Psychiatric manifestations of Parkinson’s disease

More than 60% of patients with Parkinson’s disease (PD) report having one or more psychiatric symptom.¹ Such complaints may arise from the same pathology underlying the Parkinson’s disease, including depression, anxiety, apathy and cognitive impairment, which may worsen as the disease progresses. Dementia is a well recognised complication of Parkinson’s disease with a reported prevalence varying from 10-40% in patients with Parkinson’s disease.²

Other psychiatric aspects relate more to the treatment of Parkinson’s disease and may present as sleep disturbances with vivid dreams and/or nightmares, visual hallucinations, delusions, mania and confusion.

These presentations may in fact occur independently of anti-parkinsonian treatment but are extremely rare and it is only with the introduction of dopaminergic replacement therapy (DRT) when these symptoms surface. An increasingly recognised complication of anti-parkinsonian medications is dopamine dysregulation syndrome (DDS), in which compulsive medication misuse leads to disabling motor and behavioural features.

General management of treatment-related psychosis is difficult, necessitating the need for a reduction of dopaminergic drugs, sometimes at the expense of worsening motor symptoms, and often with the addition of an atypical antipsychotic.

Further reading: Mental health problems in Parkinson’s disease

Early studies have suggested that certain psychological influences may be an important factor in the development of Parkinson’s disease.³ Those at risk tend to be introverted, calm and successful, whilst suppressing inner emotions, although these findings are not always reproducible. Twin studies however, have shown that genetic factors do not play a major role but that personality differences may be an early prodromal manifestation of the disease, typically presenting with a nervous, less aggressive, self-controlled and introspective personality.^4,5 Interestingly, some report that smoking may be protective,⁵ although this may be a reflection upon the personality type.

As with all chronic diseases, depression can be reactive in nature. However, it is generally believed that depression in Parkinson’s disease may be a consequence of the disease process itself as it is commoner than other equally disabling illnesses and may precede the onset of motor symptoms by up to five years.^6,7  Pathophysiologically, there is likely to be a greater degeneration of the dopaminergic neurons in the ventral mesencephalon, which has a role in mediating cognition, emotions and reward-seeking behaviour.⁷  Additionally, a reduction in the activity of other neurotransmitters is likely to be involved, particularly noradrenaline in the locus caeruleus and serotonin in the dorsal raphe nucleus.⁷

The diagnosis of depression is difficult as many features overlap with those of Parkinson’s disease. Anhedonia and feelings of low mood, guilt, hopelessness and suicidal ideation are characteristic of depression.⁸  Furthermore, depression also needs differentiating from apathy-typified by abulia in the absence of anhedonia and feelings of negativity. This is important as antidepressants are not effective in apathy and improved control of the Parkinson’s disease is usually the best strategy.  Trials with dopamine agonists or methylphenidate may be considered but are frequently disappointing.¹

Treatment of depression in Parkinson’s disease generally consists of DRT or an antidepressant. Optimising dopaminergic therapy in order to improve motor symptoms often helps. Levodopa is not considered to have a consistent mood effect, but the use of dopamine agonists (particularly those that also stimulate D3 receptors such as pramipexole or ropinirole) and the monoamine oxidase-B inhibitor, selegiline, exert antidepressant properties.⁷ The anticholinergic and sedative side effects limit the use of tricyclic antidepressants in Parkinson’s disease, but however may be beneficial in some as it may improve drooling, tremor and also sleep.^1,7 In general, selective serotonin reuptake inhibitors (SSRIs) are favoured due to their effectiveness and tolerability. Furthermore, psychotherapy such as cognitive behavioural therapy (CBT), problem-solving therapy (PST) and maladaptive coping strategies may prove useful for depression and anxiety. Only in severe refractory cases should electroconvulsive therapy be considered, when it can temporarily improve parkinsonism.^1,9

Cognitive changes are often subtle-particularly early in, or even before, the disease when such changes involve impairments of executive functions, eg. ability to plan, initiate, organise, and regulate goal-directed behaviour.^1,2 With progression of the disease, the dementia syndrome often manifests with dysexecutive, attentional and visuospatial deficits with or without behavioural disturbance. Retrieval of memory may be impaired with relatively preserved mnemonic function.¹

Dementia in Parkinson’s disease (PDD) overlaps with the features of dementia with Lewy bodies (DLB), which is associated more with prominent fluctuations in cognitive performance and alertness and visual hallucinations.¹⁰ However, as these features may also occur in PDD, the disorders are clinically differentiated by the temporal relationship between onset of motor symptoms and of dementia-those with motor symptoms for at least one year before the onset of dementia are diagnosed with PDD.²

Several theories exist explaining the cognitive decline seen in Parkinson’s disease.^3,11 The pathology of Parkinson’s disease and the dopamine deficiency itself, particularly affecting the mesolimbic and mesocortical projections, may be responsible for the subcortical dementia that ensues.  However, Alzheimer-type pathology, ie. amyloid plaques and neurofibrillary tangles, is commonly found in patients with Parkinson’s disease and may correlate with the severity of dementia.

Additionally, marked cholinergic deficits of the cerebral cortex and neuronal loss in the nucleus basalis of Meynert may also contribute to the cognitive decline. Alike that of DLB, alpha-synuclein positive Lewy intraneuronal inclusion bodies are found in all patients with Parkinson’s disease, the number of which in the cortex (especially the frontal lobe) correlates significantly to cognitive impairment.

There is controversy over the site and type of pathology that causes PDD but it is likely that this Lewy body-type degeneration in the cerebral cortex and limbic structures is the main determinant of PDD.¹¹

Treatment of PDD should commence with elimination of exacerbating factors such as drugs (eg. anticholinergics), infection, dehydration, etc. A trial of a cholinesterase inhibitor, such as donepezil or rivastigmine, may improve cognition and activities of daily living in patients with PDD.

There may also be an improvement in any associated psychosis, behavioural problems, apathy and mood disturbance.¹ Most evidence for efficacy for PDD lies with rivastigmine, which can result in a clinically meaningful benefit in about 15% of cases.¹²

Much of the psychiatric symptoms seen in Parkinson’s disease are complications of anitparkinsonian treatment. Such symptoms include vivid dreams, rapid eye movement (REM) sleep behaviour disorder, hallucinations, delusions mania, delirium, and dopamine dysregulation syndrome. These can, however, occur occasionally due to the natural progression of Parkinson’s disease but are commonly precipitated by medication.³ A continuum hypothesis has been suggested to explain these symptoms that tend to accumulate over the treatment period but it is likely that various factors determine the phenomenology of symptoms.¹

Dopaminergic activity, particularly in the mesocortical and mesolimbic systems, appears to play a great role in the generation of hallucinations. This is supported by the fact that cocaine and amphetamines, that have dopaminergic activity, can induce psychosis, whereas dopaminergic antagonists, such as haloperidol, are effective antipsychotics.¹³ Furthermore, serotonin is thought to be similarly involved, as agonists at the 5-HT2 receptor may also induce psychosis and antagonists at that receptor (eg. novel antipsychotics) help relieve it. It is also believed that the cholinergic system is also implicated as typified by anticholinergics causing psychosis. Some believe that hallucinations are fragments of dreams released from their usual cholinergic inhibition, as there is cholinergic degeneration of the pedunculopontine neurons, which control REM sleep.¹³  However, some also believe that hallucinations are often treatment-related although some may be independent of treatment and related to a hypodopaminergic state.¹⁴ Moreover, impairments of visual processing and categorisation probably contribute to the development of hallucinations.¹³

Visual hallucinations are the most common of the psychotic symptoms, occurring in 30% of patients with Parkinson’s disease, and are persistent and progressive.¹³ They typically occur with the patient’s eyes open, but generally in poor lighting conditions, with a blurry image suddenly appearing in an area of the visual field. The hallucinations are usually complex, possibly containing familiar people, animals, buildings or scenery and are often Lilliputian and moving, and last for a few seconds before suddenly vanishing.^1,15  Auditory (10%) and tactile (8%) hallucinations may also co-exist with the visual hallucinations, and at least 5% do not have insight.¹³

DDS is a neuropsychiatric behavioural syndrome impacting on social or occupational functioning, which is characterised by compulsive levodopa use beyond that needed to achieve relief of motor symptoms, and the need to perform certain appetitive acts associated with the impulse control system. The diagnostic criteria for DDS can be found in Box 1.  All of the behavioural features of DDS have been strongly associated with DRT, which is believed to activate brain “reward” pathways ultimately causing addiction. A theory regarding addiction based on psychostimulants (including cocaine and amphetamines) inducing some kind of pleasure and hence acting as a reward driving its compulsive use is
too simplistic.

Opponent process theory proposes that these drugs induce a euphoria-like state followed by an unpleasant withdrawal phase signifying reduced dopamine function, which predominates with repeated drug exposure.  In Parkinson’s disease, there is less reward-related activity (or less dopamine function) and therefore, there is an increased risk of addiction to DRT. Some believe that the use of DRT begins as an explicit, goal-directed action but with overlearning, it progresses into an implicit, automated, habitual behaviour with loss of voluntary control.  Many features of compulsive DRT use are compatible with an incentive sensitisation theory, during which plasticity changes cause mesolimbic dopaminergic hypersensitivity to the rewarding effects of drugs.^16,17 Male gender and early onset Parkinson’s disease are the main risk factors for acquiring DDS.¹⁸ The various features of DDS are discussed below.

Pathological use of dopamine

Early in DDS, patients tend to self-medicate and increase their levodopa, often in large increments, to a dose well beyond that needed to control parkinsonian motor symptoms.  Indeed, these patients will usually have quite dramatic, but well-tolerated, dyskinesias and is the only time when they feel “on”.  Any attempts to reduce the dose of DRT will probably be resisted and is often unsuccessful.^18,19

Patients will often hoard extra medication and may even adopt devious strategies (such as simulating tremor) or become aggressive and dishonest to acquire additional DRT.²⁰ Consequently, patients may display hypomanic behaviour or progress into a manic psychosis, during which there may be feelings of euphoria and joy with grandiose ideation and/or paranoia. Psychomotor agitation may be present, with disorganised speech and thought. However, these episodes may be short-lived or cyclothymic with emotional blunting, social withdrawal, depression and apathy during “off” periods.^18-20

Punding and Parkinson’s disease

This is a complex, stereotyped behaviour illustrated by intense fascination with purposeless and repetitive tasks, which is recognised in amphetamine and cocaine addiction and more recently with DRT.^17,21  Despite recognising these acts as irrational, patients continue to perform them and would become irritable if prevented.²² In fact, these actions are described as calming and associated with intense curiosity.²²  These tasks will vary according to the patient’s occupation and hobbies, but typically may include men dismantling technical equipment (eg. clocks, radios, engines, etc.) and analysing and sorting the parts but rarely assembling it back again; whereas women more often tidy, brush their hair or sort their handbags.²⁰  It is commonly associated with levodopa, apomorphine and other dopamine agonists (DA) such
as carbergoline.¹⁷

Appetitive behaviours

Hypersexuality is a common feature manifesting as increased libido, and in men, recurrent penile erections accompanied with inappropriate behaviour (e.g. exhibitionism, compulsive masturbation, excessive sexual demands etc.).^18,19  It is more frequent with pramipexole and in men, but is commonly under-reported.¹⁷ The patient may deny this behaviour and it is often the partner that opens up since the problem can cause family tension.¹⁹ Pathological gambling is also a recognised feature, which is often the result of DA therapy, particularly pramipexole, and frequently leads to dramatic financial, psychological and family consequences.  This is also true of compulsive shopping, but is commonly associated with a mood disorder and therefore antidepressants may help decrease the frequency and severity of uncontrolled buying.¹⁹ Compulsive eating is also described, particularly with pramipexole, but the prevalence is unknown.^17,19 Other addiction-like behaviours may also present such as excessive use of the internet, excessive participation in sports and, more recently, risk-seeking driving behaviour.^19,23

Patients should be warned of the potential risk of these behaviours, particularly if in the presence of risk factors. Avoidance of intermittent subcutaneous apomorphine is best since it may cause a “high” that may exacerbate DDS.¹⁸ Exacerbating factors, such as infection, should be sought and eliminated. The most effective treatment strategy is to reduce and/or withdraw the treatment in order of their psychogenicity as laid out in Box 2. This may also involve cautiously increasing the levodopa whilst decreasing DA therapy. Patients may have to receive their treatment daily under supervision and encouraged to use on-off diaries.¹⁸ However, this strategy is at the expense of worsening motor symptoms and therefore is not always appropriate.

The next step would be the introduction of an atypical antipsychotic. In 2002, the Movement Disorder Task Force reviewed the efficacy and safety of various drugs to treat psychosis in Parkinson’s disease.²⁴ Low dose clozapine (less than 50mg/day) has the most evidence for short-term (four weeks) efficacy with an acceptable risk of agranulocytosis if regularly monitored. It may also improve parkinsonian rest tremor. However, the Task Force deduced that there is insufficient evidence to conclude any long-term efficacy. There is insufficient evidence to conclude upon the efficacy and safety of the use of quetiapine in Parkinson’s disease, although many reports give a good impression with >80% of patients having an improved psychosis and 13-32% showing mild deterioration of motor symptoms.¹³ Therefore, in practice this tends to be a reasonable alternative to clozapine which does not require blood monitoring.  Insufficient evidence regarding the efficacy of olanzapine and the unacceptable risk of motor deterioration makes this drug not useful for the routine use.  Other drugs such as risperidone, zotepine and ondansetron have failed to show consistent results.

The use of a cholinesterase inhibitor, as discussed earlier, may help improve psychotic symptoms.  Once the psychosis settles there is often a profound negative affective state of depression with or without suicidal ideation. Therefore, there is usually the need for an antidepressant with close supervision during this period.¹⁸ ECT is reserved for those who are unresponsive to conventional treatments.¹³ Surgical management, such as deep brain stimulation of the subthalamic nucleus, has been successful in some but, paradoxically, is also known to cause these behaviours in others.¹⁷

The psychiatric complications of Parkinson’s disease are often overlooked but are known to cause great disability, reduced quality of life, and greater carer burden.  Moreover, many of these symptoms are common and therefore should be enquired about by the clinician.  Psychiatric symptoms manifesting during “off” periods can often be relieved by dopaminergic therapy, whereas those related to “on” periods usually respond to a reduction. However, this can be difficult to accomplish and other medications are often needed, eg. antidepressants and antipsychotics. Cholinesterase inhibitors are valuable if there is dementia, particularly if psychosis and/or mood disturbance is present. Further work is needed to improve our understanding of the pathophysiology of psychiatric manifestations in Parkinson’s disease with the aim of developing novel treatments, both medical and surgical, without the iatrogenic difficulties.

Conflict of interest: none declared

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Peter Ng, Acute Medical Registrar, Mid Cheshire Foundation Trust

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References

1. Schrag A. Psychiatric aspects of Parkinson’s disease. An update. J Neurol 2004; 251: 795-804
2. Grujic Z. Cognitive disturbances in Parkinson’s disease. Dis Mon 2007; 53: 302-308
3. Lishman WA. Organic psychiatry. The psychological consequences of cerebral disorder. Third edition, 2004. Blackwell Publishing
4. Duvoisin RC, Eldridge R, Williams A, et al. Twin study of Parkinson disease. Neurology 1981; 31(1): 77-80
5. Ward CD, Duvoisin RC, Ince SE, et al. Parkinson’s disease in twins. Adv Neurol 1984; 40: 341-44
6. Shiba M, Bower JH, Maraganore DM, et al. Anxiety disorders and depressive disorders preceding Parkinson’s disease: a case-control study. Mov Disord 2000; 15: 669-77
7. Lieberman A. Depression in Parkinson’s disease – a review. Acta Neurol Scand 2006; 113: 1-8
8. World Health Organisation. International statistical classification of diseases and related health problems. Tenth Revision. Geneva. World Health Organisation, 2004
9. Weintraub D, Stern MB. Psychiatric complications in Parkinson’s disease. Am J Geriatr Psychiatry 2005; 13: 844-51
10. McKeith IG, Perry EK, Perry RH. Report of the second dementia with Lewy body international workshop: diagnosis and treatment. Consortium on dementia with Lewy bodies. Neurology 1999; 53(5): 902-905
11. Emre M. What causes mental dysfunction in Parkinson’s disease. Mov Disord 2003; 18(suppl 6): S63-S71
12. Maidment I, Fox C, Bowtani M. Cholinesterase inhibitors for Parkinson’s disease dementia. Cochrane database of systematic reviews 2006, Issue 1. Art No.:CD004744. DOI:10.102/14651858.CD004747.pub2
13. Wint DP, Okun MS, Fernandez HH. Psychosis in Parkinson’s disease. J Geriatr Psychiatry Neurol 2004; 17: 127-36
14. Onofrj M, Bonanai L, Albani G, et al. Visual hallucinations in Parkinson’s disease: clues to separate origins. J Neurolog Sci 2006; 248: 143-150
15. Barnes J, David AS. Visual hallucinations in Parkinson’s disease: a review and phenomenological survey. J Neurol Neurosurg Psychiatry 2001; 70: 727-33
16. Lawrence AD, Evans AH, Lees AJ. Compulsive use of dopamine replacement therapy in Parkinson’s disease: reward systems gone awry? Lancet Neurol 2003; 2: 595-604
17. Voon V, Potenza MN, Thomsen T. Medication-related impulse control and repetition behaviours in Parkinson’s disease. Curr Opin Neurol 2007; 20(4): 484-92
18. Giovannoni G, O’Sullivan JD, Turner K, et al. Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neuol Neurosurg Psychiatry 2000; 68: 423-28
19. Merims D, Giladi N. Dopamine dysregulation syndrome, addiction and behavioural changes in Parkinson’s disease. Parkinsonism Relat Disord (2007), doi:10.1016/j.parkreldis.2007.09.007
20. Evans EH, Lees AJ. Dopamine dysregulation syndrome in Parkinson’s disease. Curr Opin Neurol 2004; 17: 393-98
21. Rylander G. Psychoses and the punding and choreiform syndromes in addiction to central stimulant drugs. Psychiatr Neurol Neurochir 1972; 75: 203-12
22. Evan AH, Katzenschlager R, Paviour D, et al. Punding in Parkinson’s disease: its relation to the dopamine dysregulation syndrome. Mov Disord 2004; 19(4): 397-405
23. Avanzi M, Baratti M, Cabrini S, et al. The thrill of reckless driving in patients with Parkinson’s disease: an additional behavioural phenomenon in dopamine dysregulation syndrome? Parkinsonism Relat Disord (2007), doi:10.1016/j.parkreldis2007.04.006
24. The Movement Disorder Task Force. Drugs to treat dementia and psychosis. Mov Disord 2002; 17(Suppl 4): S120-S12