Needs Assessment: Recent research advances have raised the potential for clinical application of biomarkers in psychiatric care. It is important for clinicians to understand not only the benefits that biomarkers may bring to practice, but also the needed scientific hurdles these advances should clear before they can be embraced by the field.


Learning Objectives:

• Describe what biomarkers may be able to contribute to care for mental illnesses.
• Discuss proposed characteristics of a clinically-appropriate biomarker in psychiatry.
• Evaluate the applicability of potential biomarkers to patient care.

Target Audience: Primary care physicians and psychiatrists.


CME Accreditation Statement:
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.


Credit Designation:
The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.


Faculty Disclosure Policy Statement:
It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: February 20, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by March 1, 2010 to be eligible for credit. Release date: March 1, 2008. Termination date: March 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Cook is director of the Depression Research Program at the University of California, Los Angeles (UCLA) and associate director of the UCLA Laboratory of Brain, Behavior, and Pharmacology at the Semel Institute for Neuroscience and Human Behavior.

Disclosure: Dr. Cook receives grant support from Aspect Medical Systems, Cyberonics, Eli Lilly, Hi Q Foundation, the National Institutes of Health, Novartis, Pfizer, and Sepracor; and is on the speakers’ bureaus of Bristol-Myers Squibb, the Medical Education Speakers Network, and Wyeth. Dr. Cook is co-inventor of the cordance method, and his patent rights have been assigned to and are owned by the Regents of the University of California.

Acknowledgments: Dr. Cook wishes to acknowledge the mentoring of Dr. Andrew Leuchter; collegial discussions with Dr. Aimee Hunter and technical assistance from Ms. Kelly Nielson in the preparation of this manuscript; and the support of the professional staff at the UCLA Depression Research Program and the UCLA Laboratory of Brain, Behavior, and Pharmacology at the Semel Institute.

Please direct all correspondence to: Ian A. Cook, MD, UCLA Depression Research Program, Semel Institute, 760 Westwood Plaza, Los Angeles, CA 90024-1759; Tel: 310-825-0304; Fax: 310-825-7642; E-mail: icook@ucla.edu; Website: www.DepressionResearch.com.

 


 

Abstract

Advances in fundamental neurobiology, neuroimaging, neurophysiology, behavioral genetics, and other current high-throughput “omics” fields have yielded considerable advances in understanding the machinery of the brain and how it is altered in disorders of the mind. A recurrent theme for several decades of psychiatric research has been an interest in clinical biomarkers, namely, those biologic features that inform diagnosis, prognosis, or response to treatment. Recent research findings have increased the visibility of several promising biomarker approaches; some illustrative examples are drawn from studies of physiologic measures in mood disorders. The potential for biomarkers to advance the care of mental illness is great, but several caveats must be considered in order to avoid pitfalls that prevent adoption by the field. Pragmatic aspects of evaluating biomarker technologies are proposed that may guide useful development and possible adoption of these techniques.

 

Introduction

Biomarkers are commonplace in most branches of medicine: specific biologic features of an individual patient provide critical information about that person’s diagnosis, prognosis, or predicted response to treatment. Examples include tumor markers in oncology,1-4 troponin in cardiology,5-7 a-feto-protein in obstetrics,8 and inflammatory markers and specific serum antibody levels in rheumatology.9 Additionally, the use of biomarkers may be useful in drug discovery and development, by monitoring response to a test exposure of an experimental medication.10 Nonetheless, in the field of psychiatry, the biologic features of a patient’s illness generally continue to be eclipsed by the central role played by clinical signs and symptoms.11

While numerous new research findings suggest that biomarkers may soon be suitable for clinical use in psychiatric disorders, the quest for biomarkers to improve the care of mental illnesses is not new in the 21st century. For several decades, measurements of specific molecules in cerebrospinal fluid (eg, homovanillic acid, 5-hydroxy-indoleacetic acid),12 metabolites of neurotransmitters in urine (eg, 3-methoxy-4-hydroxyphenylglycol),13 and serum markers of neuroendocrine dysregulation (dexamethasone suppression test)14,15 have been complemented by studies of sleep architecture,16,17 eye movement abnormalities,18,19 and electrodermal and other autonomic responses.20 Other recent investigations have used imaging methods to detect the presence and location of abnormal proteins21,22  or abnormal organization of white matter tissue,23 to monitor neurochemistry with spectroscopy,24 or to detect brain metabolic responses to cognitive “stress tests.”25 While these approaches greatly expanded knowledge of the neurobiology of psychiatric disorders by serving as research tools, they have unfortunately found limited application in daily clinical practice or in evidence-based practice guidelines.11,26 As biologic measures (“biomeasures”26) and new techniques are reported and considered for use as clinically-applicable biomarkers, it is important for clinicians to understand how these may or may not be “ready for prime time.”

 

The Potential

Biomarkers have great potential for improving care for psychiatric patients. Three areas in particular can be identified, including enhanced diagnostic accuracy, prognostic information about the natural course of an individual’s illness, and prediction of response to treatment.

As noted above, clinical signs and symptoms are the central basis for establishing psychiatric diagnoses.11 Yet, some symptoms may be present in multiple diagnoses; a reduction in sleep can be a diagnostic element of a depressive episode, a manic episode, or generalized anxiety disorder. Biomarkers have promise for enhancing diagnostic accuracy in this arena. Consider, for example, a patient 20 years of age with a 2-month bout of disabling depression. Is this depression a component of unipolar major depressive disorder (MDD) or does the person really suffer from bipolar disorder but has not yet experienced a floridly manic episode? In an older patient with mild but clear cognitive impairments, are these problems originating from the neurodegenerative changes of Alzheimer’s disease, from ischemic damage in vascular dementia, or from MDD (the “pseudo-dementia” of depression)? In a child, are inattention and disruptive behaviors a part of attention-deficit/hyperactivity disorder, the early onset of bipolar disorder, or simply reflective of coping skills that are overwhelmed by stressful circumstances (eg, parental divorce)? For most patients, clinical information is sufficient to converge on the salient psychiatric diagnosis rapidly, but for some, diagnostic ambiguity may challenge even expert clinicians. The use of biologic markers has potential to assist in this important process, but more work is needed before the field will have useful tools for this application.

Prognostic information is another area where biomarkers could offer valuable insights. In oncology, the elevation of a tumor marker may lead to a workup for a recurrence of disease and initiation of treatment, even before clinical manifestations would have prompted a re-evaluation. In psychiatry, in contrast, an impending full relapse of psychosis in schizophrenia is heralded principally by the return of symptoms. In recurrent depressions, the question can be framed by a patient as “when is a bad day just a ‘bad day,’ and when is it the start of a new episode?” In the care of older adults with depression, some will likely progress from late-life depression to dementia,27 but identification of this subset of patients remains problematic. Lastly, many patients with mood disorders experience recurrent thoughts of death and perceive life as painful and/or meaningless. While this group of patients has an elevated risk for suicidal behaviors, accurately determining which individuals will go on to harm themselves and which will not cannot be forecast reliably on clinical or historical grounds.28 Some preliminary work suggests measures of brain structure and function29 or genotyping30,31 may be developed to refine this process. Rather than believing that research will eventually identify the single, measurable factor that leads to a phenomenon as complex as suicide, it may be more reasonable to anticipate that the greatest utility for this prediction may emerge from a model combining genetic and neurobiologic features with current and past clinical features and familial history, though the relative weightings of these factors remains indeterminate at this time.

Prediction of individual treatment response is viewed by some as a critical area for improvement in psychiatry. While treatments are effective for managing psychiatric illnesses in general, no single treatment works for everyone with a given disorder, and selection of the best treatment for each patient remains a challenge. The general standard of care is to embark upon a course of treatment that is likely to be effective for that disorder, based on evidence from randomized clinical trials and myriad other data (eg, clinical experience, past patient response to treatment); one then monitors for a good outcome and allows for course correction if improvement fails to occur. Both steps fundamentally rely on clinical findings to assess the degree of symptomatic or functional response. Nobel laureate Niels Bohr is often considered to have observed that “prediction is difficult, especially about the future,” and this statement rings true in this aspect of psychiatric care. The failure of depressive symptoms to improve early in treatment is often a harbinger of poor eventual outcome,32 but what is true on a group level does not necessarily provide useful guidance patient by patient, and some patients simply may take longer than others to respond to treatment that will eventually work well for them.33 Measurement-based care,34,35 with its systematic collection of clinical data with rating scales, can improve detection of good or poor response to treatment with greater utility than a clinician’s global impression, but fundamentally these are better observations of what is already occurring, rather than predictions of future outcomes.

Genetic factors have been examined with inconsistent results (eg, as summarized by Rasmussen-Torvik and McAlpine36). In the largest prospective treatment trial dataset examined in MDD, several genes have been linked with response to antidepressants, including serotonin-2A receptor polymorphisms,37 differences in the GRIK4 gene encoding for a glutamate receptor,38 and a chaperone protein that may regulate hypothalamic-pituitary-adrenal axis function (FKBP5 gene).39 While group differences between responders and non-responders can be found, none of these genetic factors have yet shown adequate utility for guiding individual patient treatment decisions. Similarly, the Evaluation of Genomic Applications in Practice and Prevention Working Group was convened by the federal Centers for Disease Control and Prevention to evaluate the evidence for genetic tests and other genomics applications, and their recommendation for depression was that routine genotyping was not yet supported by the evidence.40 In the care of schizophrenia, there is promise that polymorphisms in the genes that relate to drug metabolism may help guide medication dosing,41 but the choice of a specific agent for any given patient cannot yet be guided by biomarkers. In terms of anxiety disorders, it appears that some genes may predispose individuals to develop anxiety disorders under conditions of stress, but predicting individual response to treatment remains elusive.42 Indeed, it may be that consideration of gene-environment interactions becomes essential to take full advantage of genetic information in the care of psychiatric patients.43

Three physiologically based biomarker approaches to predicting outcomes have emerged in recent years in the area of depression with peer-reviewed publication and independent replication of findings, and can serve as useful examples for evaluating a candidate biomarker for clinical use.

The first measure uses changes in resting-state prefrontal brain activity (“quantitative electroencephalography [EEG] cordance”)44 over the course of a test exposure to an antidepressant; that early change is predictive of later treatment outcome with that agent for an individual patient’s care, in studies using either serotonin reuptake inhibitors or dual-reuptake inhibitors. (n=7,45 n=51,46 n=1247).45-49 Cordance is a measure which combines features of absolute and relative EEG power. Because cordance is better correlated with regional cerebral blood flow than other EEG measures,44 findings with this measure can be interpreted within the same conceptual framework as other functional neuroimaging studies. A multi-site replication and extension project (NCT00375843) has recently closed enrollment (200 subjects), and data analysis is now underway. The relationship between early change in cordance and later clinical outcome was independently replicated in an inpatient sample (n=17).50 These findings collectively supported an even larger collaborative, multi-site trial, Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (NCT00289523; n=375), using a related EEG measure (the antidepressant treatment response [ATR] index). The ATR can be computed using a simplified electrode array with five electrodes placed over prefrontal and frontal brain regions, instead of approximately 35–40 electrodes placed over all scalp locations for measuring cordance (“full head montage”); thus, this is a technology well suited for use in outpatient physicians’ offices, avoiding the need to send patients to a dedicated EEG facility. After a 1-week test period of escitalopram, subjects were randomized to receive either continued escitalopram treatment, a switch to bupropion, or a combination of the two medications; EEG data were recorded before and after the 1-week test period. In a real-world sample of outpatients with MDD, individuals who received treatment consistent with their biomarker prediction were significantly more likely to experience response and remission than individuals who were randomized to a treatment not predicted to be useful.51-53 Further development and replication projects are underway and must be completed before this paradigm of early physiologic change can be considered for clinical application.

The second approach utilizes an EEG measure which is proposed to reflect central serotonergic activity, the loudness dependent auditory evoked potential (LDAEP),54-56 though some other reports have suggested that the interpretation may be more complex than just central serotonergic activity.57,58 EEG data recorded prior to treatment are interpreted to indicate whether a depressed patient has a low or high level of serotonergic activity, and those with low activity are predicted to have a favorable response to a serotonergic medication (while high activity is linked to better outcomes with a noradrenergic agent). This method has been examined using treatment with serotonergic reuptake inhibitors (n=29,59 n=15,60 n=10061) or a noradrenergic agent (n=14,62 n=2063). The relationship between level of serotonergic activity and predicted treatment response has been observed in all these studies, though data presented in these reports generally does not permit evaluation on an individual case-prediction level. That level of detail in reporting of results would facilitate evaluation of the LDAEP approach for use in guiding clinical decisions. LDAEP values were calculated using dipole source analysis methods and data from full-head EEG electrode arrays.
The third approach links resting-state pretreatment measures of activity in the rostral anterior cingulate cortex (rACC) to outcome with a variety of treatments, including sleep deprivation (n=15,64 n=3665), numerous different medications (n=1866), nortriptyline (n=1867), and paroxetine (n=2768). Across all these studies, higher rACC activity was significantly associated with good treatment response. All utilized positron emission tomography methods to study regional brain metabolism, except one study67 in which an EEG method (low resolution electromagnetic tomography) was used to determine the level of electrical activity at current sources located in the rACC. An inexpensive, non-invasive measure, such as that used by Pizzagalli and colleagues,67 presents an intriguing approach, and independent replication with that methodology would be important for evaluating clinical applicability.

 

Some Pitfalls

There are numerous pitfalls that prior biomarker work has encountered, and researchers and clinicians should learn from past experiences. Perhaps most worrisome is the problem of premature clinical application, both because of the risk for harm to patients (misdirected in treatment decisions) and for the cynicism about biomarkers in general this engenders; still, the need for useful biomarkers is so great that sometimes enthusiasm and optimism may overtake consideration of results from carefully conducted controlled clinical trials. To paraphrase the film Jerry Maguire, “show me the data!” must be the watchword if clinicians are to make prudent choices for their patients. The usual vetting of new biomedical innovations—procedures, techniques, medications, and devices—requires peer review of findings and independent replication. What applicability is there to a biomarker if it has only been shown to work in a single laboratory and other researchers are unable to validate the results? Furthermore, it must be clearly disclosed what patient group was used to develop the biomarker, as this has great relevance to generalizability. In the universe of all patients with any psychiatric disorder, only a minority will have a syndrome that is refractory to multiple treatments; yet, this is just the sort of patient who may seek out expert care in desperation and consequently be enrolled in a biomarker discovery research program. The generalizability of such a biomarker may be quite limited, and without clear disclosure of these details it is difficult to evaluate the quality of a biomarker.

An additional caveat about biomarkers relates to the heterogeneity within a given clinical diagnosis. With current clinically defined diagnostic categories, there is variety both in the patients who seek care and in the individuals enrolled in research projects. A telling example is shown in Table 1, in which two individuals who both meet the diagnostic criteria for MDD have zero symptoms in common. Thus, development of biomarkers also should disclose the nature of the patient population and consider evaluating whether the accuracy and reliability of the measure are improved or degraded in some sub-populations (eg, psychotic depression, depression in bipolar type I versus bipolar type II patients).

 

 

While biomarkers should have a high degree of clinical utility in order to be considered for use, there is also a need for them to be interpretable in the context of the rest of neuroscience. What aspect of a patient’s pathophysiology is being assessed by a test? Is it the form of a reuptake transporter that is associated with greater or lesser efficiency, the level of activity in a particular brain region, or a component of a neuroendocrine feedback loop? Biomarker methods which fail to be comprehensible within or integrated into the extant body of neurobiologic knowledge are unlikely to gain clinical acceptance, even if an empiric trial suggests that they might be useful.

Finally, it is worthwhile to note that statistical significance is not the same thing as clinical significance. Studies may report that a result is significant at the P<.05 level, meaning simply that there is less than one chance in 20 that a finding arose by chance alone. Given a large enough sample, even a clinically-irrelevant difference (eg, a very small improvement on a clinical rating scale) might be reported to occur with an impressive P-value. An important measure for evaluating biomarkers includes the number needed to treat,69 which assesses the number of patients needed to be treated differently (eg, with biomarker guidance, with a new medication) in order to have one additional patient experience the desired, positive outcome. Predictive biomarkers are also often characterized by a series of metrics which can help evaluate the usefulness of a potential biomarker, ie, receiver operating characteristic (ROC) curves and measures such as sensitivity, specificity, and overall predictive accuracy.70-72 Sensitivity is the ratio of “true positive” tests to the number of individuals with the condition. For an outcome predictor, it would be the number of people in a sample who are predicted to respond to a treatment, divided by the total number of people who actually respond. Specificity is the ratio of “true negative” tests to the number of people who do not have a particular condition. In the outcome predictor context, this would be the number of people predicted not to respond divided by the total number of non-responders. Overall predictive accuracy is the proportion of predictions that are correct. ROC curves plot the trade-offs between sensitivity and specificity as different thresholds (cut-points) are used to differentiate between positive and negative tests (eg, between predicting response and non-response to a treatment).

 

Pragmatic Evaluation of Biomarkers for Psychiatric Management

Given the potential for improving care and the pitfalls that may await possible biomarkers, how then can one judge a biomarker for use in psychiatric management? Table 2 summarizes some key, desirable characteristics of psychiatric biomarkers. Many of them follow directly from the pitfalls detailed above, but the last three on the list merit special mention.

First, the information provided by the biomarker must be timely, clinically useful, and cost effective. A test that is able to predict 8-week treatment response at week 5 is much less timely than a prediction made at week 1. A biomarker that identifies an individual with a treatment-refractory illness (a “biomarker of doom”) is less useful than one which points the way to an alterative treatment strategy. It is unlikely that the field would adopt a biomarker which consumes more resources than it saves, either by direct expenses or by wrongly suggesting an alternative treatment.

Second, the technology needed to assess the biomarker must be available and well tolerated by the target patient population. For example, some neuroimaging methods may be well suited to neuroscience research applications, where a small number of subjects can be observed with great detail, but if the scanning technology costs too much to be deployed widely in the community, the method may not come to be translated into practice. Similarly, a procedure that is perceived as painful (eg, lumbar puncture) or challenging (eg, agitated children remaining conscious yet immobile during a scanning procedure) may have low penetration into the clinical arena for reasons of practicality.

Third, methods that can be seamlessly integrated into existing clinical care practice patterns are more likely to be accepted than those that require major shifts in the delivery of care. For example, sending a patient to a different facility for a biomarker procedure and waiting for test results is less desirable than being able to perform a test in one’s office or ward.

 

Conclusion

Biomarkers have great potential for improving the care of patients with psychiatric disorders, much as they have in other medical specialties. Adoption of biomarkers into clinical care, however, requires careful and thorough evaluation, and there is risk to patients if measures are embraced prematurely. A set of proposed criteria can be used in the pragmatic evaluation of candidate biomarkers. PP

 

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55.    Nathan PJ, Segrave R, Phan KL, O’Neill B, Croft RJ. Direct evidence that acutely enhancing serotonin with the selective serotonin reuptake inhibitor citalopram modulates the loudness dependence of the auditory evoked potential (LDAEP) marker of central serotonin function. Hum Psychopharmacol. 2006;21(1):47-52.
56.    Pogarell O, Juckel G, Norra C, et al. Prediction of clinical response to antidepressants in patients with depression: neurophysiology in clinical practice. Clin EEG Neurosci. 2007;38(2):74-77.
57.    Norra C, Becker S, Bröcheler A, Kawohl W, Kunert HJ, Buchner H. Loudness dependence of evoked dipole source activity during acute serotonin challenge in females. Hum Psychopharmacol. 2008;23(1):31-42.
58.    Guille V, Croft RJ, O’Neill BV, Illic S, Phan KL, Nathan PJ. An examination of acute changes in serotonergic neurotransmission using the loudness dependence measure of auditory cortex evoked activity: effects of citalopram, escitalopram and sertraline. Hum Psychopharmacol. Jan 15, 2008; [Epub ahead of print].
59.    Gallinat J, Bottlender R, Juckel G, et al. The loudness dependency of the auditory evoked N1/P2-component as a predictor of the acute SSRI response in depression. Psychopharmacology (Berl). 2000;148(4):404-411.
60.    Mulert C, Juckel G, Augustin H, Hegerl U. Comparison between the analysis of the loudness dependency of the auditory N1/P2 component with LORETA and dipole source analysis in the prediction of treatment response to the selective serotonin reuptake inhibitor citalopram in major depression. Clin Neurophysiol. 2002;113(10):1566-1572.
61.    Lee TW, Yu YW, Chen TJ, et al. Loudness dependence of the auditory evoked potential and response to antidepressants in Chinese patients with major depression. J Psychiatry Neurosci. 2005;30(3):202-205.
62.    Linka T, Müller BW, Bender S, Sartory G, Gastpar M. The intensity dependence of auditory evoked ERP components predicts responsiveness to reboxetine treatment in major depression. Pharmacopsychiatry. 2005;38(3):139-143.
63.    Mulert C, Juckel G, Brunnmeier M, et al. Prediction of treatment response in major depression: integration of concepts. J Affect Disord. 2007;98(3):215-225.
64.    Wu JC, Gillin JC, Buchsbaum MS, Hershey T, Johnson JC, Bunney WE Jr. Effect of sleep deprivation on brain metabolism of depressed patients. Am J Psychiatry. 1992;149(4):538-543.
65.    Wu J, Buchsbaum MS, Gillin JC, et al. Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex. Am J Psychiatry. 1999;156(8):1149-1158. Erratum in: Am J Psychiatry. 1999;156(10):1666.
66.    Mayberg HS, Brannan SK, Mahurin RK, et al. Cingulate function in depression: a potential predictor of treatment response. Neuroreport. 1997;8(4):1057-1061.
67.    Pizzagalli D, Pascual-Marqui RD, Nitschke JB, et al. Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical tomography analysis. Am J Psychiatry. 2001;158(3):405-415.
68.    Saxena S, Brody AL, Ho ML, et al. Differential brain metabolic predictors of response to paroxetine in obsessive-compulsive disorder versus major depression. Am J Psychiatry. 2003;160(3):522-532.
69.    Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med. 1988;318(26):1728-1733.
70.    Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chemistry. 1993;39(8):561-577.
71.    Altman DG, Bland JM. Diagnostic tests 1: sensitivity and specificity. BMJ. 1994;308(6943):1552.
72.    Altman DG, Bland JM. Diagnostic tests 2: predictive values. BMJ. 1994;309(6947):102.

 

Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.

Disclosure: Dr. Levenson is on the depression advisory board for Eli Lilly.

 


 

Important psychiatric issues affecting diagnosis and management arise in patients with neurologic illness more often than any other area of medicine. These include cognitive impairment either as a primary feature or a secondary complication of a known neurologic disorder, other psychiatric symptoms as a manifestation or complication of neurologic disease, and physical neurologic symptoms that do not correspond to any recognized pattern of neurologic disease (ie, conversion disorder or somatization disorder). In addition, behavioral, cognitive, or emotional symptoms may occur as a complication of drug therapy of neurologic disease. More detailed coverage of these topics can be found elsewhere.1,2 In previous columns, psychiatric issues in stroke, Parkinson’s disease, multiple sclerosis, and epilepsy were reviewed.3-5 In this column, psychiatric issues related to amnestic syndromes and conversion disorder are reviewed.

 

Amnestic Syndromes

Amnestic syndromes are conditions in which memory functions are disproportionately impaired compared to other cognitive functions in an otherwise alert patient. Causes include the Wernicke-Korsakoff syndrome, carbon monoxide poisoning, herpes encephalitis and other central nervous system infections, hypoxic and other acquired brain injuries, stroke, brain tumors, and neurosurgical resections (eg, for intractable epilepsy).1 There are also transient amnestic syndromes, and amnesia can be a manifestation of conversion disorder, posttraumatic stress disorder (PTSD), dissociative disorders, or malingering. Transient as well as persistent amnestic symptoms also occur following electroconvulsive therapy.

 

Wernicke-Korsakoff Syndrome

The Wernicke-Korsakoff syndrome (WKS) is the most common amnestic disorder and is the result of thiamine deficiency of any cause. The great majority of cases in the developed world are caused by chronic alcohol abuse which results in both decreased intake and absorption of thiamine. However, the disorder has also been reported in patients with a wide array of causes of malnutrition, including anorexia nervosa, chronic schizophrenia, post-gastric surgery for obesity, gastrointestional disorders, and hemodialysis. Thiamine deficiency may also result in beriberi, a cardiac and peripheral nervous system disease, and may also result in cerebellar degeneration and peripheral neuropathy. The onset of Wernicke’s encephalopathy is usually acute, manifested by confusion, ataxia, nystagmus, and ophthalmoplegia. The administration of intravenous fluid with glucose to a thiamine-deficient patient is a common iatrogenic precipitant of acute WKS. Emergent administration of parenteral thiamine is indicated to avoid irreversible nervous system damage. Since alcoholics and others with thiamine deficiency are also often deficient in other B vitamins (especially folate, niacin, and vitamin B12), they should receive parenteral multivitamins. In refeeding starving patients of whatever cause, phosphate supplementation is often required.

Chronic thiamine deficiency results in Korsakoff syndrome, with most cases following an earlier acute Wernicke’s encephalopathy. On clinical examination, patients with classic Korsakoff syndrome have severe impairment of memory with both anterograde and retrograde deficits.6 Such patients have particular difficulty encoding new information. While retrieval of recent memories is most impaired, Korsakoff patients also have difficulty retrieving more remote memories. Confabulation (the replacement of a gap in a patient’s memory by a falsification that he or she believes to be true) commonly but not invariably occurs in Korsakoff syndrome.

Other cognitive, behavioral, and emotional changes may accompany the amnesia, such as executive dysfunction, disorientation, apathy, and labile irritability. However, since most cases of Korsakoff syndrome are caused by chronic alcoholism, it is impossible to know which deficts in cerebral function can be attributed to thiamine deficiency and which are due to other causes common in alcoholics, including other B vitamin deficiencies, head trauma, and the toxic effects of alcohol itself.

With vitamin replacement and abstinence from alcohol, the prognosis in Korsakoff syndrome is fair. Twenty five percent of patients will recover, 50% will improve but with some persistent memory impairment, and 25% will show no change.1 Thiamine is inexpensive and harmless. Hence, any patient presenting with an acute amnestic syndrome should probably receive high-dose thiamine, even in the absence of a history of alcoholism or obvious malnutrition (the absence of proof of alcohol abuse is not proof of the absence of alcohol abuse). There are no good data to guide how long thiamine (and other B vitamins) should be given to patients with chronic alcoholism.

 

Transient Amnestic Syndromes

Transient amnesia occurs in a variety of neuropsychiatric disorders and as a normal phenomenon starting in midlife (at a relatively minor but annoying magnitude and frequency). There are some disorders in which dramatic but short-lived amnesia is the sole symptom. The best known, though still poorly understood, is transient global amnesia (TGA). TGA is a benign and temporary disorder affecting middle-aged or elderly individuals who present with the abrupt onset of loss of anterograde memory with the preservation of remote memories and immediate recall. They become amnestic for recent events and unable to lay down new memories for a few hours. They tend to repetitively question their companions. Episodes can be provoked by physical or emotional stress. A recent review7 of 142 cases of TGA found that in women, TGA episodes mainly follow emotional precipitating events, whereas in men they occur more frequently after a physical precipitating event. Most episodes of TGA are single isolated events; however, the recurrence rate is approximately 14% to 18%.8,9 A variety of hypthoses of its pathophysiology have been proposed, but the etiology remains uncertain. Cases of TGA have been reported after a diversity of apparent precipitants such as temporal lobectomy for epilepsy,10 divers breathing hyperoxic mixtures,11 sildenafil,12 sexual intercourse,13 coronary angiography, and aortic dissection. No link has been found with vascular risk factors.7 In addition, there is no increased risk of transient ischemic attack or stroke in patients who have had TGA nor is there any increase in mortality.

Temporal lobe epilepsy occasionally mimics TGA, and this is described in the literature as transient epileptic amnesia (TEA). In contrast to TGA, amnestic episodes caused by epilepsy are frequent and recurrent (median=12 episodes/year), brief (median duration=30–60 minutes), and often occur on waking (approximately 66% of cases). The diagnosis of epilepsy is very often initially missed even by specialists. TEA episodes typically disappear after treatment with anticonvulsants, but many patients continue to complain of persistent memory difficulties despite normal performance on standard memory tests.14

Other common causes of transient amnesia include transient cerebral ischemia (usually accompanied by other neurologic symptoms and signs), migraine, alcohol intoxication (“blackouts”), drugs (eg, benzodiazepines, barbiturates, ketamine15) and head injury. Concussion is often followed by temporary retrograde and anterograde amnesia; the more prolonged the anterograde amnesia, the more severe the injury.
Several psychiatric conditions can also be the cause of amnestic symptoms. Amnesia should not be attributed to a psychogenic cause solely on the basis of an otherwise normal neurologic examination, electroencephalogram (EEG), and imaging studies, since they would be normal in most cases of TGA and many cases of TEA. Psychogenic amnesia is one form of conversion disorder. In patients whose amnesia is due to conversion disorder, memory for their personal life histories is much more severely affected than is their ability to learn and retain new information; that is, they have isolated retrograde amnesia.16 This pattern is the opposite of that seen in TGA. In cases where the diagnostic picture is unclear, neuropsychological testing is very helpful in distinguishing conversion (and other psychogenic memory disturbances) from neurologic amnestic syndromes. Amnesia also occurs frequently in PTSD and dissociative disorders. Psychogenic amnesia serves to block out memory of a traumatic experience with intolerable associated affect, such as terror or shame.17 While controlled trials are lacking, psychotherapy and hypnosis have often been used successfully in treatment of conversion amnesia.

Amnesia is also a common symptom of malingering, especially in forensic contexts. Neuropsychological testing is invaluable in identifying suspected malingering in amnestic patients. The tests are based on the assumption that naive simulators or exaggerators do not know either that amnestic patients can perform some tests normally, or near normally, or that subjects can only fail them by deliberate suppression of the correct response.18

 

Conversion Disorder

Neurologic symptoms in the absence of neurologic disease or grossly disproportionate to disease affect approximately one-third of patients attending neurologic clinics.19 Many such patients have somatoform disorders, one of which is conversion disorder. Pain is the most common symptom in outpatient neurological practice,19 but the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,20 criteria for conversion disorder exclude pain. Patients with conversion disorder are those who develop other (ie, nonpain) neurologic symptoms or deficits that do not conform to known pathophysiology or are grossly disproportionate to it. Almost any neurologic symptom may be produced, such as paralysis, weakness, seizures, anesthesia, aphonia, blindness, amnesia, and stupor. Conversion disorder often coexists with neurologic illness, the most common example being epileptic seizures and “pseudoseizures” in the same patient.

Conversion symptoms can occur at any age but are most likely in adolescence or early adulthood. New onset of unexplained neurologic symptoms in elderly patients without a prior psychiatric history is rarely due to conversion disorder. Some conversion symptoms occur as brief, isolated episodes, but others are chronic and recurrent. Many individuals with chronic conversion symptoms have a history of having been sexually abused in childhood. Conversion symptoms are usually precipitated by an acute stressor or a current emotional conflict. The prevalence of conversion disorder has varied culturally and historically. The major task in differential diagnosis is determining whether the patient has a neurologic disorder, conversion, or both.

Symptoms remit spontaneously in <50% of patients.21 Recent stressful life events, a history of childhood abuse and neglect, personality dysfunction, abnormal illness beliefs, and/or secondary gain (financial or otherwise) are all common in conversion disorder, but their presence does not allow one to infer a diagnosis of conversion disorder.22 The neurologic examination plays a key role in diagnosis. Examples of helpful signs include tunnel vision, collapsing (“giveaway”) weakness, and unusual distribution of sensory loss. Physicians tend to worry excessively about missing “organic” disease and are, therefore, often very conservative in making a diagnosis of conversion disorder, erring in the other direction (ie, ordering too many diagnostic tests and prescribing unneeded treatment for presumptive neurologic disorders). This, in turn, reinforces the patient’s illness beliefs and sick role and risks iatrogenic complications and invalidism. In fact, the evidence suggests that diagnostic accuracy for conversion disorder is high with an error rate in modern studies of <5%.23

Conversion disorders have classically been thought to arise out of unconscious psychological conflicts, needs, or responses to trauma. Sigmund Freud posited that conversion symptoms served to protect the individual from unacceptable feelings or unresolvable conflicts, which keep such feelings out of conscious awareness. This function of conversion symptoms is referred to as “primary gain.” However, this model only fits some patients. Furthermore, while conversion symptoms often have unconscious meaning, this will not usually be apparent in initial encounters. Patients with conversion disorder tend to be very suggestible. Some but not all have a strikingly blasé attitude toward their symptoms (eg, la belle indifferénce), but it is neither sensitive nor specific enough to be useful in the diagnosis of conversion disorder.24

Patients with conversion disorder are usually consciously unaware of the cause of the symptoms, even when the cause might seem obvious to the clinician (eg, onset of paraplegia following rape). Such symptoms often elicit gratifying or protective responses from the environment (eg, sympathy, extra assistance, release from obligations, disability payments), which in turn reinforce the symptom.

The management of conversion symptoms begins with careful assessment; a thorough neurologic and physical examination can often distinguish between conversion disorder and organic neurologic disease without the need for other tests. In some cases, specific studies may be required including imaging, EEG, and electromyogram. It is never helpful to confront the patient in a negative way. Telling the patient “It is all in your head” or “There is nothing wrong with you” angers the patient, reinforces their insistence that the symptoms are “real,” and undermines the doctor-patient relationship. The appropriate approach is to first offer explicit acceptance of the reality of the symptoms and then reassure the patient that serious causes like tumor, stroke, or multiple sclerosis have been ruled out. This is then followed by telling the patient that they have a form of benign neurologic dysfunction that tends to be exacerbated by stress. An analogy to migraine can be helpful, ie, that even though stress aggravates migraine, there is no question that migraine pain and other symptoms are real. Psychotherapy can be very helpful, and the patient is more likely to pursue it if the clinician takes an encouraging and destigmatizing attitude toward the patient’s symptoms. For patients whose conversion disorder is manifested in weakness or paralysis, physical therapy can be very helpful in providing “a graceful way out” of the disabled sick role.25 Physical therapy is essential for patients who have been chronically immobilized by conversion disorder because they develp disuse atrophy. PP

 

References

1.    Carson AJ, Zeman A, Myles L, Sharpe MC. Neurology and neurosurgery. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:701-732.
2.    Carson AJ, Zeman A, Myles L, Sharpe MC. Neurology and neurosurgery. In: Levenson JL, ed. Essentials of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2007:313-342.
3.    Levenson JL. Psychiatric issues in neurology, part 1: stroke. Primary Psychiatry, 2007;14(9):37-40.
4.    Levenson JL. Psychiatric issues in neurology, part 2: parkinson’s disease and multiple sclerosis. Primary Psychiatry. 2007;14(11):35-39.
5.    Levenson JL. Psychiatric issues in neurology, part 3: epilepsy. Primary Psychiatry, 2008;15(1):21-25.
6.    Kopelman MD, Stanhope N, Kingsley D. Retrograde amnesia in patients with diencephalic temporal lobe or frontal lesions. Neuropsychologia. 1999;37(8):939-958.
7.    Quinette P, Guillery-Girard B, Dayan J, et al. What does transient global amnesia really mean? Review of the literature and thorough study of 142 cases. Brain. 2006;129(Pt 7):1640-1658.
8.    Agosti C, Akkawi NM, Borroni B, Padovani A. Recurrency in transient global amnesia: a retrospective study. Eur J Neurol. 2006;13(9):986-989.
9.    Gandolfo C, Caponnetto C, Conti M, Dagnino N, Del Sette M, Primavera A. Prognosis of transient global amnesia: a long-term follow-up study. Eur Neurol. 1992;32(1):52-57.
10.    Dupont S, Samson S, Baulac M. Is anterior temporal lobectomy a precipitating factor for transient global amnesia? J Neurol Neurosurg Psychiatry. 2007 Nov 21 [Epub ahead of print].
11.    Spigno F, De Lucchi M, Migliazzi L, Cocito L. Transient global amnesia after breathing hyperoxic mixtures in otherwise regular dives. Clin Neurol Neurosurg. 2007 Oct 5 [Epub ahead of print].
12.    Shihman B, Auriel E, Bornstien NM. Two cases of transient global amnesia (TGA) following sildenafil use [Hebrew]. Harefuah. 2006;145(9):656-657,703.
13. Bucuk M, Muzur A, Willheim K, Jurjevic A, Tomic Z, Tuskan-Mohar L. Make love to forget: two cases of transient global amnesia triggered by sexual intercourse. Coll Antropol. 2004;28(2):899-905.
14.    Butler CR, Graham KS, Hodges JR, Kapur N, Wardlaw JM, Zeman AZ. The syndrome of transient epileptic amnesia. Ann Neurol. 2007;61(6):587-598.
15.    Morgan CJ, Curran HV. Acute and chronic effects of ketamine upon human memory: a review.Psychopharmacology (Berl). 2006;188(4):408-424.
16.    Brandt J, Van Gorp WG. Functional (“psychogenic”) amnesia. Semin Neurol. 2006;26(3):331-340.
17. Wong CK. Too shameful to remember: a 17-year-old Chinese boy with psychogenic amnesia. Aust N Z J Psychiatry. 1990;24(4):570-574.
18. Leng NR, Parkin AJ. The detection of exaggerated or simulated memory disorder by neuropsychological methods. J Psychosom Res. 1995;39(6):767-776.
19. Carson AJ, Ringbauer B, Stone J, MacKenzie L, Warlow C, Sharpe M. Do medically unexplained symptoms matter? A study of 300 consecutive new referrals to neurology outpatient clinics. J Neurol Neurosurg Psychiatry. 2000;68:207-210.
20.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
21. Carson AJ, Postma K, Stone J, Warlow C. Sharpe M. The outcome of neurology patients with medically unexplained symptoms: a prospective cohort study. J Neurol Neurosurg Psychiatry. 2003;74(7):897-900.
22. Stone J, Zeman A, Sharpe M. Physical signs: functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry. 2002:73(3):241-245.
23. Stone J, Smyth R, Carson A, Lewis S, Prescott R, Warlow C, Sharpe M. Systematic review of misdiagnosis of conversion symptoms and “hysteria”. BMJ. 2005;331(7523):989.
24. Stone J, Smyth R, Carson A, Warlow C, Sharpe M. La belle indifférence in conversion symptoms and hysteria: systematic review. Br J Psychiatry. 2006;188:204-209.
25. Ness D. Physical therapy management for conversion disorder: case series. J Neurol Phys Ther. 2007;31(1):30-39.

 

Return

 

Dr. Levenson is professor in the Departments of Psychiatry, Medicine, and Surgery, chair of the Division of Consultation-Liaison Psychiatry, and vice chair for clinical affairs in the Department of Psychiatry at Virginia Commonwealth University School of Medicine in Richmond.

Disclosure: Dr. Levenson is on the depression advisory board for Eli Lilly.

 


 

Important psychiatric issues affecting diagnosis and management arise in patients with neurologic illness more often than any other area of medicine. These include cognitive impairment either as a primary feature or a secondary complication of a known neurologic disorder, other psychiatric symptoms as a manifestation or complication of neurologic disease, and physical neurologic symptoms that do not correspond to any recognized pattern of neurologic disease (ie, conversion disorder or somatization disorder). In addition, behavioral, cognitive, or emotional symptoms may occur as a complication of drug therapy of neurologic disease. More detailed coverage of these topics can be found elsewhere.1,2 In previous columns, psychiatric issues in stroke, Parkinson’s disease, multiple sclerosis, and epilepsy were reviewed.3-5 In this column, psychiatric issues related to amnestic syndromes and conversion disorder are reviewed.

 

Amnestic Syndromes

Amnestic syndromes are conditions in which memory functions are disproportionately impaired compared to other cognitive functions in an otherwise alert patient. Causes include the Wernicke-Korsakoff syndrome, carbon monoxide poisoning, herpes encephalitis and other central nervous system infections, hypoxic and other acquired brain injuries, stroke, brain tumors, and neurosurgical resections (eg, for intractable epilepsy).1 There are also transient amnestic syndromes, and amnesia can be a manifestation of conversion disorder, posttraumatic stress disorder (PTSD), dissociative disorders, or malingering. Transient as well as persistent amnestic symptoms also occur following electroconvulsive therapy.

 

Wernicke-Korsakoff Syndrome

The Wernicke-Korsakoff syndrome (WKS) is the most common amnestic disorder and is the result of thiamine deficiency of any cause. The great majority of cases in the developed world are caused by chronic alcohol abuse which results in both decreased intake and absorption of thiamine. However, the disorder has also been reported in patients with a wide array of causes of malnutrition, including anorexia nervosa, chronic schizophrenia, post-gastric surgery for obesity, gastrointestional disorders, and hemodialysis. Thiamine deficiency may also result in beriberi, a cardiac and peripheral nervous system disease, and may also result in cerebellar degeneration and peripheral neuropathy. The onset of Wernicke’s encephalopathy is usually acute, manifested by confusion, ataxia, nystagmus, and ophthalmoplegia. The administration of intravenous fluid with glucose to a thiamine-deficient patient is a common iatrogenic precipitant of acute WKS. Emergent administration of parenteral thiamine is indicated to avoid irreversible nervous system damage. Since alcoholics and others with thiamine deficiency are also often deficient in other B vitamins (especially folate, niacin, and vitamin B12), they should receive parenteral multivitamins. In refeeding starving patients of whatever cause, phosphate supplementation is often required.

Chronic thiamine deficiency results in Korsakoff syndrome, with most cases following an earlier acute Wernicke’s encephalopathy. On clinical examination, patients with classic Korsakoff syndrome have severe impairment of memory with both anterograde and retrograde deficits.6 Such patients have particular difficulty encoding new information. While retrieval of recent memories is most impaired, Korsakoff patients also have difficulty retrieving more remote memories. Confabulation (the replacement of a gap in a patient’s memory by a falsification that he or she believes to be true) commonly but not invariably occurs in Korsakoff syndrome.

Other cognitive, behavioral, and emotional changes may accompany the amnesia, such as executive dysfunction, disorientation, apathy, and labile irritability. However, since most cases of Korsakoff syndrome are caused by chronic alcoholism, it is impossible to know which deficts in cerebral function can be attributed to thiamine deficiency and which are due to other causes common in alcoholics, including other B vitamin deficiencies, head trauma, and the toxic effects of alcohol itself.

With vitamin replacement and abstinence from alcohol, the prognosis in Korsakoff syndrome is fair. Twenty five percent of patients will recover, 50% will improve but with some persistent memory impairment, and 25% will show no change.1 Thiamine is inexpensive and harmless. Hence, any patient presenting with an acute amnestic syndrome should probably receive high-dose thiamine, even in the absence of a history of alcoholism or obvious malnutrition (the absence of proof of alcohol abuse is not proof of the absence of alcohol abuse). There are no good data to guide how long thiamine (and other B vitamins) should be given to patients with chronic alcoholism.

 

Transient Amnestic Syndromes

Transient amnesia occurs in a variety of neuropsychiatric disorders and as a normal phenomenon starting in midlife (at a relatively minor but annoying magnitude and frequency). There are some disorders in which dramatic but short-lived amnesia is the sole symptom. The best known, though still poorly understood, is transient global amnesia (TGA). TGA is a benign and temporary disorder affecting middle-aged or elderly individuals who present with the abrupt onset of loss of anterograde memory with the preservation of remote memories and immediate recall. They become amnestic for recent events and unable to lay down new memories for a few hours. They tend to repetitively question their companions. Episodes can be provoked by physical or emotional stress. A recent review7 of 142 cases of TGA found that in women, TGA episodes mainly follow emotional precipitating events, whereas in men they occur more frequently after a physical precipitating event. Most episodes of TGA are single isolated events; however, the recurrence rate is approximately 14% to 18%.8,9 A variety of hypthoses of its pathophysiology have been proposed, but the etiology remains uncertain. Cases of TGA have been reported after a diversity of apparent precipitants such as temporal lobectomy for epilepsy,10 divers breathing hyperoxic mixtures,11 sildenafil,12 sexual intercourse,13 coronary angiography, and aortic dissection. No link has been found with vascular risk factors.7 In addition, there is no increased risk of transient ischemic attack or stroke in patients who have had TGA nor is there any increase in mortality.

Temporal lobe epilepsy occasionally mimics TGA, and this is described in the literature as transient epileptic amnesia (TEA). In contrast to TGA, amnestic episodes caused by epilepsy are frequent and recurrent (median=12 episodes/year), brief (median duration=30–60 minutes), and often occur on waking (approximately 66% of cases). The diagnosis of epilepsy is very often initially missed even by specialists. TEA episodes typically disappear after treatment with anticonvulsants, but many patients continue to complain of persistent memory difficulties despite normal performance on standard memory tests.14

Other common causes of transient amnesia include transient cerebral ischemia (usually accompanied by other neurologic symptoms and signs), migraine, alcohol intoxication (“blackouts”), drugs (eg, benzodiazepines, barbiturates, ketamine15) and head injury. Concussion is often followed by temporary retrograde and anterograde amnesia; the more prolonged the anterograde amnesia, the more severe the injury.
Several psychiatric conditions can also be the cause of amnestic symptoms. Amnesia should not be attributed to a psychogenic cause solely on the basis of an otherwise normal neurologic examination, electroencephalogram (EEG), and imaging studies, since they would be normal in most cases of TGA and many cases of TEA. Psychogenic amnesia is one form of conversion disorder. In patients whose amnesia is due to conversion disorder, memory for their personal life histories is much more severely affected than is their ability to learn and retain new information; that is, they have isolated retrograde amnesia.16 This pattern is the opposite of that seen in TGA. In cases where the diagnostic picture is unclear, neuropsychological testing is very helpful in distinguishing conversion (and other psychogenic memory disturbances) from neurologic amnestic syndromes. Amnesia also occurs frequently in PTSD and dissociative disorders. Psychogenic amnesia serves to block out memory of a traumatic experience with intolerable associated affect, such as terror or shame.17 While controlled trials are lacking, psychotherapy and hypnosis have often been used successfully in treatment of conversion amnesia.

Amnesia is also a common symptom of malingering, especially in forensic contexts. Neuropsychological testing is invaluable in identifying suspected malingering in amnestic patients. The tests are based on the assumption that naive simulators or exaggerators do not know either that amnestic patients can perform some tests normally, or near normally, or that subjects can only fail them by deliberate suppression of the correct response.18

 

Conversion Disorder

Neurologic symptoms in the absence of neurologic disease or grossly disproportionate to disease affect approximately one-third of patients attending neurologic clinics.19 Many such patients have somatoform disorders, one of which is conversion disorder. Pain is the most common symptom in outpatient neurological practice,19 but the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,20 criteria for conversion disorder exclude pain. Patients with conversion disorder are those who develop other (ie, nonpain) neurologic symptoms or deficits that do not conform to known pathophysiology or are grossly disproportionate to it. Almost any neurologic symptom may be produced, such as paralysis, weakness, seizures, anesthesia, aphonia, blindness, amnesia, and stupor. Conversion disorder often coexists with neurologic illness, the most common example being epileptic seizures and “pseudoseizures” in the same patient.

Conversion symptoms can occur at any age but are most likely in adolescence or early adulthood. New onset of unexplained neurologic symptoms in elderly patients without a prior psychiatric history is rarely due to conversion disorder. Some conversion symptoms occur as brief, isolated episodes, but others are chronic and recurrent. Many individuals with chronic conversion symptoms have a history of having been sexually abused in childhood. Conversion symptoms are usually precipitated by an acute stressor or a current emotional conflict. The prevalence of conversion disorder has varied culturally and historically. The major task in differential diagnosis is determining whether the patient has a neurologic disorder, conversion, or both.

Symptoms remit spontaneously in <50% of patients.21 Recent stressful life events, a history of childhood abuse and neglect, personality dysfunction, abnormal illness beliefs, and/or secondary gain (financial or otherwise) are all common in conversion disorder, but their presence does not allow one to infer a diagnosis of conversion disorder.22 The neurologic examination plays a key role in diagnosis. Examples of helpful signs include tunnel vision, collapsing (“giveaway”) weakness, and unusual distribution of sensory loss. Physicians tend to worry excessively about missing “organic” disease and are, therefore, often very conservative in making a diagnosis of conversion disorder, erring in the other direction (ie, ordering too many diagnostic tests and prescribing unneeded treatment for presumptive neurologic disorders). This, in turn, reinforces the patient’s illness beliefs and sick role and risks iatrogenic complications and invalidism. In fact, the evidence suggests that diagnostic accuracy for conversion disorder is high with an error rate in modern studies of <5%.23

Conversion disorders have classically been thought to arise out of unconscious psychological conflicts, needs, or responses to trauma. Sigmund Freud posited that conversion symptoms served to protect the individual from unacceptable feelings or unresolvable conflicts, which keep such feelings out of conscious awareness. This function of conversion symptoms is referred to as “primary gain.” However, this model only fits some patients. Furthermore, while conversion symptoms often have unconscious meaning, this will not usually be apparent in initial encounters. Patients with conversion disorder tend to be very suggestible. Some but not all have a strikingly blasé attitude toward their symptoms (eg, la belle indifferénce), but it is neither sensitive nor specific enough to be useful in the diagnosis of conversion disorder.24

Patients with conversion disorder are usually consciously unaware of the cause of the symptoms, even when the cause might seem obvious to the clinician (eg, onset of paraplegia following rape). Such symptoms often elicit gratifying or protective responses from the environment (eg, sympathy, extra assistance, release from obligations, disability payments), which in turn reinforce the symptom.

The management of conversion symptoms begins with careful assessment; a thorough neurologic and physical examination can often distinguish between conversion disorder and organic neurologic disease without the need for other tests. In some cases, specific studies may be required including imaging, EEG, and electromyogram. It is never helpful to confront the patient in a negative way. Telling the patient “It is all in your head” or “There is nothing wrong with you” angers the patient, reinforces their insistence that the symptoms are “real,” and undermines the doctor-patient relationship. The appropriate approach is to first offer explicit acceptance of the reality of the symptoms and then reassure the patient that serious causes like tumor, stroke, or multiple sclerosis have been ruled out. This is then followed by telling the patient that they have a form of benign neurologic dysfunction that tends to be exacerbated by stress. An analogy to migraine can be helpful, ie, that even though stress aggravates migraine, there is no question that migraine pain and other symptoms are real. Psychotherapy can be very helpful, and the patient is more likely to pursue it if the clinician takes an encouraging and destigmatizing attitude toward the patient’s symptoms. For patients whose conversion disorder is manifested in weakness or paralysis, physical therapy can be very helpful in providing “a graceful way out” of the disabled sick role.25 Physical therapy is essential for patients who have been chronically immobilized by conversion disorder because they develp disuse atrophy. PP

 

References

1.    Carson AJ, Zeman A, Myles L, Sharpe MC. Neurology and neurosurgery. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:701-732.
2.    Carson AJ, Zeman A, Myles L, Sharpe MC. Neurology and neurosurgery. In: Levenson JL, ed. Essentials of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2007:313-342.
3.    Levenson JL. Psychiatric issues in neurology, part 1: stroke. Primary Psychiatry, 2007;14(9):37-40.
4.    Levenson JL. Psychiatric issues in neurology, part 2: parkinson’s disease and multiple sclerosis. Primary Psychiatry. 2007;14(11):35-39.
5.    Levenson JL. Psychiatric issues in neurology, part 3: epilepsy. Primary Psychiatry, 2008;15(1):21-25.
6.    Kopelman MD, Stanhope N, Kingsley D. Retrograde amnesia in patients with diencephalic temporal lobe or frontal lesions. Neuropsychologia. 1999;37(8):939-958.
7.    Quinette P, Guillery-Girard B, Dayan J, et al. What does transient global amnesia really mean? Review of the literature and thorough study of 142 cases. Brain. 2006;129(Pt 7):1640-1658.
8.    Agosti C, Akkawi NM, Borroni B, Padovani A. Recurrency in transient global amnesia: a retrospective study. Eur J Neurol. 2006;13(9):986-989.
9.    Gandolfo C, Caponnetto C, Conti M, Dagnino N, Del Sette M, Primavera A. Prognosis of transient global amnesia: a long-term follow-up study. Eur Neurol. 1992;32(1):52-57.
10.    Dupont S, Samson S, Baulac M. Is anterior temporal lobectomy a precipitating factor for transient global amnesia? J Neurol Neurosurg Psychiatry. 2007 Nov 21 [Epub ahead of print].
11.    Spigno F, De Lucchi M, Migliazzi L, Cocito L. Transient global amnesia after breathing hyperoxic mixtures in otherwise regular dives. Clin Neurol Neurosurg. 2007 Oct 5 [Epub ahead of print].
12.    Shihman B, Auriel E, Bornstien NM. Two cases of transient global amnesia (TGA) following sildenafil use [Hebrew]. Harefuah. 2006;145(9):656-657,703.
13. Bucuk M, Muzur A, Willheim K, Jurjevic A, Tomic Z, Tuskan-Mohar L. Make love to forget: two cases of transient global amnesia triggered by sexual intercourse. Coll Antropol. 2004;28(2):899-905.
14.    Butler CR, Graham KS, Hodges JR, Kapur N, Wardlaw JM, Zeman AZ. The syndrome of transient epileptic amnesia. Ann Neurol. 2007;61(6):587-598.
15.    Morgan CJ, Curran HV. Acute and chronic effects of ketamine upon human memory: a review.Psychopharmacology (Berl). 2006;188(4):408-424.
16.    Brandt J, Van Gorp WG. Functional (“psychogenic”) amnesia. Semin Neurol. 2006;26(3):331-340.
17. Wong CK. Too shameful to remember: a 17-year-old Chinese boy with psychogenic amnesia. Aust N Z J Psychiatry. 1990;24(4):570-574.
18. Leng NR, Parkin AJ. The detection of exaggerated or simulated memory disorder by neuropsychological methods. J Psychosom Res. 1995;39(6):767-776.
19. Carson AJ, Ringbauer B, Stone J, MacKenzie L, Warlow C, Sharpe M. Do medically unexplained symptoms matter? A study of 300 consecutive new referrals to neurology outpatient clinics. J Neurol Neurosurg Psychiatry. 2000;68:207-210.
20.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
21. Carson AJ, Postma K, Stone J, Warlow C. Sharpe M. The outcome of neurology patients with medically unexplained symptoms: a prospective cohort study. J Neurol Neurosurg Psychiatry. 2003;74(7):897-900.
22. Stone J, Zeman A, Sharpe M. Physical signs: functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry. 2002:73(3):241-245.
23. Stone J, Smyth R, Carson A, Lewis S, Prescott R, Warlow C, Sharpe M. Systematic review of misdiagnosis of conversion symptoms and “hysteria”. BMJ. 2005;331(7523):989.
24. Stone J, Smyth R, Carson A, Warlow C, Sharpe M. La belle indifférence in conversion symptoms and hysteria: systematic review. Br J Psychiatry. 2006;188:204-209.
25. Ness D. Physical therapy management for conversion disorder: case series. J Neurol Phys Ther. 2007;31(1):30-39.

 

 

This interview took place on December 4, 2007, and was conducted by Norman Sussman, MD.

 

This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

Disclosure: Dr. Clayton is a consultant to or on the advisory boards of Boehringer-Ingelheim, Concert Pharmaceuticals, Eli Lilly, Fabre-Kramer Pharmaceuticals, GlaxoSmithKline, Novartis, PGx Health, sanofi-aventis, and Wyeth; receives grant support from Biosante, Boehringer-Ingelheim, Eli Lilly, Novartis, sanofi-aventis, and Wyeth; and receives honoraria from Eli Lilly, Palatin Technologies, Pfizer, and Wyeth.

 

Dr. Clayton is David C. Wilson professor of psychiatry and professor of clinical obstetrics and gynecology at the University of Virginia in Charlottesville. She is distinguished fellow of the American Psychiatric Association and certified by the American Board of Psychiatry and Neurology. Dr. Clayton is consulting editor for the Journal of Sex & Marital Therapy and received the Columnist of the Year award in 2005 for her bi-monthly column in Primary Psychiatry, “Considerations in Women’s Mental Health.” In 2007, her book, Satisfaction: Women, Sex and the Quest for Intimacy, was published for the general public.

 

Why were the sexual side effects of selective serotonin reuptake inhibitors (SSRIs) initially overlooked?

The initial clinical focus was on the improved tolerability and safety of SSRIs compared to tricyclic antidepressants (TCAs). The TCAs first appeared approximately 20 years ago, followed by fluoxetine entering the market in 1998. Their side effects included constipation, blurred vision, urinary retention, and cardiac effects. In addition, newer agents appeared to be safer than TCAs, particularly with respect to overdose risk. Since a systemic study of adverse events was not conducted and published at that time, the prevalence rate of sexual dysfunction was determined by spontaneous reports in registration trials. These reports dramatically underestimate the occurrence rates of sexual dysfunction. In addition, depression is associated with sexual dysfunction, possibly making it difficult to separate illness effects from antidepressant side effects.

 

Are today’s clinicians both better at recognizing and more comfortable with addressing the issue of sexual dysfunction?

Yes. In the past, patients did not easily mention issues of adverse sexual events, and physicians hardly ever asked about them. Patients would easily disclose problems such as nausea without trepidation, but they would not necessarily discuss their problems concerning sexual function. Clinicians were not even aware of this potential problem and it went unrecognized. However, today’s clinicians recognize that sexual dysfunction is a problem and are becoming more comfortable with the concept. They routinely ask their patients about it, and are more willing to help those who have a problem in this area stay on their medication.

 

What are the side effects of these drugs?

SSRIs, and serotonin norepinephrine reuptake inhibitors (SNRIs) like venlafaxine appear to affect all phases of the sexual response cycle. Approximately 40% of patients on antidepressant monotherapy reported global sexual dysfunction.1 There are some differences in the degree and form of sexual dysfunction with respect to gender. For example, desire and orgasm are more significantly affected in men, but arousal is more diminished in women on antidepressants.2 In addition, drugs such as bupropion, mirtazapine, nefazodone, and reboxetine, the latter of which is prescribed in Europe, work by other mechanisms and so have different effects. Clinicians should talk to patients about both a variety of sexual problems in all phases of the sexual response cycle and the timing of onset. In addition, clinicians should let patients know that these problems may persist for an extended period of time.

In a recently published study,3 interactive voice response technology was used to measure sexual function in normal healthy men without depression. It consisted of the Changes in Sexual Functioning Questionnaire (CSFQ), which was administered at very close time periods (ie, within 1–2 days of the previous administration). The study made sure to only involve normal, mentally healthy men in order to measure the drug effects without the results being confounded by the presence of depression. The study found that the SSRI paroxetine was associated with significantly greater orgasmic dysfunction than placebo by day 4. Problems with arousal developed by day 6, and difficulties and adverse events with desire and satisfaction appeared by day 14. In addition, the study suggests that medication therapy involving drugs with relatively short half-lives may worsen global sexual dysfunction within 2 weeks. This pattern of onset suggests that sexual dysfunction progressively worsens over time. It starts once a steady state of the drug is achieved and all phases may be subsequently affected. Thus, time to steady state appears to reflect the time to onset in susceptible patients.

 

Are the side effects generally dose related?

Yes. In our study examining the prevalence of sexual dysfunction in patients taking antidepressant therapy, sexual dysfunction is seen in a greater percentage of depressed patients on doses of antidepressants in the upper half of the normal dose range than those taking doses in the lower half of the normal range.1 However, there were a couple of exceptions in which the effects varied. Fluoxetine showed no difference in sexual dysfunction regardless of the dose, while bupropion and mirtazapine had fewer negative sexual side effects at higher doses.

 

Do the side effects diminish as a patient continues to use the medication?

Approximately 5% to 10% of people who initially develop sexual dysfunction associated with antidepressants develop tolerance to the side effects 4–6 months after the initiation of drug therapy. However, this means that 90% to 95% of people do not see the adverse events diminish over time. In addition, as people get older they tend to have more problems with sexual functioning. Therefore, aging may contribute to sexual dysfunction as well as the effects of chronic antidepressant therapy.

 

Is there an increasing or decreasing risk of experiencing certain sexual side effects among the drugs within their respective classes?

No. I think sexual dysfunction is a class effect associated with serotonin reuptake inhibition. However, norepinephrine reuptake inhibition in a clinically meaningful ratio of <10:1 could possibly mitigate this effect. This might explain the results of a clinical trial which found duloxetine to have significantly fewer sexual side effects than the SSRI escitalopram in a long-term study of approximately 8 months.4 In another study, the effects on sexual functioning were similar for escitalopram, as measured by the Changes in Sexual Functioning Questionnaire in both studies. In addition, other studies have demonstrated nominal differences between the SSRIs and the SNRIs available in 2001.1

 

Was the dose that was used to compare duloxetine to escitalopram greater or less than duloxetine’s recommended dose of ≤60 mg?

During the acute phase of treatment, duloxetine 60 mg and escitalopram 10 mg were used for 8 weeks Significant differences between escitalopram and placebo were found. However, sexual dysfunction with duloxetine did not differ from either placebo or escitalopram during the 8-week acute treatment phase. After the acute phase of treatment, a significant number of patients were increased to higher doses of duloxetine (120 mg/day) and escitalopram (20 mg/day). During the long-term phase, there were statistically significant differences between the two active treatment groups, and sexual dysfunction, once it occurred, persisted in 95% of the patients. It is possible that the sexual dysfunction may be an effect of depression. However, both groups showed fairly equivalent response rates in terms of antidepressant efficacy, thus suggesting a negative effect on sexual functioning with the SSRI escitalopram compared to the SNRI duloxetine. Studies of the SNRI venlafaxine demonstrated effects similar to those of the SSRIs, with doses in the upper half of the normal range for venlafaxine associated with greater sexual dysfunction than doses in the lower half of the normal dose range.1 In a study comparing venlafaxine to bupropion,5 the percentage of patients experiencing sexual dysfunction, as measured with the same patient-rated scale (CSFQ), on venlafaxine was similar to the SSRIs and significantly greater than bupropion.

 

What serotonergic drug is the least likely to induce sexual dysfunction?

A clinician might try duloxetine or the selegiline transdermal system. However, I think it is rather difficult to address that with ultimate certainty because there are other factors to consider such as the primary diagnosis, other adverse effects, comorbid medical/psychiatric conditions, and concomitant medications.

 

Which forms of sexual dysfunction are associated with TCAs?

TCAs and the monoamine oxidase inhibitors also cause sexual dysfunction, but may affect the phases of the sexual response cycle in different ways. For example, men who take TCAs tend to experience more problems with arousal than do men who take SSRIs. The MAOI patch known as the selegiline transdermal system seems to cause fewer sexual side effects than oral MAOIs. A recent study discusses the selegiline transdermal system and its effects on sexual functioning as comparable to placebo using a patient-rated scale.6

 

Are there treatments available in the market that have been proven to mitigate anorgasmia or the loss of sexual desire?

Yes, but the effects are not robust or were secondary outcome measures, and so potentially underpowered. One study7 was originally designed to look at buspirone as an adjunctive treatment in SSRI partial-responders with major depressive disorder. In another study examining effects on SSRI-induced sexual dysfunction,8 buproprion in antidepressant doses was superior to placebo even when the dose of the SSRI was maintained at the baseline level, and it is difficult to overcome SSRI-associated sexual side effects when the dose is maintained. Other potential treatments examined in placebo-controlled studies include testosterone and sildenafil in men. However, systematic placebo-controlled data examining potential antidotes are lacking. This is the reason why drugs in development need to be studied in terms of their potential effects on sexual functioning; these effects can be predicted to some degree based on the mechanism of action.

 

In the clinical world, what percentage of people discontinue their antidepressants because of either sexual or other side effects?

Ashton and colleagues9 conducted a study in patients taking psychotropic medications that examined both medication discontinuation, which is completely stopping treatment, and non-compliance, which is not taking the drug the way it is prescribed. Approximately 60% of patients taking an antidepressant acknowledged the discontinuation of their treatment with lack of efficacy as their primary reason. Medication non-compliance resulted from weight gain and fatigue. However, sexual side effects were the most frequently cited reason for medication discontinuation. Approximately 20% of patients reported anorgasmia, and a similar percentage of patients reported a loss of interest in sex. In addition, both the inability to have an erection and problems reaching orgasm were extremely difficult for patients to live with. Although many patients in clinical practice are non-compliant with their dosing regimen and decide to discontinue antidepressant therapy due to negative sexual side effects, patients are often reluctant to tell their physicians that the reason why they stopped treatment was due to sexual side effects.

 

Does the treatment have other unusual side effects?

Very different drugs that clinicians do not commonly prescribe often lead to unusual side effects. For example, patients report spontaneous orgasms in association with some medications, eg, trazodone. In addition, SSRIs can change sensation, including increased pain sensation or hyperalgesia, and diminished genital sensation. These are often issues reported by older people. They complain of diminished orgasms, diminished sensation, or delayed reaction to sexual stimulation, all of which may also be related to effects of aging on the serotonin system.

 

What is the developmental impact of TCAs on adolescents and young adults who already experience decreased desire, lowered libido, and weakened sexual functioning?

There have been neither studies nor case reports published about this subject, and I think it should be more carefully examined and studied. The effect of antidepressants on adolescent development is a heavy concern and a potentially long-term, lifelong, iatrogenically induced problem. During their teenage years, adolescents establish who they are as sexual beings. If these drugs inhibit sexual functioning, they can make it difficult for young adults to sexually identify themselves. Although parents do not really want to give their children medication, parents often view sexual side effects in a positive light as they lead to inhibition of sexual impulses. However, while this may have short-term benefits such as abstinence, in the long-run, it could become a real problem in the adolescent’s personal and sexual development. The repercussions of the long-term effects on sexuality should be more carefully studied in adolescents. PP

 

References

1.    Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63(4):357-366.
2.    Clayton A, Keller A, McGarvey EL. Burden of phase-specific sexual dysfunction with SSRIs. J Affect Disord. 2006;91(1):27-32.
3.    Dunn J, Arakawa R, Greist JH, Clayton AH. Assessing the onset of antidepressant induced sexual dysfunction using interactive voice response technology. J Clin Psychiatry. 2007;68(4):525-532.
4.    Clayton A, Kornstein S, Prakash A, Mallinckrodt C, Wohlreich M. Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder. J Sex Med. 2007;4(4 Pt 1):917-929.
5.    Thase ME, Clayton AH, Haight BR, Thompson AH, Modell JG, Johnston JA. A double-blind comparison between bupropion XL and venlafaxine XR: sexual functioning, antidepressant efficacy, and tolerability. J Clin Psychopharmacol. 2006;26(5):482-488.
6.    Clayton AH, Campbell BJ, Favit A, et al. Symptoms of sexual dysfunction in patients treated for major depressive disorder: a meta-analysis comparing selegiline transdermal system and placebo using a patient-rated scale. J Clin Psychiatry. 2007;68(12);1860-1866.
7.    Landen M, Eriksson E, Agren H, Fahlen T. Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 1999;19(3):268-271.
8.    Clayton AH, Warnock JK, Kornstein SG, Pinkerton R, Sheldon-Keller A, McGarvey EL. A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor – induced sexual dysfunction. J Clin Psychiatry. 2004;65(1):62-67.
9.    Ashton AK, Jamerson BD, Weinstein WL, et al. Antidepressant-related adverse effects impacting treatment compliance: results of a patient survey. Curr Ther Res Clin Exp. 2005;66:96-106.

Return

 

This interview took place on December 4, 2007, and was conducted by Norman Sussman, MD.

 

This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

Disclosure: Dr. Clayton is a consultant to or on the advisory boards of Boehringer-Ingelheim, Concert Pharmaceuticals, Eli Lilly, Fabre-Kramer Pharmaceuticals, GlaxoSmithKline, Novartis, PGx Health, sanofi-aventis, and Wyeth; receives grant support from Biosante, Boehringer-Ingelheim, Eli Lilly, Novartis, sanofi-aventis, and Wyeth; and receives honoraria from Eli Lilly, Palatin Technologies, Pfizer, and Wyeth.

 

Dr. Clayton is David C. Wilson professor of psychiatry and professor of clinical obstetrics and gynecology at the University of Virginia in Charlottesville. She is distinguished fellow of the American Psychiatric Association and certified by the American Board of Psychiatry and Neurology. Dr. Clayton is consulting editor for the Journal of Sex & Marital Therapy and received the Columnist of the Year award in 2005 for her bi-monthly column in Primary Psychiatry, “Considerations in Women’s Mental Health.” In 2007, her book, Satisfaction: Women, Sex and the Quest for Intimacy, was published for the general public.

 

Why were the sexual side effects of selective serotonin reuptake inhibitors (SSRIs) initially overlooked?

The initial clinical focus was on the improved tolerability and safety of SSRIs compared to tricyclic antidepressants (TCAs). The TCAs first appeared approximately 20 years ago, followed by fluoxetine entering the market in 1998. Their side effects included constipation, blurred vision, urinary retention, and cardiac effects. In addition, newer agents appeared to be safer than TCAs, particularly with respect to overdose risk. Since a systemic study of adverse events was not conducted and published at that time, the prevalence rate of sexual dysfunction was determined by spontaneous reports in registration trials. These reports dramatically underestimate the occurrence rates of sexual dysfunction. In addition, depression is associated with sexual dysfunction, possibly making it difficult to separate illness effects from antidepressant side effects.

 

Are today’s clinicians both better at recognizing and more comfortable with addressing the issue of sexual dysfunction?

Yes. In the past, patients did not easily mention issues of adverse sexual events, and physicians hardly ever asked about them. Patients would easily disclose problems such as nausea without trepidation, but they would not necessarily discuss their problems concerning sexual function. Clinicians were not even aware of this potential problem and it went unrecognized. However, today’s clinicians recognize that sexual dysfunction is a problem and are becoming more comfortable with the concept. They routinely ask their patients about it, and are more willing to help those who have a problem in this area stay on their medication.

 

What are the side effects of these drugs?

SSRIs, and serotonin norepinephrine reuptake inhibitors (SNRIs) like venlafaxine appear to affect all phases of the sexual response cycle. Approximately 40% of patients on antidepressant monotherapy reported global sexual dysfunction.1 There are some differences in the degree and form of sexual dysfunction with respect to gender. For example, desire and orgasm are more significantly affected in men, but arousal is more diminished in women on antidepressants.2 In addition, drugs such as bupropion, mirtazapine, nefazodone, and reboxetine, the latter of which is prescribed in Europe, work by other mechanisms and so have different effects. Clinicians should talk to patients about both a variety of sexual problems in all phases of the sexual response cycle and the timing of onset. In addition, clinicians should let patients know that these problems may persist for an extended period of time.

In a recently published study,3 interactive voice response technology was used to measure sexual function in normal healthy men without depression. It consisted of the Changes in Sexual Functioning Questionnaire (CSFQ), which was administered at very close time periods (ie, within 1–2 days of the previous administration). The study made sure to only involve normal, mentally healthy men in order to measure the drug effects without the results being confounded by the presence of depression. The study found that the SSRI paroxetine was associated with significantly greater orgasmic dysfunction than placebo by day 4. Problems with arousal developed by day 6, and difficulties and adverse events with desire and satisfaction appeared by day 14. In addition, the study suggests that medication therapy involving drugs with relatively short half-lives may worsen global sexual dysfunction within 2 weeks. This pattern of onset suggests that sexual dysfunction progressively worsens over time. It starts once a steady state of the drug is achieved and all phases may be subsequently affected. Thus, time to steady state appears to reflect the time to onset in susceptible patients.

 

Are the side effects generally dose related?

Yes. In our study examining the prevalence of sexual dysfunction in patients taking antidepressant therapy, sexual dysfunction is seen in a greater percentage of depressed patients on doses of antidepressants in the upper half of the normal dose range than those taking doses in the lower half of the normal range.1 However, there were a couple of exceptions in which the effects varied. Fluoxetine showed no difference in sexual dysfunction regardless of the dose, while bupropion and mirtazapine had fewer negative sexual side effects at higher doses.

 

Do the side effects diminish as a patient continues to use the medication?

Approximately 5% to 10% of people who initially develop sexual dysfunction associated with antidepressants develop tolerance to the side effects 4–6 months after the initiation of drug therapy. However, this means that 90% to 95% of people do not see the adverse events diminish over time. In addition, as people get older they tend to have more problems with sexual functioning. Therefore, aging may contribute to sexual dysfunction as well as the effects of chronic antidepressant therapy.

 

Is there an increasing or decreasing risk of experiencing certain sexual side effects among the drugs within their respective classes?

No. I think sexual dysfunction is a class effect associated with serotonin reuptake inhibition. However, norepinephrine reuptake inhibition in a clinically meaningful ratio of <10:1 could possibly mitigate this effect. This might explain the results of a clinical trial which found duloxetine to have significantly fewer sexual side effects than the SSRI escitalopram in a long-term study of approximately 8 months.4 In another study, the effects on sexual functioning were similar for escitalopram, as measured by the Changes in Sexual Functioning Questionnaire in both studies. In addition, other studies have demonstrated nominal differences between the SSRIs and the SNRIs available in 2001.1

 

Was the dose that was used to compare duloxetine to escitalopram greater or less than duloxetine’s recommended dose of ≤60 mg?

During the acute phase of treatment, duloxetine 60 mg and escitalopram 10 mg were used for 8 weeks Significant differences between escitalopram and placebo were found. However, sexual dysfunction with duloxetine did not differ from either placebo or escitalopram during the 8-week acute treatment phase. After the acute phase of treatment, a significant number of patients were increased to higher doses of duloxetine (120 mg/day) and escitalopram (20 mg/day). During the long-term phase, there were statistically significant differences between the two active treatment groups, and sexual dysfunction, once it occurred, persisted in 95% of the patients. It is possible that the sexual dysfunction may be an effect of depression. However, both groups showed fairly equivalent response rates in terms of antidepressant efficacy, thus suggesting a negative effect on sexual functioning with the SSRI escitalopram compared to the SNRI duloxetine. Studies of the SNRI venlafaxine demonstrated effects similar to those of the SSRIs, with doses in the upper half of the normal range for venlafaxine associated with greater sexual dysfunction than doses in the lower half of the normal dose range.1 In a study comparing venlafaxine to bupropion,5 the percentage of patients experiencing sexual dysfunction, as measured with the same patient-rated scale (CSFQ), on venlafaxine was similar to the SSRIs and significantly greater than bupropion.

 

What serotonergic drug is the least likely to induce sexual dysfunction?

A clinician might try duloxetine or the selegiline transdermal system. However, I think it is rather difficult to address that with ultimate certainty because there are other factors to consider such as the primary diagnosis, other adverse effects, comorbid medical/psychiatric conditions, and concomitant medications.

 

Which forms of sexual dysfunction are associated with TCAs?

TCAs and the monoamine oxidase inhibitors also cause sexual dysfunction, but may affect the phases of the sexual response cycle in different ways. For example, men who take TCAs tend to experience more problems with arousal than do men who take SSRIs. The MAOI patch known as the selegiline transdermal system seems to cause fewer sexual side effects than oral MAOIs. A recent study discusses the selegiline transdermal system and its effects on sexual functioning as comparable to placebo using a patient-rated scale.6

 

Are there treatments available in the market that have been proven to mitigate anorgasmia or the loss of sexual desire?

Yes, but the effects are not robust or were secondary outcome measures, and so potentially underpowered. One study7 was originally designed to look at buspirone as an adjunctive treatment in SSRI partial-responders with major depressive disorder. In another study examining effects on SSRI-induced sexual dysfunction,8 buproprion in antidepressant doses was superior to placebo even when the dose of the SSRI was maintained at the baseline level, and it is difficult to overcome SSRI-associated sexual side effects when the dose is maintained. Other potential treatments examined in placebo-controlled studies include testosterone and sildenafil in men. However, systematic placebo-controlled data examining potential antidotes are lacking. This is the reason why drugs in development need to be studied in terms of their potential effects on sexual functioning; these effects can be predicted to some degree based on the mechanism of action.

 

In the clinical world, what percentage of people discontinue their antidepressants because of either sexual or other side effects?

Ashton and colleagues9 conducted a study in patients taking psychotropic medications that examined both medication discontinuation, which is completely stopping treatment, and non-compliance, which is not taking the drug the way it is prescribed. Approximately 60% of patients taking an antidepressant acknowledged the discontinuation of their treatment with lack of efficacy as their primary reason. Medication non-compliance resulted from weight gain and fatigue. However, sexual side effects were the most frequently cited reason for medication discontinuation. Approximately 20% of patients reported anorgasmia, and a similar percentage of patients reported a loss of interest in sex. In addition, both the inability to have an erection and problems reaching orgasm were extremely difficult for patients to live with. Although many patients in clinical practice are non-compliant with their dosing regimen and decide to discontinue antidepressant therapy due to negative sexual side effects, patients are often reluctant to tell their physicians that the reason why they stopped treatment was due to sexual side effects.

 

Does the treatment have other unusual side effects?

Very different drugs that clinicians do not commonly prescribe often lead to unusual side effects. For example, patients report spontaneous orgasms in association with some medications, eg, trazodone. In addition, SSRIs can change sensation, including increased pain sensation or hyperalgesia, and diminished genital sensation. These are often issues reported by older people. They complain of diminished orgasms, diminished sensation, or delayed reaction to sexual stimulation, all of which may also be related to effects of aging on the serotonin system.

 

What is the developmental impact of TCAs on adolescents and young adults who already experience decreased desire, lowered libido, and weakened sexual functioning?

There have been neither studies nor case reports published about this subject, and I think it should be more carefully examined and studied. The effect of antidepressants on adolescent development is a heavy concern and a potentially long-term, lifelong, iatrogenically induced problem. During their teenage years, adolescents establish who they are as sexual beings. If these drugs inhibit sexual functioning, they can make it difficult for young adults to sexually identify themselves. Although parents do not really want to give their children medication, parents often view sexual side effects in a positive light as they lead to inhibition of sexual impulses. However, while this may have short-term benefits such as abstinence, in the long-run, it could become a real problem in the adolescent’s personal and sexual development. The repercussions of the long-term effects on sexuality should be more carefully studied in adolescents. PP

 

References

1.    Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63(4):357-366.
2.    Clayton A, Keller A, McGarvey EL. Burden of phase-specific sexual dysfunction with SSRIs. J Affect Disord. 2006;91(1):27-32.
3.    Dunn J, Arakawa R, Greist JH, Clayton AH. Assessing the onset of antidepressant induced sexual dysfunction using interactive voice response technology. J Clin Psychiatry. 2007;68(4):525-532.
4.    Clayton A, Kornstein S, Prakash A, Mallinckrodt C, Wohlreich M. Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder. J Sex Med. 2007;4(4 Pt 1):917-929.
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