but if steroids were used at 6 months, an increase in

depression was noted [1]. The exact mechanisms of ste-

roid-associated depressive symptoms are not understood.

Pies [55] stated that ‘‘steroid hormones affect the brain

though both indirect effects on gene transcription and

direct effects on neuronal membranes or receptors. It is

probable that steroid-mediated effects on enzymes such as

tyrosine hydroxylase and monoamine oxidase modulate

both normal and abnormal mood states.’’ Another possi-

bility relates to disruption of sleep cycles. Patients taking

glucocorticosteroid medications frequently have difficulties

with sleep. Disturbed sleep cycles contribute to the

depressive symptomatology.

Other treatments used in patients with brain tumors may

be associated with depression. These pharmacological

agents include alpha-interferon, phenabarbitol, Dilantin,

opioid analgesics, benzodiazepines and hypnotics [11].

Impact of treatment for depression

Treatment options for depression include psychotherapy

and pharmacotherapy. Data regarding either treatment

options is sparse. Treatment of diagnosed depression is

sometimes problematic in patients with brain tumors, just

like in patients with other medical conditions. About 5% of

patients with high-grade gliomas are treated with anti-

depressant medications prior to diagnosis of their tumors

[1, 42]. The timing of the initial prescription of the medi-

cations relative to the diagnosis of the tumor is unknown.

The Glioma Outcomes Project also examined the use of

antidepressant medications immediately postoperatively

and over time during the course of patients’ glioma care.

When physicians diagnosed depression in patients imme-

diately after surgery, the number of patients that were

treated pharmacologically for depression was significantly

discordant, with only about 50% of patients diagnosed with

158 J Neurooncol (2009) 94:153–161

123

depression receiving anti-depressant medications. How-

ever, the discordance improved over time, so that by

6 months after surgery, a much greater percentage of

depressed patients (about 75% of patients diagnosed

with depression) were receiving medications to treat their

depression [1]. In another study, only 26% of patients with

depression were treated with anti-depressant medication

[32]. This frequency increased to 55% if the patients also

suffered from concurrent anxiety.

The reasons why physicians are not treating brain tumor

patients with antidepressant medications is not certain.

Patients frequently refuse such medications. Patients may

not acknowledge that they are depressed in addition to

having a brain tumor. Physicians may be focused on

morbidities other than depression. Physicians may wish to

attempt other treatment options, particularly since the side-

effects of antidepressant medications on patients with brain

tumors are not well characterized. Numerous questions are

cause for concern. For instance, although almost all anti-

depressant medications may lower seizure threshold

[56, 57], which antidepressant medications would be least

likely to be associated with increased seizure activity in

this circumstance is not clearly defined. Another issue is

whether the usual side-effects of particular anti-depressant

medications are at risk for being magnified by the presence

of the brain tumor. Perhaps most importantly, the efficacy

of anti-depressant medications in this patient population is

unknown.

One of the major concerns which may need to be

addressed in a patient with depression who also has a brain

tumor is the safety of electroconvulsive therapy (ECT). A

number of physiologic effects occur during ECT. Blood

flow to the brain increases by 300%, glucose and oxygen

metabolism increases by 200%, vascular permeability

increases in concert with a temporary breakdown of the

blood-brain barrier. A small, asymptomatic brain mass

probably represents little risk to a patient receiving ECT

[58]. However, ECT is usually used in patients who are

either refractory to antidepressant medications or who

cannot tolerate their side effects. Treatment resistance is a

potential marker of a central nervous system tumor [5]. For

larger lesions, ECT is considered to be relatively contra-

indicated, as the physiological changes can be associated

with the development of elevated intracranial pressure and

subsequent adverse neurological consequences [58]. Vari-

ous pre-treatments of patients with brain tumors can

enhance patient safety. Frequently these interventions are

instituted in patients who have large central nervous system

neoplasms, regardless of the need for ECT. Glucocorti-

costeroids reduce vascular permeability and edema. Lasix

can reduce intracranial pressure via diuresis. Propranolol

can reduce blood pressure and heart rate elevations.

Hyperventilation reduces intracranial pressure by causing

vasoconstriction [59]. Additional considerations, such as

placing the electrodes unilaterally, usually contralateral to

the tumor, lowering the stimulus dose used to create the

convulsion, spacing treatments apart in time, and avoiding

or reducing anti-cholinergic medications enhance ECT

safety [58].

Conclusions

Many questions remain to be answered concerning the

relationships between depression and brain tumors. Further

study is clearly warranted. The best method for screening

brain tumor patients for depression remains to be defined.

Is the non-psychiatrist physician using DSM-IV criteria

satisfactory or should other instruments be used to assist

with making the diagnosis? One value of other instruments

is that the patient can complete these data forms and then

objective measures are available to follow over time. Many

neurosurgeons and other physicians do not routinely use

DSM-IV criteria and may not ask their patients questions

that would allow them to make the diagnosis. Screening

instruments may be an easier way for physicians dealing

with a brain tumor patient to address this issue. Does the

treatment of depression in brain tumor patients improve

survival? Some studies suggest that survival is diminished

if patients are depressed. But it is unknown if treating

depression actually leads to improvement and survival.

Similarly, does the treatment of depression in brain tumor

patients improve quality of life? Quality of life is altered by

depression, but it is unknown if treating that depression

improves quality of life. Does the treatment of depression

in brain tumor patients have harmful side effects? What is

the best treatment for depression in brain tumor patients?

Should psychotherapy be an important component of

therapy or should patients be treated primarily with phar-

macological therapy? Or is a combination of therapies

best?

Depression is common in patients with brain tumors.

The mechanisms of depression in brain tumors are not well

understood. A number of factors are probably involved.

Depression can have a significant negative impact on out-

come in brain tumor patients. The role of pharmacologic

therapy is unknown because few if any studies have been

done. With further study, these questions can be answered

and hopefully improve patient care and outcome.

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