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Psychiatric manifestations of common neurological disorders

16th Jul 2013

THIS Update will discuss five common neurological disorders and their psychiatric associations.

Dr Ralf Ilchef 

Consultant Psychiatrist, Royal North Shore Hospital, Sydney.

Conflicts: nothing to declare


It is not surprising, given that they emanate from the same organ, that psychiatric disorders are common comorbidities in disorders of the central nervous system (CNS), and may in fact be the presenting symptoms. 

When psychiatric disorders arise in the presence of a neurological disorder, they may be a physiological or psychological consequence of the disorder itself, a complication of its treatment, or may arise from a common underlying pathology. This article looks at five common neurological disorders — migraine, stroke, Parkinson’s disease, epilepsy and multiple sclerosis — and their psychiatric associations.


Migraine affects more than 10% of people and has been ranked by the World Health Organization (WHO) as the 19th most disabling disorder worldwide. 1,2 Some sufferers experience hallucinations or illusions in various sensory modalities. While its pathogenesis remains incompletely understood, there is an established link with psychiatric disorders. For example, migraine patients are up to four times more likely than controls to experience depression,3 and anxiety disorders such as panic disorder, generalised anxiety disorder and obsessive-compulsive disorder (OCD) are also more common. 

When migraine and depression are comorbid, treating both conditions can present challenges. Tricyclic antidepressants and SNRIs such as venlafaxine can be effective for both, but antidepressants can sometimes worsen headache control. 

Some migraine prophylactic treatments such as beta-blockers have been reported to worsen or provoke psychiatric symptoms, although the evidence base for this long-held belief is not strong.5 Although topiramate is increasingly popular for migraine prophylaxis, studies have shown a rate of psychiatric adverse events as high as 23.9%.6 Increased suicidal ideation has been described with anticonvulsants as a class, although the significance of this association has been debated.7

When prescribing NSAIDs for headache, be mindful that co-prescription of SSRI antidepressants may increase the risk of upper GI haemorrhage. 8


Sixty thousand strokes occur annually in Australia, and represent a leading cause of disability. 9 Almost a fifth occur in people under 55 years of age,10 and at least a quarter are associated with the development of a depressive disorder in the first year.11 

The risk of depression is significantly higher than in other comparably disabling disorders,12 and stroke is an identified risk factor for suicide,13 as well as all-cause mortality.14 

A number of studies have looked at lesion location, with some showing higher rates of depression with left hemispheric and frontal pole lesions, 15 while others have failed to replicate this.16 The peak prevalence of depressive symptoms is between three and six months post-stroke.12 After the acute phase, level of disability is the strongest predictor of depressive symptoms, especially inability to walk.17

A two-way causal relationship has been established, with a history of depression predicting an increased likelihood of stroke as well as stroke mortality.18 It is unclear whether this is due to direct neuroendocrine or immunological changes, lifestyle factors or medication.

Several antidepressants have been shown to treat post-stroke depression effectively, including nortriptyline, sertraline, citalopram and fluoxetine,12 and there is some evidence that they may independently improve stroke outcome; for example, leading to improvements in frontal/executive function.19

Another correlation between stroke and psychiatric illness is the increased risk of stroke noted in some studies in users of antipsychotic medications. With the broadening of diagnostic criteria for bipolar disorder and widespread off-label use of second-generation antipsychotic drugs such as quetiapine, this needs to be borne in mind, especially in older patients, whose relative risk of stroke may be as much as doubled.20 A more recent Australian study did not show an increased risk of adverse cerebrovascular events.21 Finally, antidepressants of all classes appear to be associated with a small increase in stroke risk (relative risk approximately 1.5).22

Parkinson’s disease

Depression is the most common comorbid psychiatric disorder seen in Parkinson’s disease (PD), occurring in 50% of cases.23 Nortriptyline, but not paroxetine, was demonstrated in a randomised controlled trial to be effective for depression in PD,24 although enthusiasm for this drug may be tempered by a recent study that indicated an elevated risk of out-of-hospital cardiac arrest.25 Small studies have also been carried out using sertraline, atomoxetine and mirtazapine but were unable to demonstrate a statistically significant benefit.26 A 10-week trial of cognitive behavioural therapy (CBT) demonstrated significant improvement in mood, quality of life and even Parkinson’s disease severity scores.27 In severe depression, electroconvulsive therapy (ECT) is effective, and may also be dramatically beneficial for Parkinson’s disease symptoms.28 

Depression occurs in 50% of Parkinson’s disease cases.

Psychosis is relatively uncommon in untreated Parkinson’s disease but is a well-recognised complication of PD in the setting of levodopa therapy. Most antipsychotic medications will worsen motor symptoms and the clinical consensus is to move towards clozapine (the only agent with level I evidence to support its use) early if symptoms are not readily responsive to another agent.29 

A recent study suggests ziprasidone may be an effective alternative.30 ECT may also have a place in the treatment of Parkinson’s disease related psychosis.31

Deep brain stimulation involving the subthalamic and adjacent nuclei has been a very exciting development in the treatment of PD in the last 15 years and has led to spectacularly good motor outcomes for many people. Perhaps unsurprisingly though, the procedure can be associated in a minority of cases with adverse psychiatric events including anxiety and mood disorders and psychosis, with incidents of attempted and completed suicide having been recorded. It is generally recognised that close psychiatric follow-up pre- and post-operatively is mandatory.32


The relationship between epilepsy and psychiatric disorders is complex enough to warrant an article of its own, but some associations can be highlighted here. Patients with epilepsy have higher rates of mood and anxiety disorders and ADHD than controls.33 This association holds for uncomplicated epilepsy but is especially strong for those with early onset epilepsy, and where epilepsy occurs in the presence of macroscopic brain lesions. The cognitive and social deficits that can be associated with epilepsy are likely to play a role, as may neuropathological factors such as hippocampal atrophy.34 As with stroke, evidence is emerging of a bidirectional relationship, with some psychiatric disorders associated with an increased risk of subsequent epilepsy.35

Psychotic symptoms in epilepsy are classified as interictal; occurring between seizures or ictal; occurring concurrently with seizures, usually as part of a complex partial seizure disorder. While this has been traditionally known as ‘temporal lobe epilepsy’, in some cases the seizures emanate from deep midline frontal structures. Although these psychoses respond well to antipsychotic medication, they typically have a very different course from schizophrenia, with brief episodes, and lower rates of hospitalisation or psychosocial deterioration.36

Some of the more recent GABAergic anticonvulsants including topiramate (as noted earlier) and levetiracetam are associated with significant risks of psychiatric adverse events (PAEs), including severe depression, anxiety and psychosis. 

Phenytoin, valproate, carbamazepine and lamotrigine have comparatively low rates of PAEs.37 

Additionally, a class concern has recently been raised for all anticonvulsants regarding an increased risk of suicidal ideation.38 A very recent consensus guideline notes that while suicidal ideation or behaviour may emerge in patients on antiepileptic drugs (AEDs), “[t]he risk of stopping AEDs or refusing to start AEDs is significantly worse and can actually result in serious harm including death to the patient… If necessary, patients should be referred for a psychiatric evaluation, but AED treatment should not be withheld, even in patients with positive suicidal risks”.39

Some doctors may be concerned about starting psychotropic medication in patients with comorbid epilepsy and a psychiatric disorder because of the risk of worsening seizure control. This risk needs to be looked at proportionately. Most antidepressants are associated with a ≤0.5% risk of precipitating a seizure, with the possible exception of clomipramine, so that SSRIs can be regarded as reasonably safe, with the suggestion even having been made that they may have anticonvulsant actions at low dose.33, 40 

When instituting antipsychotic treatment, chlorpromazine and clozapine are proconvulsant at higher doses but olanzapine (0.9%), quetiapine (0.9%) and risperidone (0.3%) have very low seizure rates. It should be noted that electroconvulsive therapy is not contra-indicted in epilepsy and is in fact typically well tolerated. There is evidence of effectiveness for cognitive behavioural therapy (CBT) in adolescents and adults with epilepsy
and depression.41,42

A final association that should be noted is the phenomenon of non-epileptic seizures, seen most typically in children, people with developmental disorders and adults with trauma histories or significant personality disorders. These are more common than might be imagined, accounting for over a quarter of referrals to one adult epilepsy clinic.43 

There is considerable overlap between epileptic and non-epileptic seizures, with 20% of patients with established epilepsy experiencing a non-epileptic seizure at least once.33 

A recent study showed that neither physicians nor psychiatrists could reliably distinguish them on clinical grounds.44 While engagement, establishing the diagnosis and reassurance are the mainstays of intervention, psychological therapies and SSRIs have a modest evidence base.45, 46

Multiple sclerosis

Multiple sclerosis (MS) is the most common non-traumatic cause of neurological disability in the Western world.47 

Neuropsychiatric complications are common, and can be broadly divided into disorders of cognition and disorders of mood and affect. The first are largely directly related to the distribution and density of demyelinating plaques, and outside the scope of this review. 

Mood symptoms including dysphoria are seen in up to 80% of people with MS, and anxiety symptoms in about one third.48 

Multiple sclerosis is the most common non-traumatic cause of neurological disability in the Western world.

There is some evidence that depression is more common in patients with a high lesion load in the dominant anterior temporal lobe and medial inferior prefrontal cortex. Early concerns that beta-interferons might worsen depressive symptoms have been largely allayed, but caution should still be observed in initiating these drugs in patients with a history of depression.

Depression is a key predictor of quality of life in this group of patients, who have a higher suicide rate than people with comparably disabling neurological disorders.48

With regard to treatment, a Cochrane review in 2011 found only two small studies of adequate design, showing a trend for efficacy with desipramine (no longer available in Australia) and paroxetine. 49 

Open trials suggest sertraline, fluoxetine and moclobemide may also have utility. Open studies similarly support the effectiveness of psychological interventions with an emphasis on coping skills, such as CBT and mindfulness-based interventions.50 

In patients who have not responded to antidepressants or psychotherapy and those with acute suicidality, limited evidence suggests that ECT can be effective,51 although it has been suggested that patients with gadolinium enhancing lesions on MRI may be at risk of an exacerbation of MS symptoms.52 


The title of this article, which after all could be translated as ‘brain manifestations of common brain disorders’, reminds us of the Cartesian knots neurologists and psychiatrists get themselves into while trying to bring their quite different paradigms to bear on disorders of the brain. Any attempt to ring-fence ‘organic’ from ‘functional’ disorders of the brain does not really stand up to close scrutiny as the complex inter-relationships of these conditions hinted at in this paper suggest. For example, evidence is accumulating that at least some psychiatric disorders have an inflammatory or autoimmune basis. The relationship between the macroscopic brain diseases that neurologists treat and the complex disorders of higher cognitive function seen by psychiatrists will be a fascinating field of enquiry into the next century. Meanwhile GPs, psychiatrists and neurologists will need to continue liaising closely in managing the fascinatingly complex care needs of these patients.

Acknowledgments: The author would like to thank his colleague, neurologist Dr John Parratt for his valuable comments in reviewing the manuscript.


1. Fenstermacher N et al. Pharmacological prevention of migraine. BMJ 2011;342:540-543

2. Magis D et al. Treatment of migraine: update on new therapies Curr Opin Neurol 2011;24:203–210

3. Pompili N et al. Psychiatric comorbidity in patients with chronic daily headache and migraine: a selective overview including personality traits and suicide risk. Journal of Headache & Pain 2009;10(4):283-90

4. Gambini O et al. Consultation-liaison psychiatry for headaches. Neurological Sciences 2011;32(s1):S81-S83

5. Aggarwal V et al. Incidence of depression, chronic fatigue and sexual dysfunction with beta-blocker use: a meta-analysis of randomised controlled trials. J Am Coll Cardiol 2012;59(13s1):E1461

6. Mula M et al. Topiramate and psychiatric adverse events in patients with epilepsy. Epilepsia 2003;44(5):659–663

7. Kanner AM. Are anticonvulsant drugs used in the treatment of migraine associated with an increased risk of suicidality?. Current Pain & Headache Reports 2011; 15(3):164-169

8. Loke YK, Trivedi AN, Singh S. Meta-analysis: gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2008;27(1):31-40

9. Australian Institute of Health and Welfare. Australia’s Health 2006.

10. AIHW: Heart, stroke and vascular diseases, Australian Facts 2004

11. Hackett ML, Yapa C, Parag V, Anderson CS. Frequency of depression after stroke: a systematic review of observational studies. Stroke 2005;36:1330–1340.

12. Santos M et al. The neuroanatomical model of post-stroke depression: Towards a change of focus? J Neurol Sci. 2009 August 15; 283(1-2): 158–162.

13. Pompili M. Do Stroke Patients have an Increased Risk of Developing Suicidal Ideation or Dying by Suicide? An Overview of the Current Literature. CNS Neuroscience & Therapeutics 2012;18:711–721

14. Ellis C et al. Depression and increased risk of death in adults with stroke. J Psychosom Res. 2010;68(6): 545–551

15. Kouwenhouven SE et al. Depression in acute stroke: prevalence, dominant symptoms and associated factors. A systematic literature review. Disability and Rehabilitation, 2011; 33(7): 539–556

16. Aben I, Lodder J, Honig A, Lousberg R, Boreas A, Verhey F. Focal or generalized vascular brain damage and vulnerability to depression after stroke: a 1-year prospective follow-up study. Int Psychogeriatr 2006;18:19–35.

17. Caeiro L, Ferro JM, Santos CO, Figueira ML. Depression in acute stroke. J Psychiatr Neurosci 2006;31:377–383.

18. Pan A et al. Depression and risk of stroke morbidity and mortality: a meta-analysis and systematic review. JAMA 2011;306(11):1241-1249

19. Narushima K et al. Effect of antidepressant therapy on executive function after stroke. Br J Psychiatry. 2007 Mar;190:260-5.

20. Douglas IJ. Exposure to antipsychotics and risk of stroke: self controlled case series study. BMJ 2008; 337:a1227

21. Pratt NL. Risk of Hospitalization for Stroke Associated with Antipsychotic Use in the Elderly. Drugs & Aging 2010; 27(11): 885-893

22. Wu C-S et al. Association of Cerebrovascular Events With Antidepressant Use: A Case-Crossover Study, Am J Psychiatry 2011;168:511-521.

23. Dobkin RD et al. Depression in Parkinson’s disease: Symptom Improvement and Residual Symptoms Following Acute Pharmacological Management. Am J Geriatr Psychiatry. 2011;19(3): 222–229.

24. Menza M et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology 2009;72:886-892

25. Weeke P et al. Antidepressant Use and Risk of Out-of-Hospital Cardiac Arrest: A Nationwide Case–Time–Control Study. Clinical Pharmacology & Therapeutics 2012;92:72-79

26. Price A et al. Antidepressants for the treatment of depression in neurological disorders: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry 201. doi:10.1136/jnnp.2010.230862

27. Dobkin RD et al. Cognitive Behavior Therapy for Depression in Parkinson’s Disease: A Randomized Controlled Trial. Am J Psychiatry. 201; 168(10): 1066–1074

28. Popeo D et al. ECT for Parkinson’s disease. Medical Hypotheses 2009;73(4):468–469

29. Friedman JH. Parkinson’s disease psychosis 2010: a review article. Parkinsonism Relat Disord. 2010;16(9):553-60

30. Pinter L et al. Ziprasidone Versus Clozapine in the Treatment of Psychotic Symptoms in Parkinson Disease: A Randomized Open Clinical Trial. Clinical Neuropharmacology 2012;35(2): 61–66

31. Ueda S et al. Marked Improvement of Psychotic Symptoms After Electroconvulsive Therapy in Parkinson Disease. Journal of ECT 2010;26(2):111-115

32. Meagher LJ et al. Psychiatric morbidity in patients with Parkinson’s disease following bilateral subthalamic deep brain stimulation: literature review. Acta Neuropsychiatrica 2008;20( 4):182–192

33. Lin JJ et al. Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. Lancet 2012; 380: 1180–92

34. Finegersh A et al. Bilateral hippocampal atrophy in temporal lobe epilepsy: effect of depressive symptoms and febrile seizures. Epilepsia 2011; 52: 689–97.

35. Hesdorffer DC, Ishihara L, Mynepalli L, Webb DJ, Weil J, Hauser WA. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann Neurol 2012; 72: 184–91.

36. Sachdev P. Schizophrenia-like psychosis and epilepsy: the status of the association. Am J Psychiatry 1998;155:325-336.

37. Mula M, Monaco F. Antiepileptic drugs and psychopathology of epilepsy: an update. Epileptic Disord 2009; 11: 1–9.

38. FDA. Antiepileptic drugs and suicidality. 2008. Available at:

39. Mula M et al. Antiepileptic drugs and suicidality: An expert consensus statement from the Task Force on Therapeutic Strategies of the ILAE Commission on Neuropsychobiology. Epilepsia 2013, 54(1): 199–203

40. Alper K et al. Seizure Incidence in Psychopharmacological Clinical Trials: An Analysis of Food and Drug Administration(FDA) Summary Basis of Approval Reports. Biol. Psychiatry 2007;62:345–354

41. Crail-Melendez D, Herrera-Melo A, Martinez-Juarez IE, Ramirez-Bermudez J. Cognitive-behavioral therapy for depression in patients with temporal lobe epilepsy: a pilot study. Epilepsy Behav 2012; 23: 52–56.

42. Martinovic Z. Adjunctive behavioural treatment in adolescents and young adults with juvenile myoclonic epilepsy. Seizure 2001; 10: 42–47.

43. Smith D et al. The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic. QJM 1999;92 (1): 15–23

44. McDonald T et al. Psychiatry versus general physicians: who is better at differentiating epileptic from psychogenic non-epileptic seizures? Australasian Psychiatry 2012;20(5):379-383.

45. Bodde NM et al. Psychogenic non-epileptic seizures--definition, etiology, treatment and prognostic issues: a critical review. Seizure. 2009 Oct;18(8):543-53

46. LaFrance WC et al. Pilot pharmacologic randomized controlled trial for psychogenic nonepileptic seizures. Neurology 2010;75:1166–1173

47. Paparrigopoulos T et al. The neuropsychiatry of multiple sclerosis: Focus on disorders of mood, affect and behaviour. International Review of Psychiatry 2010; 22(1): 14–21

48. Figved N et al. Neuropsychiatric symptoms in patients with multiple sclerosis. Acta Psychiatrica Scandinavica 2005;112:463–468.

49. Koch MW. Pharmacologic treatment of depression in multiple sclerosis (Review) 2011; The Cochrane Library 2011;2:1-34

50. Siegert RJ et al. Depression in multiple sclerosis: a review. J Neurol Neurosurg Psychiatry 2005;76:469–475

51. Rasmussen KG and Keegam BM. Electroconvulsive therapy in patients with multiple sclerosis. J ECT 2007;23: 179–180

52. Feinstein A. Multiple sclerosis and depression. Multiple Sclerosis Journal 2011;17:1276-1281








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