Parkinson’s symptoms or depression? Look for clinical signs

Many depressive symptoms are seen in the normal course of Parkinson’s disease (PD) (Table 1).¹ As a result, depression—the most common neuropsychiatric disturbance in PD—is difficult to assess in PD and easily can go undetected and untreated.²

Making the diagnosis is important, however, because depression causes PD patients suffering and may accelerate decline in motor and cognitive function, activities of daily living, and quality of life.³ In the absence of specific guidelines (Box),⁴ we provide evidence to help you sort through the overlapping symptoms to find clinical signs that differentiate depression from PD symptoms.^5,6

Table 1

Symptoms of depression that occur in or mimic those in the natural course of PD

Psychomotor retardation (bradykinesia)
Depressed or emotionless appearance (‘masked facies,’ stooped posture)
Agitation (dyskinesias)
Decreased interest and enjoyment (apathy and decreased initiative)
Impaired memory and concentration
Fatigue or decreased energy
Impaired sleep
Weight and appetite changes
Physical complaints
Source: Adapted from reference 1

DSM-IV-TR depression criteria

Approximately 20% of PD patients meet DSM-IV-TR criteria for major depression, and another 20% meet criteria for dysthymia.⁵ By DSM-IV-TR criteria,⁶ diagnosis of a major depressive episode requires ≥5 of 9 symptoms, of which at least 1 is depressed mood or loss of interest or pleasure. Because these symptoms must be present during the same 2-week period and represent a change in functioning, this diagnosis has an acute quality.

Dysthymia—also frequently called “chronic depression”—is characterized by a mostly depressed mood for 2 years, accompanied by ≥2 of 6 symptoms: appetite changes, sleep changes, low energy/fatigue, low self-esteem, poor concentration/indecisiveness, and hopelessness.⁶

All of these depression symptoms may overlap with those of PD.

1 Mood. In mid-stage and late PD, mood often fluctuates in concert with daily periods of increased rigidity and tremor (“off” periods) interspersed with improved motor functioning (“on” periods).⁷ Thus, when evaluating the PD patient:

• take a detailed history of motor fluctuations and their associations with mood symptoms
  
• also evaluate mood during “on” periods.
  

2 Interest and pleasure. Differentiating decreased interest from apathy is one of the greatest challenges in diagnosing depression in PD. The neurologic symptom of apathy in PD includes 3 features:

• behavioral (lack of effort)
  
• cognitive (loss of interest/concern)
  
• affective (decreased emotional response or “flat” affect).
  

Some studies have described apathy as a common feature of PD that can occur independent of depression;⁸ others have associated apathy with cognitive impairment.⁹ Anhedonia also seems to be more common in PD patients than in matched controls, apparently independent of PD’s neurologic, frontal, and depressive aspects.¹⁰

3 Weight changes. Patients with PD tend to have lower body weight than matched subjects. As a result, weight loss in the course of PD can be confused with weight loss associated with depression.

Weight loss appears to start 2 to 4 years before a PD diagnosis and continues thereafter. Despite the weight loss, PD patients report higher energy intake after the diagnosis compared with individuals without PD.¹¹ A related, not necessarily contradictory finding is that a higher premorbid body mass index (BMI) seems to be associated with an increased risk of developing PD.¹²

In general, dopaminergic treatment of PD seems to be associated with weight loss.¹³ However, weight gain has been reported after pramipexole treatment, which the authors of the study attributed to limbic D3 receptor stimulation.¹⁴

4 Sleep and excessive daytime sleepiness. Sleep disturbances are very common in individuals with PD.¹⁵ A community study found that two-thirds of PD patients complained of sleep problems, with sleep fragmentation and early awakening being the most common complaints.¹⁶ Initial insomnia was less common, and a surprisingly high number of PD patients reported symptoms that suggested obstructive sleep apnea, periodic limb movements of sleep, and REM sleep behavior disorder.¹⁷

Excessive daytime sleepiness has been associated with PD and with the medications used to treat it. Give special consideration to diagnosing sleep attacks—abrupt, unavoidable transitions from wakefulness to sleep—which are reported in up to 30% of PD patients taking dopaminergic agonists. These attacks can occur during critical activities, such as driving,¹⁸ and likely are a class effect of dopamine replacement therapies.¹⁹

5 Psychomotor retardation as a core symptom of PD is clinically indistinguishable from that seen in severe depression.

6 Fatigue. Most studies of fatigue in PD do not define whether the term applies to prolonged mental exhaustion or lack of physical endurance. In any case, one-third to one-half of PD patients report fatigue, and many consider it one of the most disabling symptoms—worse in this regard than motor symptoms.²⁰ Fatigue is more than twice as common in PD patients as in healthy controls and is associated with depression, dementia, disease severity, disease duration, levodopa dose, and use of sleep medications.²¹

 

7 Feeling worthless/excessive or inappropriate guilt. DSM-IV-TR defines this symptom as not merely self-reproach or guilt about being sick.⁶ Guilt or self-blame seem to be less common in PD depression compared with dysphoria, pessimism, and somatic symptoms.²² Nonetheless, feelings of decreased self-worth are common in PD patients, especially as the illness limits work, productivity at home, and social activities.

8 Concentration and decision-making. PD patients show cognitive changes such as difficulty in changing tasks and impaired executive function (planning, sequencing, and executing). In tasks of divided attention—such as “multitasking”—PD patients have difficulty filtering out nonrelevant information.²³ Difficulties with memory, attention, and language also have been observed in PD and often are exacerbated by depression.²⁴ These cognitive changes affect PD patients’ ability to concentrate, maintain focus, and engage in effective decision making.²⁵

Attention problems in PD are compounded by dementia, which affects at least 20% to 40% of PD patients²⁶ and perhaps considerably more.²⁷

Box

9 Suicide in PD. Recurrent thoughts of death, suicidal ideation, a suicide attempt, or a specific plan for committing suicide are included in DSM-IV-TR criteria for depression.⁶ Thoughts of death also may be a common symptom in PD, although a large American study found that individuals with PD—despite their extremely high rates of depression—had a significantly lower risk of suicide than age-matched controls without PD.²⁸

Features of depression in PD

The specificity and clinical usefulness of individual depression symptoms in PD is variable. Some symptoms seem to be as common in nondepressed as in depressed PD patients (Table 2).²⁹

Distinguishing characteristics. Using Hamilton Depression Rating Scale (HAM-D) and Montgomery-Åsburg Depression Rating Scale items, a study of nondemented PD patients found the presence of suicidal thoughts to be the most reliable discriminator between depressed and nondepressed patients. Other symptoms with good discriminating reliability for depression in PD were (in descending order):

• feelings of guilt
  
• psychic anxiety
  
• reduced appetite
  
• depressed mood
  
• reduction of work and interest.
  

Somatic items—such as fatigue, somatic anxiety, weight loss, and early and middle insomnia—had the lowest discriminative properties.³⁰

Symptom profile. The most recent studies comparing depression symptoms in PD patients with those in non-PD populations seem to indicate:

• the profile of depression in PD is not different from that of other elderly depressed populations
  
• or PD patients show more cognitive symptoms, which is not surprising considering PD’s cognitive involvement.³¹
  

Keep in mind that if the same definition of depression is used in 2 different populations, the symptomatic profiles are likely to be the same.

Psychiatric comorbidities. A relatively high association with anxiety, cognitive impairment, and psychosis also complicates depression’s picture in PD.³² Often this relationship seems to be bidirectional, with the comorbidities increasing the risk for depression and vice versa.

Table 2

Frequency of depressive symptoms in PD

Effect	Symptoms
Significantly higher frequency in PD patients with depression	Worrying, brooding, loss of interest, hopelessness, suicidal tendencies, social withdrawal, self-depreciation, ideas of reference, anxiety symptoms, loss of appetite, initial and middle insomnia, loss of libido
No significant differences in frequency compared with PD patients without depression	Anergia, motor retardation, early morning awakening
PD: Parkinson’s disease
Source: Reference 29

Recommendations

As we have seen, depression’s somatic and cognitive symptoms and PD’s motor, somatic, and cognitive features overlap substantially. How, then, should clinicians handle symptoms that can be attributed to either depression or PD? Several approaches are possible (Table 3),³³ and each has strengths and weaknesses.

An exclusionary approach may be indicated for research, whereas an inclusive approach may be better suited to clinical settings. As mentioned, the National Institute of Neurological Disorders and Stroke/National Institute of Mental Health Work Group on Depression in Parkinson’s Disease⁴ supports an inclusive approach when evaluating depression symptoms. This group (Box) also recommends eliminating the DSM-IV-TR general exclusion criterion “due to the effects of a medical condition” applied to the diagnosis of depression.⁴

 

As we have seen, however, most DSM-IV-TR depressive symptoms overlap with PD symptoms. The false-positive results likely to occur with an inclusive definition of depression might discourage clinicians from screening PD patients for depression.

In clinical practice, finding recent changes in these overlapping symptoms might point to depression. Therefore, try to establish recent changes—associated with depression—in a PD patient’s somatic or cognitive symptoms, such as weight loss, lack of interest, impaired concentration, or decreased energy. This may be difficult, however, given:

• the subjective nature of many of these symptoms
  
• the decreased reporting ability of patients with cognitive deterioration
  
• medical comorbidities in PD that also could produce the referred symptoms.
  

For these reasons, in clinical practice perhaps the best way to detect depression in PD is by giving primacy to mood symptoms, with the option of using cognitive and somatic DSM-IV-TR symptoms when reliable and clear information is available. Some changes in the approach to specific depressive symptoms in PD also are probably worth considering:

1. Mood. Try to differentiate pervasive depressed mood from mood fluctuations associated with motor fluctuations and poorly controlled motor symptoms. Start with simple, open-ended questions and progress toward precise estimates.

Ask the patient about how often he or she feels sad or “down” and if these feelings are related to something specific or PD symptoms such as “freezing.” Depression rating scales such as the HAM-D and Geriatric Depression Rating scale, though useful for mass screening or research, have very limited clinical application.

2. Interest. Depressive loss of interest may be more acute and fluctuating than apathy. Also, selective loss of interest in some areas—such as social life, work, or hobbies—as opposed to the pervasive character of apathy, may suggest depression.

When evaluating interest in PD patients, consider that they may be avoiding activities that interest them out of fear that motor impairment may cause poor performance or social embarrassment.

3. Weight/appetite. Appetite may be a better indicator of depression than weight changes, as weight loss seems to be common in PD patients. Keep in mind, however, that the GI side effects of dopaminergic medications may limit what patients can eat.

4. Insomnia/hypersomnia. Insomnia associated with PD is usually characterized by sleep maintenance problems (middle insomnia or “broken” sleep). Thus, initial and terminal insomnia are probably better indicators of the presence of depression.

5. Agitation/retardation. Psychomotor retardation is common in PD, but acute exacerbations associated with depression may be noticed. Also note that depression-associated anxiety may exacerbate dyskinesias.

Table 3

4 options for diagnosing depression in PD patients

Approach	Definition	Comment
Inclusive	Count all depressive symptoms toward a depression diagnosis	Recommended by NINDS/NIMH Work Group on Depression in Parkinson’s Disease, but may result in overdiagnosis of depression in PD patients
Exclusive	Ignore any depressive symptoms that could otherwise be explained	May be indicated for research
Etiologic exclusive	Ignore symptoms that likely are the result of the medical illness	The NINDS/NIMH Work Group on Depression in Parkinson’s Disease recommends avoiding attributing symptoms to a particular cause
Substitutive	Replace the most confusing diagnostic features with others that are less controversial	Theoretically the best approach, but establishing this approach as evidence-based would require substantial research
PD: Parkinson’s disease; NINDS/NIMH: National Institute of Neurological Disorders and Stroke/National Institute of Mental Health
Source: References 4,33

6. Fatigue or loss of energy is a very difficult symptom to ascribe either to PD or depression unless they change acutely.

7. Worthlessness/guilt. PD is an incapacitating illness that causes work, family, and social dysfunction. To count as a depression criterion, worthlessness and guilty feelings need to be excessive or inappropriate and relatively constant and not merely self-reproach or guilt about being sick.

8. Diminished ability to think and concentrate is another a symptom that is difficult to ascribe to either depression or PD. A recent change in the context of mood symptoms might point to depression.

9. Recurrent thoughts of death. As mentioned, suicide seems to be less common in patients with PD than in the general population, but suicidal ideation—when found—is highly specific. Fear of dying from PD is not considered a depressive criterion, however.

Related resources

• Menza M, Marsh L, eds. Psychiatric issues in Parkinson’s disease: a practical guide. New York: Taylor and Francis; 2006.
  
• Marsh L, McDonald WM, Cummings J, et al. Provisional diagnostic criteria for depression in Parkinson’s disease: report of an NINDS/NIMH work group. Mov Disord 2006;21:148-58.
  
• Parkinson’s Disease Foundation: www.pdf.org.
  
• Michael J. Fox Foundation: www.michaeljfox.org.
  

 

Drug brand names

• Levodopa • Dopar, Larodopa
  
• Pramipexole • Mirapex
  

Disclosure

Dr. Marin reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Menza receives research support from the National Institutes of Health, Astra-Zeneca, Bristol-Myers Squibb, Cephalon, Forest Laboratories, GlaxoSmithKline, Janssen, Lilly, Merck, Pfizer, sanofi-aventis, Sepracor, Takeda, and Wyeth. He is a consultant for the National Institutes of Health, GlaxoSmithKline, Kyowa, Lilly Research Laboratories, Ono, Pfizer, Sepracor, and Takeda. He is a speaker for Bristol-Myers Squibb, Lilly Research Laboratories, Sepracor, sanofi-aventis, and Takeda.

Dr. Dobkin receives research grants from Takeda.

Many depressive symptoms are seen in the normal course of Parkinson’s disease (PD) (Table 1).¹ As a result, depression—the most common neuropsychiatric disturbance in PD—is difficult to assess in PD and easily can go undetected and untreated.²

Making the diagnosis is important, however, because depression causes PD patients suffering and may accelerate decline in motor and cognitive function, activities of daily living, and quality of life.³ In the absence of specific guidelines (Box),⁴ we provide evidence to help you sort through the overlapping symptoms to find clinical signs that differentiate depression from PD symptoms.^5,6

Table 1

Symptoms of depression that occur in or mimic those in the natural course of PD

Psychomotor retardation (bradykinesia)
Depressed or emotionless appearance (‘masked facies,’ stooped posture)
Agitation (dyskinesias)
Decreased interest and enjoyment (apathy and decreased initiative)
Impaired memory and concentration
Fatigue or decreased energy
Impaired sleep
Weight and appetite changes
Physical complaints
Source: Adapted from reference 1

DSM-IV-TR depression criteria

Approximately 20% of PD patients meet DSM-IV-TR criteria for major depression, and another 20% meet criteria for dysthymia.⁵ By DSM-IV-TR criteria,⁶ diagnosis of a major depressive episode requires ≥5 of 9 symptoms, of which at least 1 is depressed mood or loss of interest or pleasure. Because these symptoms must be present during the same 2-week period and represent a change in functioning, this diagnosis has an acute quality.

Dysthymia—also frequently called “chronic depression”—is characterized by a mostly depressed mood for 2 years, accompanied by ≥2 of 6 symptoms: appetite changes, sleep changes, low energy/fatigue, low self-esteem, poor concentration/indecisiveness, and hopelessness.⁶

All of these depression symptoms may overlap with those of PD.

1 Mood. In mid-stage and late PD, mood often fluctuates in concert with daily periods of increased rigidity and tremor (“off” periods) interspersed with improved motor functioning (“on” periods).⁷ Thus, when evaluating the PD patient:

• take a detailed history of motor fluctuations and their associations with mood symptoms
  
• also evaluate mood during “on” periods.
  

2 Interest and pleasure. Differentiating decreased interest from apathy is one of the greatest challenges in diagnosing depression in PD. The neurologic symptom of apathy in PD includes 3 features:

• behavioral (lack of effort)
  
• cognitive (loss of interest/concern)
  
• affective (decreased emotional response or “flat” affect).
  

Some studies have described apathy as a common feature of PD that can occur independent of depression;⁸ others have associated apathy with cognitive impairment.⁹ Anhedonia also seems to be more common in PD patients than in matched controls, apparently independent of PD’s neurologic, frontal, and depressive aspects.¹⁰

3 Weight changes. Patients with PD tend to have lower body weight than matched subjects. As a result, weight loss in the course of PD can be confused with weight loss associated with depression.

Weight loss appears to start 2 to 4 years before a PD diagnosis and continues thereafter. Despite the weight loss, PD patients report higher energy intake after the diagnosis compared with individuals without PD.¹¹ A related, not necessarily contradictory finding is that a higher premorbid body mass index (BMI) seems to be associated with an increased risk of developing PD.¹²

In general, dopaminergic treatment of PD seems to be associated with weight loss.¹³ However, weight gain has been reported after pramipexole treatment, which the authors of the study attributed to limbic D3 receptor stimulation.¹⁴

4 Sleep and excessive daytime sleepiness. Sleep disturbances are very common in individuals with PD.¹⁵ A community study found that two-thirds of PD patients complained of sleep problems, with sleep fragmentation and early awakening being the most common complaints.¹⁶ Initial insomnia was less common, and a surprisingly high number of PD patients reported symptoms that suggested obstructive sleep apnea, periodic limb movements of sleep, and REM sleep behavior disorder.¹⁷

Excessive daytime sleepiness has been associated with PD and with the medications used to treat it. Give special consideration to diagnosing sleep attacks—abrupt, unavoidable transitions from wakefulness to sleep—which are reported in up to 30% of PD patients taking dopaminergic agonists. These attacks can occur during critical activities, such as driving,¹⁸ and likely are a class effect of dopamine replacement therapies.¹⁹

5 Psychomotor retardation as a core symptom of PD is clinically indistinguishable from that seen in severe depression.

6 Fatigue. Most studies of fatigue in PD do not define whether the term applies to prolonged mental exhaustion or lack of physical endurance. In any case, one-third to one-half of PD patients report fatigue, and many consider it one of the most disabling symptoms—worse in this regard than motor symptoms.²⁰ Fatigue is more than twice as common in PD patients as in healthy controls and is associated with depression, dementia, disease severity, disease duration, levodopa dose, and use of sleep medications.²¹

 

7 Feeling worthless/excessive or inappropriate guilt. DSM-IV-TR defines this symptom as not merely self-reproach or guilt about being sick.⁶ Guilt or self-blame seem to be less common in PD depression compared with dysphoria, pessimism, and somatic symptoms.²² Nonetheless, feelings of decreased self-worth are common in PD patients, especially as the illness limits work, productivity at home, and social activities.

8 Concentration and decision-making. PD patients show cognitive changes such as difficulty in changing tasks and impaired executive function (planning, sequencing, and executing). In tasks of divided attention—such as “multitasking”—PD patients have difficulty filtering out nonrelevant information.²³ Difficulties with memory, attention, and language also have been observed in PD and often are exacerbated by depression.²⁴ These cognitive changes affect PD patients’ ability to concentrate, maintain focus, and engage in effective decision making.²⁵

Attention problems in PD are compounded by dementia, which affects at least 20% to 40% of PD patients²⁶ and perhaps considerably more.²⁷

Box

9 Suicide in PD. Recurrent thoughts of death, suicidal ideation, a suicide attempt, or a specific plan for committing suicide are included in DSM-IV-TR criteria for depression.⁶ Thoughts of death also may be a common symptom in PD, although a large American study found that individuals with PD—despite their extremely high rates of depression—had a significantly lower risk of suicide than age-matched controls without PD.²⁸

Features of depression in PD

The specificity and clinical usefulness of individual depression symptoms in PD is variable. Some symptoms seem to be as common in nondepressed as in depressed PD patients (Table 2).²⁹

Distinguishing characteristics. Using Hamilton Depression Rating Scale (HAM-D) and Montgomery-Åsburg Depression Rating Scale items, a study of nondemented PD patients found the presence of suicidal thoughts to be the most reliable discriminator between depressed and nondepressed patients. Other symptoms with good discriminating reliability for depression in PD were (in descending order):

• feelings of guilt
  
• psychic anxiety
  
• reduced appetite
  
• depressed mood
  
• reduction of work and interest.
  

Somatic items—such as fatigue, somatic anxiety, weight loss, and early and middle insomnia—had the lowest discriminative properties.³⁰

Symptom profile. The most recent studies comparing depression symptoms in PD patients with those in non-PD populations seem to indicate:

• the profile of depression in PD is not different from that of other elderly depressed populations
  
• or PD patients show more cognitive symptoms, which is not surprising considering PD’s cognitive involvement.³¹
  

Keep in mind that if the same definition of depression is used in 2 different populations, the symptomatic profiles are likely to be the same.

Psychiatric comorbidities. A relatively high association with anxiety, cognitive impairment, and psychosis also complicates depression’s picture in PD.³² Often this relationship seems to be bidirectional, with the comorbidities increasing the risk for depression and vice versa.

Table 2

Frequency of depressive symptoms in PD

Effect	Symptoms
Significantly higher frequency in PD patients with depression	Worrying, brooding, loss of interest, hopelessness, suicidal tendencies, social withdrawal, self-depreciation, ideas of reference, anxiety symptoms, loss of appetite, initial and middle insomnia, loss of libido
No significant differences in frequency compared with PD patients without depression	Anergia, motor retardation, early morning awakening
PD: Parkinson’s disease
Source: Reference 29

Recommendations

As we have seen, depression’s somatic and cognitive symptoms and PD’s motor, somatic, and cognitive features overlap substantially. How, then, should clinicians handle symptoms that can be attributed to either depression or PD? Several approaches are possible (Table 3),³³ and each has strengths and weaknesses.

An exclusionary approach may be indicated for research, whereas an inclusive approach may be better suited to clinical settings. As mentioned, the National Institute of Neurological Disorders and Stroke/National Institute of Mental Health Work Group on Depression in Parkinson’s Disease⁴ supports an inclusive approach when evaluating depression symptoms. This group (Box) also recommends eliminating the DSM-IV-TR general exclusion criterion “due to the effects of a medical condition” applied to the diagnosis of depression.⁴

 

As we have seen, however, most DSM-IV-TR depressive symptoms overlap with PD symptoms. The false-positive results likely to occur with an inclusive definition of depression might discourage clinicians from screening PD patients for depression.

In clinical practice, finding recent changes in these overlapping symptoms might point to depression. Therefore, try to establish recent changes—associated with depression—in a PD patient’s somatic or cognitive symptoms, such as weight loss, lack of interest, impaired concentration, or decreased energy. This may be difficult, however, given:

• the subjective nature of many of these symptoms
  
• the decreased reporting ability of patients with cognitive deterioration
  
• medical comorbidities in PD that also could produce the referred symptoms.
  

For these reasons, in clinical practice perhaps the best way to detect depression in PD is by giving primacy to mood symptoms, with the option of using cognitive and somatic DSM-IV-TR symptoms when reliable and clear information is available. Some changes in the approach to specific depressive symptoms in PD also are probably worth considering:

1. Mood. Try to differentiate pervasive depressed mood from mood fluctuations associated with motor fluctuations and poorly controlled motor symptoms. Start with simple, open-ended questions and progress toward precise estimates.

Ask the patient about how often he or she feels sad or “down” and if these feelings are related to something specific or PD symptoms such as “freezing.” Depression rating scales such as the HAM-D and Geriatric Depression Rating scale, though useful for mass screening or research, have very limited clinical application.

2. Interest. Depressive loss of interest may be more acute and fluctuating than apathy. Also, selective loss of interest in some areas—such as social life, work, or hobbies—as opposed to the pervasive character of apathy, may suggest depression.

When evaluating interest in PD patients, consider that they may be avoiding activities that interest them out of fear that motor impairment may cause poor performance or social embarrassment.

3. Weight/appetite. Appetite may be a better indicator of depression than weight changes, as weight loss seems to be common in PD patients. Keep in mind, however, that the GI side effects of dopaminergic medications may limit what patients can eat.

4. Insomnia/hypersomnia. Insomnia associated with PD is usually characterized by sleep maintenance problems (middle insomnia or “broken” sleep). Thus, initial and terminal insomnia are probably better indicators of the presence of depression.

5. Agitation/retardation. Psychomotor retardation is common in PD, but acute exacerbations associated with depression may be noticed. Also note that depression-associated anxiety may exacerbate dyskinesias.

Table 3

4 options for diagnosing depression in PD patients

Approach	Definition	Comment
Inclusive	Count all depressive symptoms toward a depression diagnosis	Recommended by NINDS/NIMH Work Group on Depression in Parkinson’s Disease, but may result in overdiagnosis of depression in PD patients
Exclusive	Ignore any depressive symptoms that could otherwise be explained	May be indicated for research
Etiologic exclusive	Ignore symptoms that likely are the result of the medical illness	The NINDS/NIMH Work Group on Depression in Parkinson’s Disease recommends avoiding attributing symptoms to a particular cause
Substitutive	Replace the most confusing diagnostic features with others that are less controversial	Theoretically the best approach, but establishing this approach as evidence-based would require substantial research
PD: Parkinson’s disease; NINDS/NIMH: National Institute of Neurological Disorders and Stroke/National Institute of Mental Health
Source: References 4,33

6. Fatigue or loss of energy is a very difficult symptom to ascribe either to PD or depression unless they change acutely.

7. Worthlessness/guilt. PD is an incapacitating illness that causes work, family, and social dysfunction. To count as a depression criterion, worthlessness and guilty feelings need to be excessive or inappropriate and relatively constant and not merely self-reproach or guilt about being sick.

8. Diminished ability to think and concentrate is another a symptom that is difficult to ascribe to either depression or PD. A recent change in the context of mood symptoms might point to depression.

9. Recurrent thoughts of death. As mentioned, suicide seems to be less common in patients with PD than in the general population, but suicidal ideation—when found—is highly specific. Fear of dying from PD is not considered a depressive criterion, however.

Related resources

• Menza M, Marsh L, eds. Psychiatric issues in Parkinson’s disease: a practical guide. New York: Taylor and Francis; 2006.
  
• Marsh L, McDonald WM, Cummings J, et al. Provisional diagnostic criteria for depression in Parkinson’s disease: report of an NINDS/NIMH work group. Mov Disord 2006;21:148-58.
  
• Parkinson’s Disease Foundation: www.pdf.org.
  
• Michael J. Fox Foundation: www.michaeljfox.org.
  

 

Drug brand names

• Levodopa • Dopar, Larodopa
  
• Pramipexole • Mirapex
  

Disclosure

Dr. Marin reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Menza receives research support from the National Institutes of Health, Astra-Zeneca, Bristol-Myers Squibb, Cephalon, Forest Laboratories, GlaxoSmithKline, Janssen, Lilly, Merck, Pfizer, sanofi-aventis, Sepracor, Takeda, and Wyeth. He is a consultant for the National Institutes of Health, GlaxoSmithKline, Kyowa, Lilly Research Laboratories, Ono, Pfizer, Sepracor, and Takeda. He is a speaker for Bristol-Myers Squibb, Lilly Research Laboratories, Sepracor, sanofi-aventis, and Takeda.

Dr. Dobkin receives research grants from Takeda.

Many depressive symptoms are seen in the normal course of Parkinson’s disease (PD) (Table 1).¹ As a result, depression—the most common neuropsychiatric disturbance in PD—is difficult to assess in PD and easily can go undetected and untreated.²

Making the diagnosis is important, however, because depression causes PD patients suffering and may accelerate decline in motor and cognitive function, activities of daily living, and quality of life.³ In the absence of specific guidelines (Box),⁴ we provide evidence to help you sort through the overlapping symptoms to find clinical signs that differentiate depression from PD symptoms.^5,6

Table 1

Symptoms of depression that occur in or mimic those in the natural course of PD

Psychomotor retardation (bradykinesia)
Depressed or emotionless appearance (‘masked facies,’ stooped posture)
Agitation (dyskinesias)
Decreased interest and enjoyment (apathy and decreased initiative)
Impaired memory and concentration
Fatigue or decreased energy
Impaired sleep
Weight and appetite changes
Physical complaints
Source: Adapted from reference 1

DSM-IV-TR depression criteria

Approximately 20% of PD patients meet DSM-IV-TR criteria for major depression, and another 20% meet criteria for dysthymia.⁵ By DSM-IV-TR criteria,⁶ diagnosis of a major depressive episode requires ≥5 of 9 symptoms, of which at least 1 is depressed mood or loss of interest or pleasure. Because these symptoms must be present during the same 2-week period and represent a change in functioning, this diagnosis has an acute quality.

Dysthymia—also frequently called “chronic depression”—is characterized by a mostly depressed mood for 2 years, accompanied by ≥2 of 6 symptoms: appetite changes, sleep changes, low energy/fatigue, low self-esteem, poor concentration/indecisiveness, and hopelessness.⁶

All of these depression symptoms may overlap with those of PD.

1 Mood. In mid-stage and late PD, mood often fluctuates in concert with daily periods of increased rigidity and tremor (“off” periods) interspersed with improved motor functioning (“on” periods).⁷ Thus, when evaluating the PD patient:

• take a detailed history of motor fluctuations and their associations with mood symptoms
  
• also evaluate mood during “on” periods.
  

2 Interest and pleasure. Differentiating decreased interest from apathy is one of the greatest challenges in diagnosing depression in PD. The neurologic symptom of apathy in PD includes 3 features:

• behavioral (lack of effort)
  
• cognitive (loss of interest/concern)
  
• affective (decreased emotional response or “flat” affect).
  

Some studies have described apathy as a common feature of PD that can occur independent of depression;⁸ others have associated apathy with cognitive impairment.⁹ Anhedonia also seems to be more common in PD patients than in matched controls, apparently independent of PD’s neurologic, frontal, and depressive aspects.¹⁰

3 Weight changes. Patients with PD tend to have lower body weight than matched subjects. As a result, weight loss in the course of PD can be confused with weight loss associated with depression.

Weight loss appears to start 2 to 4 years before a PD diagnosis and continues thereafter. Despite the weight loss, PD patients report higher energy intake after the diagnosis compared with individuals without PD.¹¹ A related, not necessarily contradictory finding is that a higher premorbid body mass index (BMI) seems to be associated with an increased risk of developing PD.¹²

In general, dopaminergic treatment of PD seems to be associated with weight loss.¹³ However, weight gain has been reported after pramipexole treatment, which the authors of the study attributed to limbic D3 receptor stimulation.¹⁴

4 Sleep and excessive daytime sleepiness. Sleep disturbances are very common in individuals with PD.¹⁵ A community study found that two-thirds of PD patients complained of sleep problems, with sleep fragmentation and early awakening being the most common complaints.¹⁶ Initial insomnia was less common, and a surprisingly high number of PD patients reported symptoms that suggested obstructive sleep apnea, periodic limb movements of sleep, and REM sleep behavior disorder.¹⁷

Excessive daytime sleepiness has been associated with PD and with the medications used to treat it. Give special consideration to diagnosing sleep attacks—abrupt, unavoidable transitions from wakefulness to sleep—which are reported in up to 30% of PD patients taking dopaminergic agonists. These attacks can occur during critical activities, such as driving,¹⁸ and likely are a class effect of dopamine replacement therapies.¹⁹

5 Psychomotor retardation as a core symptom of PD is clinically indistinguishable from that seen in severe depression.

6 Fatigue. Most studies of fatigue in PD do not define whether the term applies to prolonged mental exhaustion or lack of physical endurance. In any case, one-third to one-half of PD patients report fatigue, and many consider it one of the most disabling symptoms—worse in this regard than motor symptoms.²⁰ Fatigue is more than twice as common in PD patients as in healthy controls and is associated with depression, dementia, disease severity, disease duration, levodopa dose, and use of sleep medications.²¹

 

7 Feeling worthless/excessive or inappropriate guilt. DSM-IV-TR defines this symptom as not merely self-reproach or guilt about being sick.⁶ Guilt or self-blame seem to be less common in PD depression compared with dysphoria, pessimism, and somatic symptoms.²² Nonetheless, feelings of decreased self-worth are common in PD patients, especially as the illness limits work, productivity at home, and social activities.

8 Concentration and decision-making. PD patients show cognitive changes such as difficulty in changing tasks and impaired executive function (planning, sequencing, and executing). In tasks of divided attention—such as “multitasking”—PD patients have difficulty filtering out nonrelevant information.²³ Difficulties with memory, attention, and language also have been observed in PD and often are exacerbated by depression.²⁴ These cognitive changes affect PD patients’ ability to concentrate, maintain focus, and engage in effective decision making.²⁵

Attention problems in PD are compounded by dementia, which affects at least 20% to 40% of PD patients²⁶ and perhaps considerably more.²⁷

Box

9 Suicide in PD. Recurrent thoughts of death, suicidal ideation, a suicide attempt, or a specific plan for committing suicide are included in DSM-IV-TR criteria for depression.⁶ Thoughts of death also may be a common symptom in PD, although a large American study found that individuals with PD—despite their extremely high rates of depression—had a significantly lower risk of suicide than age-matched controls without PD.²⁸

Features of depression in PD

The specificity and clinical usefulness of individual depression symptoms in PD is variable. Some symptoms seem to be as common in nondepressed as in depressed PD patients (Table 2).²⁹

Distinguishing characteristics. Using Hamilton Depression Rating Scale (HAM-D) and Montgomery-Åsburg Depression Rating Scale items, a study of nondemented PD patients found the presence of suicidal thoughts to be the most reliable discriminator between depressed and nondepressed patients. Other symptoms with good discriminating reliability for depression in PD were (in descending order):

• feelings of guilt
  
• psychic anxiety
  
• reduced appetite
  
• depressed mood
  
• reduction of work and interest.
  

Somatic items—such as fatigue, somatic anxiety, weight loss, and early and middle insomnia—had the lowest discriminative properties.³⁰

Symptom profile. The most recent studies comparing depression symptoms in PD patients with those in non-PD populations seem to indicate:

• the profile of depression in PD is not different from that of other elderly depressed populations
  
• or PD patients show more cognitive symptoms, which is not surprising considering PD’s cognitive involvement.³¹
  

Keep in mind that if the same definition of depression is used in 2 different populations, the symptomatic profiles are likely to be the same.

Psychiatric comorbidities. A relatively high association with anxiety, cognitive impairment, and psychosis also complicates depression’s picture in PD.³² Often this relationship seems to be bidirectional, with the comorbidities increasing the risk for depression and vice versa.

Table 2

Frequency of depressive symptoms in PD

Effect	Symptoms
Significantly higher frequency in PD patients with depression	Worrying, brooding, loss of interest, hopelessness, suicidal tendencies, social withdrawal, self-depreciation, ideas of reference, anxiety symptoms, loss of appetite, initial and middle insomnia, loss of libido
No significant differences in frequency compared with PD patients without depression	Anergia, motor retardation, early morning awakening
PD: Parkinson’s disease
Source: Reference 29

Recommendations

As we have seen, depression’s somatic and cognitive symptoms and PD’s motor, somatic, and cognitive features overlap substantially. How, then, should clinicians handle symptoms that can be attributed to either depression or PD? Several approaches are possible (Table 3),³³ and each has strengths and weaknesses.

An exclusionary approach may be indicated for research, whereas an inclusive approach may be better suited to clinical settings. As mentioned, the National Institute of Neurological Disorders and Stroke/National Institute of Mental Health Work Group on Depression in Parkinson’s Disease⁴ supports an inclusive approach when evaluating depression symptoms. This group (Box) also recommends eliminating the DSM-IV-TR general exclusion criterion “due to the effects of a medical condition” applied to the diagnosis of depression.⁴

 

As we have seen, however, most DSM-IV-TR depressive symptoms overlap with PD symptoms. The false-positive results likely to occur with an inclusive definition of depression might discourage clinicians from screening PD patients for depression.

In clinical practice, finding recent changes in these overlapping symptoms might point to depression. Therefore, try to establish recent changes—associated with depression—in a PD patient’s somatic or cognitive symptoms, such as weight loss, lack of interest, impaired concentration, or decreased energy. This may be difficult, however, given:

• the subjective nature of many of these symptoms
  
• the decreased reporting ability of patients with cognitive deterioration
  
• medical comorbidities in PD that also could produce the referred symptoms.
  

For these reasons, in clinical practice perhaps the best way to detect depression in PD is by giving primacy to mood symptoms, with the option of using cognitive and somatic DSM-IV-TR symptoms when reliable and clear information is available. Some changes in the approach to specific depressive symptoms in PD also are probably worth considering:

1. Mood. Try to differentiate pervasive depressed mood from mood fluctuations associated with motor fluctuations and poorly controlled motor symptoms. Start with simple, open-ended questions and progress toward precise estimates.

Ask the patient about how often he or she feels sad or “down” and if these feelings are related to something specific or PD symptoms such as “freezing.” Depression rating scales such as the HAM-D and Geriatric Depression Rating scale, though useful for mass screening or research, have very limited clinical application.

2. Interest. Depressive loss of interest may be more acute and fluctuating than apathy. Also, selective loss of interest in some areas—such as social life, work, or hobbies—as opposed to the pervasive character of apathy, may suggest depression.

When evaluating interest in PD patients, consider that they may be avoiding activities that interest them out of fear that motor impairment may cause poor performance or social embarrassment.

3. Weight/appetite. Appetite may be a better indicator of depression than weight changes, as weight loss seems to be common in PD patients. Keep in mind, however, that the GI side effects of dopaminergic medications may limit what patients can eat.

4. Insomnia/hypersomnia. Insomnia associated with PD is usually characterized by sleep maintenance problems (middle insomnia or “broken” sleep). Thus, initial and terminal insomnia are probably better indicators of the presence of depression.

5. Agitation/retardation. Psychomotor retardation is common in PD, but acute exacerbations associated with depression may be noticed. Also note that depression-associated anxiety may exacerbate dyskinesias.

Table 3

4 options for diagnosing depression in PD patients

Approach	Definition	Comment
Inclusive	Count all depressive symptoms toward a depression diagnosis	Recommended by NINDS/NIMH Work Group on Depression in Parkinson’s Disease, but may result in overdiagnosis of depression in PD patients
Exclusive	Ignore any depressive symptoms that could otherwise be explained	May be indicated for research
Etiologic exclusive	Ignore symptoms that likely are the result of the medical illness	The NINDS/NIMH Work Group on Depression in Parkinson’s Disease recommends avoiding attributing symptoms to a particular cause
Substitutive	Replace the most confusing diagnostic features with others that are less controversial	Theoretically the best approach, but establishing this approach as evidence-based would require substantial research
PD: Parkinson’s disease; NINDS/NIMH: National Institute of Neurological Disorders and Stroke/National Institute of Mental Health
Source: References 4,33

6. Fatigue or loss of energy is a very difficult symptom to ascribe either to PD or depression unless they change acutely.

7. Worthlessness/guilt. PD is an incapacitating illness that causes work, family, and social dysfunction. To count as a depression criterion, worthlessness and guilty feelings need to be excessive or inappropriate and relatively constant and not merely self-reproach or guilt about being sick.

8. Diminished ability to think and concentrate is another a symptom that is difficult to ascribe to either depression or PD. A recent change in the context of mood symptoms might point to depression.

9. Recurrent thoughts of death. As mentioned, suicide seems to be less common in patients with PD than in the general population, but suicidal ideation—when found—is highly specific. Fear of dying from PD is not considered a depressive criterion, however.

Related resources

• Menza M, Marsh L, eds. Psychiatric issues in Parkinson’s disease: a practical guide. New York: Taylor and Francis; 2006.
  
• Marsh L, McDonald WM, Cummings J, et al. Provisional diagnostic criteria for depression in Parkinson’s disease: report of an NINDS/NIMH work group. Mov Disord 2006;21:148-58.
  
• Parkinson’s Disease Foundation: www.pdf.org.
  
• Michael J. Fox Foundation: www.michaeljfox.org.
  

 

Drug brand names

• Levodopa • Dopar, Larodopa
  
• Pramipexole • Mirapex
  

Disclosure

Dr. Marin reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Menza receives research support from the National Institutes of Health, Astra-Zeneca, Bristol-Myers Squibb, Cephalon, Forest Laboratories, GlaxoSmithKline, Janssen, Lilly, Merck, Pfizer, sanofi-aventis, Sepracor, Takeda, and Wyeth. He is a consultant for the National Institutes of Health, GlaxoSmithKline, Kyowa, Lilly Research Laboratories, Ono, Pfizer, Sepracor, and Takeda. He is a speaker for Bristol-Myers Squibb, Lilly Research Laboratories, Sepracor, sanofi-aventis, and Takeda.

Dr. Dobkin receives research grants from Takeda.