Parkinson’s disease (PD) is commonly associated with psychiatric morbidity, which may include depression, anxiety, and dopaminergic psychosis. These psychiatric disturbances have a multifactorial relationship to the underlying neuropathology of PD. The treatment goals may include improvement or remission of psychiatric symptoms and restoration of optimal patient functioning.
In Parkinson’s disease (PD), the physical aspects, such as tremor, rigidity, and postural instability, are the defining characteristics of the disease and, understandably, they are the focus of most research and clinical care. However, several non-motor aspects of PD, including depression, drug-induced psychosis and impulse control disorders, cognitive impairment, anxiety, and sleep disturbances, are common and are associated with a variety of poor outcomes.1 The non-motor symptoms (NMS) complicate the clinical management of the disease and are significant determinants of poor quality of life for patients and their carers.2
Depression, anxiety, and psychosis are common complications of Parkinson’s disease and may be attributed to the medications used in PD treatment.3 Effective treatment is available and will depend upon accurate diagnosis of the psychiatric disorders and its relationship to various contributing factors, including adverse effects of PD medications and negative psychological reactions to the motor disability.
Current estimates of the prevalence of psychiatric problems, particularly depression, in PD vary considerably, mostly because of differences in sampling methods and case ascertainment. Community-based studies appear to produce lower prevalence figures. Depression is the most common psychiatric syndrome, with prevalence in PD as high as 42%.3 Anxiety is also a frequent problem for PD patients, with a prevalence of 33 to 40%.3 In addition, anxiety is comorbid with depression in up to 92% of cases and both may predate the onset of motor symptoms. Psychotic symptoms are also common in PD and may occur in at least 20% of patients on treatment. Visual hallucinations are the most common drug effect in patients with PD, although auditory and tactile hallucinations also occur.4,5 These usually take the form of non-threatening visual illusions that do not require active intervention. However, overtly threatening hallucinations can develop human or animal figures that are stereotyped for each patient and are most common at night.5
PD is commonly associated with psychiatric morbidity, which may include depression, anxiety, dopaminergic psychosis, delirium and cognitive impairment. These psychiatric disturbances have a multifactorial relationship to the underlying neuropathology of PD as well as the use of drug therapy.
Psychiatric complications of PD
Generally, the stress of anticipating and coping with a relentless degenerative disease helps to trigger depression and anxiety in patients with PD. Depression is among the most common neuropsychiatric disturbances found in PD. Approximately, 40% of persons with PD are depressed; half meet criteria for major depression and half meet criteria for a less severe form of depression, dysthymia.4
Patients with a history of depression are at particular risk.3 Those with recent deterioration or advancing severity of PD, akinesia, history of falls, or cognitive impairment are also at increased risk for depression.3 Depression correlates well with the patient’s perception of her/his degree of PD-related disability and depression symptoms seem to peak early in the illness following diagnosis and in advanced disease.3
Many of the symptoms used to make a diagnosis of depression, including poor sleep, decreased energy, psychomotor retardation, and poor concentration, are seen in nearly all patients with PD (Table 1). However, these are more properly seen as direct manifestations of PD and not of depression. Therefore, while the usual screening instruments are useful, a careful interview, focused on mood, affect, and hedonic capacity (a component of reward responsiveness and reward processing system), is critical.5 Patients also frequently have a main complaint of diminished energy or fatigue that should trigger further investigation into other depressive symptoms.3
The incidence of suicide is lower in patients with PD, despite the extremely high rates of depression.5 Several studies suggested that patients with PD and depression have damage to serotonergic systems and to dopaminergic basal ganglia-limbic-frontal systems that are involved in mood regulation, pleasure and reward. Therefore, these complex systems are probably differentially affected and combine with the psychosocial stress of this chronic illness to produce variable levels of distress.5
Management should include optimal control of the physical aspects of PD as a prerequisite to adequate treatment of depression.5,6 Despite the prevalence of depression in patients with PD, there are few controlled, well-designed studies that direct treatment of this disorder.5 An extensive clinical experience supports the efficacy of tricyclic antidepressants, but selective serotonin reuptake inhibitors (SSRIs) are the preferred treatment, although only open-label trials and case reports support their efficacy.7 Compared with tricyclics, SSRIs exhibit a relative lack of problems with sedation, orthostatic hypotension, and memory-impairing anticholinergic side effects.3 Some case reports have cited worsening of motor symptoms with SSRIs, but a prospective study found no significant worsening of PD symptoms during treatment with citalopram, fluoxetine, fluvoxamine, or sertraline.8 Co-administration of an SSRI with selegiline is not absolutely contraindicated; however, the combination does carry a very small risk of development of serotonin syndrome.3,7
Electroconvulsive therapy (ECT) should be considered in patients with severe depression when pharmacological agents have failed. ECT has been shown to be an effective treatment of depression and in most cases; both the mood and the motor symptoms improve, although the motor improvement is short-lived.5 Deep brain stimulation (DBS) may be considered in refractory depression and although these treatments are still experimental, they are promising.5 Multidisciplinary team approach with close collaboration of the treating physician, psychiatrist and therapy team may become particularly important in the later stages of the illness, when motor fluctuations and cognitive impairment become apparent. Several studies have demonstrated a tight correlation between “off” periods and depression, and unless there is good control of the fluctuations, antidepressant therapy will be suboptimal.6
Anxiety is a frequent problem in PD that typically presents with symptoms of panic disorder, generalised anxiety disorder, or social phobia. Anxiety is frequently part of the presenting symptoms of a depressive illness, and at times may be the dominant symptom. It is comorbid with depression in up to 92% of cases and—like depression—frequently predates the onset of motor symptoms.3Symptoms of anxiety have been correlated, although not consistently, with the on-off motor phenomenon often found in advanced PD, particularly accompanying the “off” state.3 These symptoms can also be an adverse effect of many of the antiparkinsonian medications, including catechol-O-methyltransferase inhibitors, selegiline, anticholinergics, and dopamine agonists.
Both anxiety and depression have been associated with an increased risk for falls.6 There are no enough well-designed studies that have examined the treatment of anxiety in PD patients. However, given the significant high comorbidity of anxiety with depression, antidepressants should probably be considered as a first-line pharmacotherapy.6 In addition, benzodiazepines should be used cautiously, as they may increase the risk of falls, sedation, and confusion in older patients.6
Psychotic symptoms are common in PD and occur in at least 20% of medication-treated patients.9 Psychotic symptoms can occur with or without the clouded sensorium characteristic of delirium. The most commonly encountered symptoms are visual hallucinations, auditory hallucinations and delusions. Benign visual hallucinations usually appear earlier, while malignant hallucinations, confusional states, delusions, paranoid beliefs, agitation, and delirium become more frequent with the progression of the disease.
About 25% of PD patients experience delusions or hallucinations.3 Cognitive impairment, increased age, disease duration and severity, depression, and sleep disorders have been consistently identified as independent risk factors for their development.9
The use of dopaminergic agents is among the common risk factors and up to one-fifth of patients using dopaminergic drugs experience psychotic symptoms.3In addition, catechol-O-methyltransferase inhibitors cause more sustained dopaminergic activity of levodopa, which can result in psychotic symptoms. Psychotic symptoms with an associated confusional state can be associated with use of anticholinergic agents and drugs such as selegiline and amantadine.3 Therefore, the use of all known classes of PD medications has been associated with drug-induced psychosis. Paranoid delusions, delusions of spousal infidelity, and visual hallucinations are common in advanced PD, whereas negative symptoms (ie. apathy, lethargy and withdrawal) and thought disturbances are not.10
Successful management of psychotic symptoms in PD may rely on a multi-target approach to restore neurotransmitter imbalances rather than focusing exclusively on the dopaminergic dysfunction.9 In addition, psychosis may be a more important contributor to caregiver distress than PD motor symptoms and may be more likely than any other factor to lead to nursing home placement of the PD patient.3
Drug reactions: psychosis and impulse control disorders
PD pharmacologic treatment emphasises dopamine replacement, dopamine receptor stimulation, or prevention of enzymatic breakdown of dopamine in the synaptic cleft.3 While these drugs have their effects on a variety of CNS neurotransmitter systems, they primarily affect dopamine transmission. Thus, it is not surprising that they often produce dramatic behavioural changes that cause significant difficulties for patients and their families and carers.5 There are convincing data that suggest that treatment with dopaminergic agents may be associated with the development of a variety of impulse control disorders in some patients.5 Impulse control disorders, including severe gambling and hyper-sexuality as well as shopping and binge eating, can be extremely disruptive to patients and families.
As with psychosis, impulse control disorders are more commonly associated with the dopamine agonists, pramipexole and ropinirole.11 Given the impact of impulse control disorders, clinicians need to educate patients and monitor them for the early signs of these disturbances.5
Delusions are uncommon in the first two years of PD therapy, but may also occur and, as with hallucinations, are often preceded by vivid dreams.5 These delusions are usually persecutory in nature, including fears of being injured, influenced, poisoned, filmed, and/or tape-recorded.5
Psychosis is very rare in untreated PD patients; however, anti-parkinsonian medications can cause hallucinations, delusions, agitation, and mania—all of which can greatly complicate care. Psychosis does occur with the older levodopa-based drugs, but it appears to be more frequently associated with the newer direct postsynaptic dopamine agonists, pramipexole and ropinirole.5 In severe cases, the psychotic symptoms are virtually indistinguishable from those seen in schizophrenia cases.
Management of drug-induced symptoms generally involves a decrease in the dosage of the antiparkinsonian medication and direct dopamine agonists are the first target, followed by the anticholinergics and by levodopa preparations.12 However, reducing the dosage of the antiparkinsonian drugs often results in an increase in the motor symptoms, which has been referred to as the “motion-emotion conundrum”.13
The atypical antipsychotics may be of help in this setting. Several studies have examined the tolerability and efficacy of these drugs in patients with PD; they show that drugs with high affinities for D2 receptor, such as atypical antipsychotics risperidone or aripiprazole, are not well tolerated. A low-dose of quetiapine is widely used, although results of controlled trials have been equivocal.14 Clozapine has been among the most extensively studied atypical antipsychotics in PD and has been shown in open and double-blind trials to be effective and well tolerated at low dosages (6.25 to 50 mg/d).3 Clozapine causes very few extrapyramidal symptoms when it is used in low doses. However, its use is more problematic because of the risk of agranulocytosis requiring strict monitoring as well as the anticholinergic, sedative, and orthostatic hypotensive adverse effects.5
Delirium, cognitive impairment and dementia
PD is associated with subtle, but widespread cognitive impairment, even in the absence of clinically apparent cognitive decline or frank dementia. Anticholinergic agents can cause a worsening of cognitive deficits and can precipitate delirium, which may include a variety of psychotic symptoms.5
Early in the course of the illness or at the time of diagnosis, there are difficulties with memory retrieval, executive functioning, attention, and visuo-spatial abilities—all of which are associated with significant functional impairment.15 More severe forms of cognitive impairment, including dementia, also occur commonly in patients with PD. The clinical feature of dementia may include cognitive decline with memory impairment, behavioural changes with aggression and/or wandering, and psychiatric symptoms, such as mood disorders.
The average prevalence of dementia in PD, which generally occurs later in the illness, is about 39.9%.16 The use of anticholinesterase drugs for the treatment of dementia in PD is somewhat limited by their efficacy and tolerability.5 In a large randomised trial, clinically meaningful improvement occurred in 5.3% more patients who received rivastigmine compared with those who received placebo.17 The most common adverse effects were nausea, vomiting, and tremors. In addition, a smaller study with memantine found that this drug produced a small beneficial effect over placebo and was well tolerated.18
Goals for psychiatric treatment of depression, anxiety, and psychosis associated with PD seem relatively straightforward, including improvement or remission of psychiatric symptoms and restoration of optimal patient functioning.3 However, compromises must be made between optimal control of parkinsonian and psychiatric symptoms to achieve the best overall patient function. In an ideal world, these goals would be achieved without causing sedation, orthostatic hypotension, or exacerbating motor symptoms. However, the older age of patients and the progressive nature of this neurodegenerative disorder predispose patients to cognitive side effects and despite the high prevalence of psychiatric disturbances in PD, evidence with which to evaluate treatment efficacy and safety and to guide treatment selection is extremely limited.3
Treatment of drug-induced symptoms generally involves a decrease in the dosage of the antiparkinsonian medication and the possible use of antipsychotic medications.5 When psychiatric medications are necessary for depression, anxiety, or psychosis, clinicians should carefully review target symptoms, treatment expectations, and possible adverse effects with the patient and carer.3
Clinicians should keep in mind the progressive nature of PD and, in addition to frequent monitoring, should educate and encourage caregivers to immediately report any suspected adverse effects.3 Patients should be encouraged to exercise, to keep up their social contacts, and to seek out local PD support groups.5 Supportive therapy directed at education and maintenance of activities outside the home is often beneficial. Furthermore, as psychiatric and PD symptoms and treatments are closely interrelated, the psychiatrist, clinician, patient, and carer must collaborate for the best therapeutic result.
A simplistic approach to treatment can result in a catastrophic downward spiral in patient functioning.3 PD patients and carers must be counselled about possible psychiatric symptoms associated with PD and antiparkinsonian therapy, as well as the potential for adverse effects from psychiatric medications.3
PD is commonly associated with psychiatric disturbances, which may include depression, anxiety, dopaminergic psychosis, delirium and cognitive impairment. Treatment of PD, particularly in the advanced stages, is complicated by the emergence of psychiatric symptoms, such as hallucinations and psychosis, as dopamine levels are increased in an attempt to smooth the motor response. Thus, the significantly distressing level of disability associated with the prominent side effects of pharmacological treatment will make the management very challenging. Psychosis may be a more important contributor to carer distress than the motor symptoms of PD and may be more likely than any other factor to lead to nursing home placement of the PD patient. Effective management of these disorders will depend upon accurate diagnosis of the psychiatric disorders and its relationship to various contributing factors, including adverse effects of PD medications and negative psychological reactions to the motor disability.
Dr N Aly, Consultant physician, DME, University Hospital Aintree, Liverpool, Lower Lane, Liverpool
Conflict of interest: none declared
8. Dell’Agnello G, Ceravolo R,Nuti A, Bellini G, Piccinni A, D’Avino C, Dell’Osso L and Bonuccelli U. SSRIs do not worsen Parkinson’s disease: evidence from an open-label, prospective study. Clin Neuropharmacol 2001; 24(4): 221–27
14. Miyasaki JM, Shannon K, Voon V, et al; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: Evaluation and treatment of depression, psychosis, and dementiain Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006; 66: 996–1002
18. Emre M, Tsolaki M, Bonuccelli U, et al, on behalf of the 11018 Study Investigators. Memantine for patients with Parkinson’s disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol 2010; 9(10): 969–77