Parkinson's disease is associated with various psychiatric manifestations that can affect up to 90% of patients. These include cognitive disturbances like dementia, depression in 40-50% of patients, anxiety in about 40%, and behavioral issues. Depression can predate motor symptoms and increases mortality risk. Mania or hypomania may occur due to dopaminergic medications. Compulsive behaviors are associated with dopamine replacement therapy. Apathy is also common and linked to cognitive and executive dysfunction. Accurate diagnosis and treatment of psychiatric conditions in Parkinson's patients is important for quality of life.

1. PSYCHIATRIC MANIFESTATIONS
OF PARKINSON’S DISEASE

2. INTRODUCTION
• Parkinson’s disease (PD) is a progressive neurodegenerative disorder
that is associated with the loss of dopaminergic neurons in the
substantia nigra pars compacta.
• Etiology unknown
• Majority of cases thought to result from a combination of
environmental and genetic factors

3. EPIDEMIOLOGY
• Second most common neurodegenerative disease after Alzheimer’s
disease
• Affects over 1 percent of the population over age 55 and nearly 3
percent of the population over age 70.(Ref CTP 9th Ed)
• Mean age of onset is 60 years
• Prevalence highest in Europe and North America, with lower rates in
Asia and Africa.
• Men are affected slightly more often than women.

4. MANIFESTATIONS OF PD
• MOTOR SYMPTOMS:
Hallmarks of the disease are its triad of motor features:
Resting tremor
Rigidity
Akinesia/bradykinesia
PSYCHIATRIC SYMPTOMS:
Due to the disease itself, or due to treatment (Pharmacological or
Surgical).

5. PSYCHIATRIC ASPECTS OF PD
• Psychiatric disturbances affect up to 90 percent of patients at some
point during the course of PD. (CTP 9th Ed)
• More than one psychiatric disturbance is often present.
• Early in the disease process, adult-onset anxiety and depressive
disorders precede the obvious onset of motor symptoms in up to 30
percent of patients. (CTP 9th Ed)

6. PSYCHIATRIC MANIFESTATIONS
• Cognitive disturbances
• Dementia and confusion
• Depression
• Mania/Hypomania
• Anxiety & Panic
• Behavioral disturbances
• Psychoses

7. PREMORBID PERSONALITY
• Industriousness
• Cautiousness
• Perfectionism
• Punctuality
These traits represent a consequence of premorbid reductions in
dopaminergic tone (Controversial).

8. COGNITIVE DISTURBANCES

9. PROBLEMS
• about two-thirds of patients with early PD will show abnormalities of
cognitive function on formal neuropsychological testing
• Bradyphrenia or slowness of thought, slowing of mental processing and
memory retrieval, and examination of neuropsychological test
performance might show delay in deciding on choices, although the final
decisions are correct.
• The “tip of the tongue” phenomenon refers to the patient’s knowing the
word he or she wants, but not being able to come up with it and say it at
that moment
• Less ability to deal with mental problems, particularly multiple tasks at the
same time.
• Such cognitive impairments may be due to comorbid depression.

10. CAUSES
• Dopamine deficiency in the non-motor regions of the striatum,
especially the caudate nucleus which receives from and projects to
prefrontal cerebral cortex
• Loss of dopamine projections from the midbrain ventral tegmental
area to the frontal lobes (mesocortical pathways)
• Loss of cortical cholinergic projections from the basal forebrain
• Loss of cortical noradrenergic projections from the locus coeruleus
(Bradyphrenia)
• Cortical Lewy body degeneration.

11. DIAGNOSIS
• The Montreal Cognitive Assessment (MoCA) was found to be a useful
screening tool for cognitive dysfunction in PD and more sensitive than the
MMSE (Gill et al., 2008; Hoops et al., 2009).
• Patients are weak in performance of tests that are sensitive to frontal lobe
dysfunction (executive function), such as verbal fluency, the Wisconsin card
sorting test, the Tower of London test and its variants, and tests of working
memory.
• Poor performance on these tests suggests abnormalities of frontal lobe
executive functions, which may be due to defective input from nonmotor
basal ganglia regions (via thalamus) into prefrontal cerebral cortical areas.
• Thus, some patients with early PD may exhibit a frontostriatal cognitive
syndrome

12. BIOCHEMICAL TESTING
• Fluorodeoxyglucose positron emission tomography (FDG PET)
scanning pattern that correlated with impaired memory and
executive functioning, these was found to be metabolic reductions in
frontal and parietal association areas and relative increases in the
cerebellar vermis and dentate nuclei

13. MANGEMENT DIFFICULTIES
• These selective cognitive impairments do not seem to respond to
dopamine replacement therapy in the way the motor problems of PD
do.
• Nor do they respond to antidepressants, unless depression is present
and is itself the cause of the slowness of thinking.
• Anticholinergics, amantadine, dopamine agonists, and even levodopa
in excess might well impair cognitive function.
• Unilateral pallidotomy for motor symptoms: transient and mild
cognitive problems mainly affecting frontosubcortical functions (e.g.
executive functions and memory)

14. DEMENTIA

15. RISK FACTORS
• Risk factors for developing dementia are low serum epidermal growth
factor (Chen-Plotkin et al., 2011), low CSF amyloid-beta (Siderowf et
al., 2010), and severity of olfactory impairment (Stephenson et al.,
2010).
• Other risk factors include older age, late onset, greater severity and
longer duration of PD, and male gender.
• Dementia in patients with PD may affect around 25%-40% of
cases(Ref. CTP 9th Ed.)
• Psychotic symptoms are more frequent in demented patients

16. PD DEMENTIA
• PD dementia (PDD) is characterized by impairment of memory,
visuospatial skills, information processing speed, attention, explicit
recall, spatial planning, perseveration, verbal fluency, and poverty of
thought.
• Executive dysfunction is especially common, resulting from deficits
that affect the ability to process new information and anticipate, plan,
initiate, maintain, and change behaviors.
• Behavioral symptoms such as affective changes, hallucinations, and
apathy are frequent.

17. DIAGNOSIS
• The Movement Disorder Society’s Task Force on Dementia developed
a set of criteria for diagnosing dementia in patients with PD (Emre et
al., 2007).
• PD dementia (PDD) is now the term applied to those whose PD
symptoms began at least one year prior to the onset of dementia.
• It is called Dementia with Lewy bodies (DLB) (McKeith et al., 1996)
when the dementia precedes or occurs within 1 year after onset of
parkinsonian motor features (Lippa et al., 2007).
• Combination (which some have called the Lewy body variant of
Alzheimer disease) is a common cause of dementia in PD.

18. PATHOLOGY
There are at least three common substrates for dementia in PD:
• Alzheimer disease
• Alzheimer disease with Lewy bodies
• Diffuse Lewy body disease (Dementia with Lewy bodies: DLB).
• A fourth possibility is dementia with just the standard pathology of
PD (PDD), typically with Lewy bodies in the cerebral cortex.

19. DIFFERENCE FROM AD
• A personality trait that distinguishes DLB/PDD from Alzheimer disease
is passivity (diminished emotional responsiveness, relinquished
hobbies, growing apathy, and purposeless hyperactivity) (Galvin et al.,
2007).
• In comparison to patients with Alzheimer’s disease, recognition
memory, aphasia, agnosia, apraxia, and higher language functions are
relatively spared.
• Neuroimaging with Pittsburgh Compound B (PIB) ligand with PET can
reveal the presence of fibrillar Abeta amyloid, which is present in
patients with PDD.

20. DIFFERENTIAL DIAGNOSES
• Prominent early memory difficulties with language, praxis, and
visuospatial problems pointing to temporo-parietal problems suggest
Alzheimer disease.
• A variable, fluctuating course with prominent hallucinations
(especially visual), confusion, and an unusual susceptibility to
neuroleptics could indicate dementia with Lewy bodies (McKeith et
al., 1996, 1999), i.e., diffuse Lewy body disease.
• Prominent behavioral, speech and memory difficulties could point to
frontotemporal dementia or Pick disease.

21. IMAGING
• FDG PET scans were correlated with the dementia score on the
UPDRS (Unified Parkinson’s Disease Rating Scale).
• A correlation was found with left limbic structures such as the
cingulate gyrus, parahippocampal gyrus, and medial frontal gyrus (Wu
et al., 2000).
• Dementia, with or without a frank confusional state, is the
commonest cause of final nursing home placement in those with PD,
and shortens life expectancy (Goetz and Stebbins, 1993).

22. TREATMENT OF COGNITIVE
PROBLEMS/DEMENTIA
• Donepezil, which provides modest benefit in Alzheimer disease, has
been found also to provide modest benefit in cognition in those with
PD who are demented without aggravating the motoric symptoms of
PD (Aarsland et al., 2002; Ravina et al., 2005).
• Rivastigmine has also been tried with some success.
• Trials with Memantine are underway.
• Overall poor response to drug therapy.

23. DEPRESSION

24. EPIDEMIOLOGY
• Most common psychiatric disorder in PD (40% - 50%)
• Mostly mild to moderate, 20% have severe depression (upto 50%
have major depression)
• Possible risk factors : female sex, younger age at onset of PD,
prominence of right sided signs, and prominence of bradykinesia and
gait disturbance
• Depression may also predate the motor features of PD
• Depression is also considered a risk factor for the development of
dementia.

25. PROBLEMS
• Depression carries a hazard ratio of 2.66 for increased mortality in PD
(Hughes et al., 2004)
• Depression may correlate with faster progression of the disease and
faster decline in cognitive status and activities of daily living.
• No association has been clearly established, between severity of PD
and presence or severity of depression.
• Patients with PD and depression show worse cognitive function than
those without depression, particularly in tests of prefrontal/executive
function.

26. CAUSES
• Disabilities and handicaps imposed by PD, with reduced activities and
independence, and the prospects of a chronic incurable condition.
• PD in itself might predispose to depression, especially that involving
serotonergic and noradrenergic systems, which have been implicated
in the neurochemical basis of primary depressive illnesses.
• ↓ dopaminergic stimulation of orbitofrontal & prefrontal cortex.
• The substantia nigra, itself, is implicated by the report that deep brain
stimulation of this structure in a patient with PD induced acute severe
depression (Bejjani et al., 1999)

27. DIAGNOSTIC DIFFICULTY
• Often difficult to distinguish true depression from the apathy (abulia)
associated with PD, especially in the presence of the characteristic
expressionless face (hypomimia), bowed posture, and slowed
movement, which resemble the psychomotor retardation of a
primary depressive illness.
• The critical factor is whether the patient has a true disturbance of
mood (dysphoria), with low spirits, loss of interest, bleak outlook,
typical depressive sleep disturbance, paranoid ruminations, and
sometimes suicidal thoughts.

28. PHARMACOLOGICAL TREATMENT
• Selective serotonin reuptake inhibitors (SSRIs), are the treatment of
choice, especially Sertraline and Escitalopram
• A few cases have been reported to interact with levodopa to induce
the “serotonin” syndrome (confusion, myoclonus, rigidity, and
restlessness) and to worsen PD symptoms.
• Tricyclic antidepressants(TCAs) can also be employed, although their
sedative and anticholinergic properties may be detrimental in elderly
patients.
• Nonselective monoamine oxidase inhibitors are contraindicated in
patients who are taking levodopa because of potential pressor
reactions

29. NONPHARMACOLOGICAL TREATMENT
• Psychotherapy(CBT) and counselling.
• If a severely depressed patient with PD fails to respond to
antidepressant drug treatment, electroconvulsive therapy (ECT) can
be used (Douyon et al., 1989).
• Indeed, ECT in itself can temporarily improve mobility in PD.

30. MANIA/HYPOMANIA

31. EPIDEMIOLOGY
• Levodopa and dopamine agonists may occasionally be associated
with mood changes ranging from a sense of wellbeing to euphoria
and mania.
• The rate of hypomania is close to 2%,and that of euphoria is about
10%.
• Patients with pre-existing bipolar disorder may experience "high"
mood swings when treatment with dopaminergic drugs is started.
• In a few patients, occasional manifestation of hypomanic symptoms
during times of peak dose.
• Antidepressants along with antiparkinsonian therapy may contribute.

32. SYMPTOMS
• Altered sexual behaviour such as increased libido, hypersexuality,
sexual deviation, and various paraphilias
• Sleep disturbances such as vivid dreams and nightmares, and multiple
awakenings.
• Can be managed by more frequent and lower dosing to avoid sudden
dosage peaks, and mood swings

33. ANXIETY & PANIC

34. CAUSES
• Prevalence near about 40%. Higher in younger patients.
• Often comorbid with depression.
• GAD, social phobia & panic disorders are common.
• Noradrenergic and serotonergic deficits
• Imbalance in noradrenergic/dopaminergic tone.
• Psychosocial factors: Loss of confidence, loss of mobility and their
nonverbal emotional responses to social interactions.
• In some patients panic attacks occur with the onset of "freezing" or
"off" episodes. Also, association with levodopa level fluctuations.

35. MANAGEMENT
• Anxiety can be relieved by effective antiparkinsonian drug therapy
• Might require an antidepressant(SSRI)
• If dysphoria is present, a benzodiazepine (e.g., lorazepam 0.5 - 2 mg
three times a day) or buspirone may be added.
• Anxiety and stress worsen tremor, and alprazolam 0.25 mg during
those periods can provide relief.
• However, all these drugs can increase confusion in those who are
cognitively impaired.

36. BEHAVIORAL
ABNORMALITIES

37. COMPULSIVE BEHAVIORS
• Impulse Control Disorders(ICDs) were more common in patients treated
with a dopamine agonist than in patients not taking a dopamine agonist.
(ICDs affect upto 14% of the patients).
• Pathological gambling, hypersexuality, compulsive buying, and binge-eating
are common.
• All dopaminergic antiparkinsonian treatments as well as deep brain
stimulation have been associated with the behaviors.
• Reward-seeking behaviors possibly related to dopaminergic stimulation in
the mesolimbic system (PET scan reflecting greater dopaminergic release)
• Patients with a younger age at PD onset, higher novelty seeking traits, and
a personal or family history of alcohol use disorders were found to have a
greater risk.

38. HEDONISTIC HOMEOSTATIC DYSREGULATION
• It is a neuropsychological behavioral disorder associated with substance misuse
and addiction.
• The disorder has been recognized as a consequence of dopamine replacement
therapy (DRT) in patients with Parkinson's disease.
• The syndrome typically develops in male patients with early onset Parkinson's
disease, and can occur with orally and subcutaneously administered DRT.
• These patients take increasing quantities of their DRT, despite increasingly severe
drug induced dyskinesias, and may develop a cyclical mood disorder with
hypomania or manic psychosis.
• There is impairment of social and occupational functioning.
• Tolerance develops to mood elevating effects of DRT and a negative affective
withdrawal state occurs if the drugs are withdrawn or doses decreased.

39. REPETITIVE BEHAVIORS
• The term punding has been used to describe an abnormal motor
behavior in which there is an intense fascination with repetitive
handling and examining of mechanical objects.
• Punding has been reported with levodopa and dopamine agonists.
• A common form is repetitive cleaning/rearranging/ordering
behaviors, which can be disabling. These have associated features of
hypomania, occur during motor “on” periods, and often occur
nocturnally.
• Repetitive behaviors are more of a compulsion, and responds poorly
to serotonin reuptake inhibitors, but may benefit from atypical
antipsychotics.

40. APATHY
• A frequent symptom seen in PD (25%), and although often related to
depression. It can be found in patients without mood disorder.
• Manifest as indifference and a lack of motivation, initiative,
perseverance, interest in new things, or concern for one’s health.
• Associated with cognitive dysfunction (mainly executive impairment).
• It has been suggested that its presence is related to dysfunction of
forebrain dopaminergic systems.
• Lack of motivation → Apathy → Abulia
• Abulia is a characterized syndrome due to caudate and prefrontal
dysfunction.

41. OTHER ABNORMALITIES IN BEHAVIOR
• Behavioral disturbances, including verbal and physical aggression,
wandering, agitation, inappropriate sexual behavior,
uncooperativeness, and urinary incontinence, cause major difficulties.

42. ASSOCIATION WITH ON-OFF PHENOMENON
• Sensory & behavioral “off” periods, either accompanying or instead of
a motor “off.”
• The behavioral symptoms can consist of depression, anxiety,
dysphoria, and panic; the sensory symptoms consist of pain or
akathisia mainly.
• Behavioral and sensory “offs” probably represent an insufficient
dopaminergic “tone” in the limbic dopaminergic areas of the brain,
such as the nucleus accumbens, amygdala, and cingulate cortex.
• Behavioral offs respond to dopaminergic medication.

43. MANAGEMENT
• Depression might require specific treatment, preferably avoiding
antidepressants with marked anticholinergic properties.
• If depression is not an issue, then dopaminergic agents, including
levodopa, dopamine receptor agonists, selegiline, amphetamines, and
amantadine, have been most consistently effective for apathy.
• Nocturnal sedation might require Quetiapine, which provides both
sedation and antihallucinatory effects.
• Clozapine does the same but requires weekly ascertainment for
neutropenia.

44. OTHER STRATEGIES
• Other bedtime hypnotics, such as benzodiazepines and zolpidem, can
be effective.
• Rivastigmine and other centrally active cholinesterase inhibitors were
found to provide some improvement in apathy, anxiety, delusions,
and hallucinations in patients with DLB (McKeith et al., 2000) and can
improve dementia (Giladi et al., 2003).
• For ICDs, drug therapy should be simplified, removing selegiline,
anticholinergic agents, amantadine, and dopamine agonists.
• ICDs in PD respond well to DBS of STN.
• Psychotherapy.

45. PSYCHOSES

46. PSYCHOSES
Psychotic features appear to be due to a complex interaction between:
• Progressive and widespread pathology of the illness (diffuse cortical Lewy
body degeneration, concurrent Alzheimer plaques and tangles)
• Cortical cholinergic, noradrenergic, and serotonergic denervation
• The unwanted effects of drugs (anticholinergics, levodopa, and dopamine
agonists). Dopaminergic therapy may lead to hypersensitivity of
mesocortical and mesolimbic dopaminergic receptors.
• Intercurrent illness (such as infections or metabolic disturbances)
• Psychotic symptoms occur in up to 40% of patients (Jankovic 6th Ed)

47. HALLUCINATIONS
• Hallucinations occur in a significant proportion of those with PD,
especially in elderly patients ( upto 50% of cases: Ref. CTP 9th Ed.)
• Risk factors were higher age at onset, dopaminergic dose, and RBD
(REM sleep Behavior Disorder) at baseline.
• Isolated visual hallucinations are fairly common, whereas auditory
and hallucinations of other sensory modalities are very uncommon

48. VISUAL HALLUCINATIONS
• Mostly nocturnal. Often associated with sleep disturbances.
• Visual hallucinations often take the form of familiar humans or animals,
which the patients know are false (pseudo-hallucinations).
• Commonly the hallucinations do not disturb the patient because the visual
images are vivid but friendly and not frightening (benign hallucinations),
and occur in clear consciousness with preservation of insight and cognition.
• “Benign” visual hallucinations are the most common psychotic symptom in
Parkinson’s disease and are related to dopaminergic medications.
• These milder forms can worsen to a more malignant type (common with
anticholinergic medications).

49. ASSOCIATIONS
• Hallucinations may develop shortly after starting treatment for PD in
some patients.
• Risk factors for the occurrence of hallucinations: Several years of
treatment, increasing age & multiple drug therapy.
• FDG-PET reveals that PD patients with visual hallucinations have a
reduced metabolic rate in the occipitotemporoparietal regions,
sparing the occipital pole (Boecker et al., 2007).

50. DELUSIONS AND PARANOIA
• The prevalence of delusions ranges from 3% to 30% and is greater when
high doses of medication are used.
• Increasing age and presence of dementia are risk factors for the
development of delusions. Antiparkinsonian drug therapy is the most likely
cause.
• Delusions tend to appear more than 2 years after initiating treatment with
levodopa.
• They are typically paranoid in nature but delusions of jealousy have also
been described.
• May also progress to a delusional paranoid state or a frank confusional
state with impairment of attentiveness and disorientation.
• Schizophrenic formal thought disorder is rare.

51. DIAGNOSIS
• Criteria for diagnosing psychosis in PD and differentiating it from
other causes of psychosis were established by an NIH working group
(Ravina et al., 2007).

52. Proposed diagnostic criteria for PD-associated psychosis
Characteristic symptoms
Presence of at least one of the following symptoms (Criterion A) (specify which of the symptoms fulfill the criteria):
• Illusions
• False sense of presence
• Hallucinations
• Delusions
Primary diagnosis
• UK brain bank criteria for PD
Chronology of the onset of symptoms of psychosis
• The symptoms in Criterion A occur after the onset of PD
Duration
• The symptom(s) in Criterion A are recurrent or continuous for 1 month
Exclusion of other causes
• The symptoms in Criterion A are not better accounted for by another cause of parkinsonism such as dementia with Lewy bodies, psychiatric
disorders such as schizophrenia, schizoaffective disorder, delusional disorder, or mood disorder with psychotic features, or a general medical
condition including delirium
Associated features (specify if associated):
• With/without insight
• With/without dementia
• With/without treatment for PD (specify drug, surgical, other)

53. TREATMENT
• Psychosis due to antiparkinsonian medications can usually be
counteracted by atypical antipsychotics, drugs that usually do not
aggravate parkinsonism at a dosage that has a therapeutic benefit in
treating the psychosis, namely Quetiapine and Clozapine.

54. QUETIAPINE
• Quetiapine appears to be effective only for milder psychosis, such as
hallucinations, but not in more severe forms of psychosis, as
demonstrated by its failure in controlled trials.
• It is practical to start therapy with quetiapine if the hallucinations are
mild. A dose of 25–50 mg at night can often control confusion and
psychosis without worsening the parkinsonism.
• Quetiapine can be utilized as a hypnotic in older patients with PD to
take advantage of suppressing the development of hallucinations in
this susceptible population.

55. CLOZAPINE & OTHER AGENTS
• Clozapine should be tried next, starting with 12.5 mg at night to avoid
daytime drowsiness and increasing the dose until benefit or adverse
effects are encountered. It is more effective than Quetiapine, but its
use requires regular monitoring of blood counts to prevent the 1–2%
risk of agranulocytosis
• Olanzapine is relegated to third choice.
• Ziprasidone has also been tried.
• Risperidone more closely resembles a typical, rather than an atypical
antipsychotic, and role is controversial in PD.
• Aripiprazole has also worsened parkinsonism (Fernandez et al., 2004).

56. OTHER DRUG THERAPIES
• An alternative to atypical antipsychotics are the centrally active
anticholinesterase drugs (Rivastigmine) that are used in the treatment
of dementia. They have been reported to have similar efficacy on
psychosis as Quetiapine.
• The serotonin 5HT3-receptor antagonist Ondansetron blocks nausea
and vomiting due to anticancer drugs. It has been reported to reduce
hallucinations, paranoia, and confusion in PD (Zoldan et al., 1995).

57. OTHER STRATEGIES
• If psychosis continues without adequate benefit from the antipsychotics,
selegiline, anticholinergics, and amantadine should be withdrawn.
• If the symptoms persist, dopamine agonists should be reduced or stopped.
If necessary, the dose of levodopa should be tapered.
• Limited drug holiday, withdrawing dopaminergic drugs for 1–2 days each
week, might help to dispel psychotoxicity, allowing a reasonable dose of
medication to maintain mobility on other days.
• As drugs are reduced to improve the mental state, mobility deteriorates. A
brittle balance is reached at which the patient either is mobile but
confused, paranoid or hallucinating, or is mentally clear but immobile.
• Intact mental function is more important than an intact motor function.
• Resistant cases may require ECT.

58. RECAPITULATION

59. PSYCHIATRIC MANIFESTATIONS OF PD
• Fairly common (90%)
• Due to the disease pathology itself along with drug therapy.
• Commonest is depression mixed with anxiety. Often a diagnostic challenge in PD.
SSRIs may be used. CBTs useful.
• Cognitive impairment often related to drug therapy. Aim is to find sweet spot
between intact mental function and reduction in motor symptoms.
• Dementia poses poor prognosis. Widespread pathology. Responds poorly to
drugs. Donepezil and Rivastigmine tried with some success.
• Psychoses almost invariably iatrogenic. Visual hallucinations common, generally
benign. To decrease/withdraw drugs gradually. Responds to Quetiapine and
Clozapine.
• Behavioral abnormalities especially ICDs and repetitive behaviors seen. Atypical
antipsychotics may be used. ECT for resistant cases.

60. THANK YOU