This interview took place on September 6, 2007, and was conducted by Norman Sussman, MD.

 

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

Disclosure: Dr. Goldberg is consultant to Abbott, AstraZeneca, Cephalon, Eli Lilly, and GlaxoSmithKline; on the speaker’s bureaus of Abbott, AstraZeneca, Eli Lilly, and GlaxoSmithKline; and on the scientific advisory boards of Eli Lilly and GlaxoSmithKline.

 

 
 Dr. Goldberg is director of the Affective Disorders Program at Silver Hill Hospital in New Canaan, Connecticut, and associate clinical professor of psychiatry at the Mount Sinai School of Medicine in New York City. His research focuses on the treatment and clinical features of bipolar disorder. He is a co-investigator in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder and has received a Career Development Award from the NIMH. He has also received research grants from the National Alliance for Research in Schizophrenia and Depression, the American Foundation for Suicide Prevention, and the Stanley Foundation.
  

How has the approach to the diagnosis of bipolar disorder changed in recent years?

The rigor of the diagnosis and the systematic approach to making a diagnosis have changed. Bipolar disorder is not just about mood; rather, it is a disorder with components that involve disregulation of mood, the sleep-wake cycle, impulse control, cognitive disturbances, and behavioral problems. Some of these phenomena persist independent of the mood state. For example, cognition or impulsivity are present much of the time but that may flare during a mood state.

When assessing a patient, I conduct a systematic overview of the patient’s pathology and symptoms in the sense of differential diagnosis. I also describe the systematic approach of recognizing dimensions of psychopathology and symptom constellations, alongside differential diagnosis.

We think about mood disorders in terms of their polarity of mood, cyclicity, recurrence rates over time, pharmacologic response, environmental correlates, cognitive aspects, and sleep aspects. This mode of thinking correlates with the idea of the spectrum, as well, where we step outside the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).1

My approach to diagnosis includes not just a cross-sectional survey of DSM-IV symptoms—though that is obviously a part of it— but a longitudinal, panoramic, perspective of how symptoms fit together. Does the context suggest a bipolar illness based on age of onset, family history, aspects that may better or worsen the illness, or medication response? Taking a systematic approach and incorporating these dimensions can give us a best-informed assessment of a likely diagnosis.

 

How is bipolar disorder generally diagnosed?

How much rigor goes into a diagnosis usually depends on what kind of specialist is conducting the assessment. For example, some base the diagnosis on mood swings alone. Thus, there is potential for misdiagnosis, incomplete diagnosis, quasi diagnosis, or nonsystematic diagnosis if one fails to take all symptoms into account. Mood instability is not diagnostic and occurs in many psychiatric disorders including bipolar disorder, among others. However, if we identified it all as synonymous with bipolar disorder, we would miss a lot of posttraumatic stress disorder, substance abuse, adjustment disorders, and personality disorders.

In the last 5–10 years, our sensitivity has gone up, meaning we are more often asking mood disorder patients about current and past symptoms of mania or hypomania, paying more attention to patterns of high recurrence, and considering when cyclical mood disorders are not unipolar depression. We are doing a better job overall in recognizing non-unipolar patients, but we are not necessarily encouraging our colleagues to think as critically about the differential diagnoses among these patients. The DSM-IV defines clinical subtypes of bipolar disorder quite strictly, and as all-or-none categories. For example, mixed episodes are defined only as occurring in bipolar I (not II) disorder, and require the presence of a full manic and depressive syndrome for at least 1 week. The “not otherwise specified (NOS)” designation thus has meaning when DSM-IV duration criteria or numbers of symptoms may not be fulfilled, but clinically important symptoms differentiable from unipolar depression are nonetheless present. Nosology advances and good clinical care occurs when we encourage clinicians to go beyond a DSM-IV diagnosis.

Mixed states are an excellent example because in the case of bipolar depression most depressed bipolar patients have some mania symptoms alongside their depression. Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) program (JF Goldberg, unpublished data, May 2007) has demonstrated that two-thirds of fully-depressed bipolar patients have at least some manic symptoms. This may not catch a clinician’s attention unless the patient has enough manic symptoms to call it a mixed state. However, if it is subsyndromal mania one must determine whether it is an agitated depression or a subsyndromal mania within a depression. The condition is considered NOS and not a DSM-IV entity, but it is extremely common.

 

Are antidepressants effective for bipolar patients?

No controlled study has ever shown antidepressants to be more effective than mood stabilizers alone for bipolar depression. According to recent STEP-BD data,2 antidepressants on an overall basis add very little benefit for patients with bipolar depression and minimal manic symptoms. They neither help nor hurt. However, there are subgroups for whom the antidepressants may be detrimental. Our recent article3 examining concomitant mania symptoms with depression, found that manic symptoms of patients with bipolar depression with some mania are worsened by antidepressants. Further, the depression is not managed with these drugs. Other reports note that patients with a history of prior switch with an antidepressant are more prone to switch into mania. A forthcoming study from the STEP-BD program by our site at Cornell Medical Center in New York City4 found that patients who have previously experienced mania with an antidepressant have double the chance of that occurring in the future with any antidepressant.

Goldstein and colleagues5 described the abrupt cessation of antidepressants triggering a manic state. It is sometimes difficult to tell whether a withdrawal phenomenon is a physiologic phenomenon as opposed to a psychiatric one. An abrupt change in an equilibrium state could destabilize mood. Therefore, I have become a proponent of gradual tapers whenever possible with almost all psychotropics.

 

Is there a relationship between bipolar disorder and alcoholism?

There is an extraordinarily high comorbidity with substance abuse in general and alcohol abuse or dependence in particular for people with bipolar disorder. The National Comorbidity Survey reported approximately 70% comorbidity.6 Other studies place comorbidity of alcohol use or dependence and bipolar disorder at 40% to 60%. There is no simple explanation for why that co-occurrence is so high. One theory is that people with bipolar disorder are reckless, impulsive, and likely to engage in hedonistic behaviors of high-risk consequence, such as excessive spending, gambling, drinking, or drugs. For some, the potential for alcohol is in the context of a mania. Other people might use alcohol to ward off depression. There is also a genetic component, where some research suggests that alcoholism tends to run in families with bipolar members.

Alcohol acts as a stimulant and then acts as a central nervous system depressant. It is very difficult to diagnose a mood disorder in someone with active substance abuse because the psychotropic effects of alcohol or drugs can mimic depression or mania. Overdiagnosis of bipolar disorder is partially a result of the high co-occurrence with substance or alcohol use. It can be challenging for a clinician to know the extent to which a patient’s mood symptoms are artifacts of substance use or consequences of withdrawal. The most systematic diagnostic approach is to obtain a longitudinal history, assessing the presence of mood symptoms during sustained periods of abstinence. Our group7 recently conducted a study attempting to disentangle “true” bipolar diagnoses from “non-bipolar I or II” mood instability among inpatients with substance use disorders and found that only approximately one-third met DSM-IV criteria for bipolar I or II disorder. Approximately half the time, we could not identify a period of abstinence in which to evaluate mood symptoms, pointing to the complexity of accurately differentiating and diagnosing separate mood disorders in patients with active substance abuse or dependence. A related study by Stewart and El-Mallakh8 recently reported similar findings.

 

Which disorders are comorbid with bipolar disorder?

According to Susan McElroy, MD, from the Stanley Network, two-thirds of people with bipolar disorder have at least a second DSM-IV psychiatric disorder. Approximately 50% have a third psychiatric disorder, and approximately 25% have a fourth. Comorbidity is the rule rather than the exception. There is less prevalence of first-episode patients with substance or alcohol abuse than there are multi-episode patients. According to the McLean-Harvard First-Episode Mania Study, the prevalence of drug or alcohol abuse in first-episode mania patients is approximately 33%—much lower than the rate seen in multi-episode patients with bipolar disorder.9 Thus, if bipolar disorder is caught early and treated effectively, the progression to alcohol and substance abuse can likely be prevented.

The second most common comorbidity, which is not mutually exclusive from alcohol or drugs, is anxiety. Rates vary for any anxiety disorder. The National Epidemiologic Study on Alcohol-related Conditions (NESARC) study by Grant and colleagues10 reports that approximately 50% of people with bipolar disorder have an anxiety disorder. It can be difficult to distinguish between agitation, psychomotor acceleration, and goal directness of mania from free-floating anxiety, generalized anxiety disorder, or panic. Therefore, we must be guided by other features as well—such as sleep patterns, cognitive features, and mood features—bearing in mind that this may represent anxiety or hypomanic activation.

Seasonal affective disorder and postpartum mood disorders are also more common in patients with bipolar disorder than in the general population.

 

Is there any evidence to support that people with recurrent manic episodes and major depressive episodes get worse cognitively after each episode?

There is evidence that cognitive functioning is poorer in patients with multiple prior affective episodes, particularly manic episodes.11 As to whether or not repeated affective episodes lead to a progressive worsening of cognitive function has not been demonstrated; however, some reports do suggest that eventual risk for dementia is higher among bipolar patients with more prior episodes.12

We are just beginning to appreciate the cognitive problems that are inherent in bipolar disorder. Much interest has focused on how much those cognitive problems are an epiphenomenon of mood symptoms (eg, depression), how much is iatrogenic from pharmacology and the long-term effects of certain medications like lithium, and how much is a neurodegenerative phenomenon. We think of mood stabilizers as being neuroprotective. It in part addresses this concern for a potential neurotoxic effect of multiple episodes. Some research discusses structural brain changes in multi-episode patients in the hippocampus and the amygdala.

Some recent cognitive data show the potential for decline over time. However, I would not encourage patients to worry and anticipate a decline in course. The kinds of deficits we see in most patients are subtle. They tend to involve things like verbal learning, practice effects, and attention. They may be trait features passed along genetically, and even seen in unaffected relatives, as a kind of “hidden” biologic marker or “endo”phenotype. A person’s actions also play a role. As mentioned, alcohol is not neuroprotective. It is difficult to know the extent to which alcohol comorbidity is having a direct neurotoxic effect. It is difficult to distinguish how much of the cognitive potential decline occurs because of the illness, treatment, delays to treatment, or comorbidities. The message for patients is to recognize the illness early, treat it early, and strive to ward off the comorbidities. If a patient takes care of oneself, the outcome can be quite good.

 

When should lithium be used?

Lithium deserves special consideration in the treatment of any first-episode mania patient. There is some suggestion in the literature that if lithium is going to work, it will do so early on coupled with the neuroprotective effects. Unfortunately, I often see patients who have already gone on 10–15 other medications. I use lithium in mania-prone patients. Patients who are more prone toward depression than mania probably struggle more with effective treatments for the depression side of the illness than the mania side. Hence, lithium may not work as well with these patients. Also, we are often fond of asking if relatives benefited from a given psychotropic agent, thinking this may help to guide treatment response for our own patient. Lithium is one of the very few drugs where this has in fact proven to be true, and so family history of lithium responsiveness is a useful parameter. In addition, one must not forget that the anti-suicide properties of lithium may be unique to that drug and can even occur regardless of whether lithium is effective for preventing manias or depressions. Lithium, therefore, deserves consideration in the regimen of any mood-disordered patient with a longitudinal suicide risk.

With so many drugs being approved for the treatment of bipolar disorder, is the term “mood stabilizer” now obsolete?
The term is imprecise and incomplete more than obsolete. Contrary to our assumptions from a decade ago, anticonvulsants do not appear to show robust effects as a class to treat or prevent manias or depressions; those psychotropic properties seem to be confined to divalproex, carbamazepine, and lamotrigine. Meanwhile, all atypical antipsychotics treat mania regardless of the presence of psychosis, and at least some have value for bipolar depression or long-term prevention of episodes. Thus, rather than identify whether or not a drug is a “mood stabilizer” based on its pharmacologic class, it may be more useful to talk about the extent to which any treatment has mood-stabilizing properties and the extent to which those properties are predominantly anti-manic, antidepressant, or both.

We can talk about the extent to which a drug derives its mood-stabilizing properties by virtue of treating or preventing one pole or the other, or both. Classic examples are lithium and lamotrigine. Neither drug has been shown in rigorous controlled studies to induce the opposite polarity of the illness. Lamotrigine is an example of a drug that does not seem to induce the opposite polarity, has a robust effect on the depression side, and a more modest effect on the mania side. It can be described as a mood-stabilizing antidepressant or an agent that has mood-stabilizing properties that are predominantly depression related. It is in many ways the complement or mirror image of lithium—which is an excellent drug choice to minimize cyclicity and polarity change, particularly in patients who are prone to recurrent manias. However, lithium is less robust against recurrent bipolar depressions than bipolar manias.13

 

What off-label drugs for treatment of bipolar symptoms have value?

Many anticonvulsants have not borne out in clinical trials to treat mania or depression or to forestall polarity changes, but they act in other relevant ways to treat the illness. Topiramate, which has not been shown in placebo-controlled studies to help severe mania, has significant effects in alcohol dependence, binge eating, and neuropathic pain, all of which are common problems for patients with bipolar disorder. Comparably, gabapentin, a drug in which two placebo-controlled studies14,15 looked at its usefulness as an add-on treatment or monotherapy in severely ill patients, did not significantly reduce manic or depressive symptoms; however, the drug helps to treat anxiety disorders, alcohol dependence, and neuropathic pain.

Comorbidity is a descriptor in helping to create a regimen that is informed by what is being treated. For example, a clinician may choose to include topiramate “off-label” in the regimen of a patient with bipolar disorder, not for mood symptoms but to target comorbid obesity, binge eating,16 alcoholism,17 or migraines. Similarly, one might include gabapentin “off label” in a regimen as a possible alternative to benzodiazepines to treat anxiety symptoms. When comorbidities are considered in addition to mood symptoms, off-label uses from evidence-based controlled studies help guide clinicians to which medications are valuable for treating each patient with bipolar disorder.

 

What are the clinical features that help differentiate between unipolar and bipolar depression?

Mania is in many ways not just a mood disorder but also a rate disorder, with the speeding up of thought, action, behavior, cognition, and so forth. Sleep duration, rate of thinking, and goal-directed activity help differentiate the polarity distinctions, rate of disturbance, and cyclicity phenomenon. Highly-recurrent or cyclical phenomena are probably a variant of bipolar disorder, or at least a separation from unipolarity. As a diagnosis, bipolar disorder can broadly encompass cyclical mood recurrences, polarity changes, impulsivity, cognitive dysfunction, possible psychosis, chronobiologic or sleep disruptions, common psychiatric comorbidities, and consequent behavioral or interpersonal problems. These factors create a complex that is not simple. A longitudinal perspective is neccessary for an accurate diagnosis. PP

 

References

1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
2. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722.
3. Goldberg JF, Perlis RH, Ghaemi SN, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD. Am J Psychiatry. 2007;164(9):1348-1355.
4. Truman CJ, Goldberg JF, Ghaemi SN, et al. Self-reported history of manic/hypomanic switch associated with antidepressant use: Data from the STEP-BD. J Clin Psychiatry. In press.
5. Goldstein TR, Frye MA, Denicoff KD, et al. Antidepressant discontinuation-related mania: critical prospective observation and theoretical implications in bipolar disorder. J Clin Psychiatry. 1999;60(8):563-576.
6. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol or other drug abuse. Results from the Epidemiologic Catchment Area (ECA) study. JAMA. 1990;264(19):2511-2518.
7. Goldberg JF, Garno JL, Callahan AC, Kearns DL. Validity of bipolar diagnoses among inpatients with substance use disorders. Poster presented at: the 7th International Conference on Bipolar Disorder; Pittsburgh, PA; June 7, 2007.
8. Stewart C, El-Mallakh RS. Is bipolar disorder overdiagnosed among patients with substance abuse? Bipolar Disord. 2007;9(6):646-648.
9. Baethge C, Baldessarini RJ, Khalsa HM, Hennen J, Salvatore P, Tohen M. Substance abuse in first-episode bipolar I disorder: indications for early intervention. Am J Psychiatry. 2005;162(5):1008-1010.
10. Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2004;61(8):807-816.
11. Robinson LJ, Ferrier IN. Evolution of cognitive impairment in bipolar disorder: a systematic review of cross-sectional evidence. Bipolar Disord. 2006;8(2):103-116.
12. Kessing LV, Andersen PK. Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder? J Neurol Neurosurg Psychiatry. 2004;75(12):1662-1666.
13. Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161(2):217-222.
14. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group. Bipolar Disord. 2000;2(3 Pt 2):249-255.
15. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20(6):607-614.
16. McElroy SL, Hudson JI, Capece JA, et al. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry. 2007;61(9):1039-1048.
17. Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003;361(9370):1677-1685.

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Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.
Disclosure: Dr. Kennedy has received research support or honoraria from AstraZeneca, Eli Lilly, Forest, Janssen, Myriad, and Pfizer.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.

 


 

Present treatments for dementia are largely palliative, providing symptomatic but temporary improvement. In contrast, agents that promise disease modification offer the hope of prevention, arrest, or deceleration of decline. However, enthusiasm for these new agents must be tempered by acknowledgment of their inevitable limitations within the present standard dementia care.

Two recent reviews1,2 of treatments being developed for Alzheimer’s disease describe a substantial number of agents in randomized clinical trials, not only to demonstrate safety or determine effective dosing, but to test efficacy and tolerability as well. Although some of the medications are targeted at neurotransmitter systems, which may be the innocent bystanders in dementia pathogenesis, several address amyloid and tau pathologies thought to be central to neurodegeneration of the Alzheimer’s type. These latter agents offer the promise of preventing, arresting, or slowing decline through disease modification. However, disease-modifying agents will have to overcome even greater challenges faced by the present generation of medications for dementia if they are to be approved by the Food and Drug Administration. Moreover, they are not expected to be curative and their preventive potential depends on as yet unrealized preclinical diagnostics. Thus, they are unlikely to supplant symptomatic treatments. Without the continued evolution in collaborative models of dementia care, it is difficult to see how disease modifiers will ever meet their full public health potential. What follows is an effort to prepare practitioners and policy makers to better address the implications of disease modification in dementia (Table).

 

 

 

Disease Modification and Symptomatic Treatments Defined

The concept of disease modification is graphically portrayed in the accompanying Figure. With the start of a symptomatic treatment such as donepezil, galantamine, rivastigmine, or memantine, measures of benefit diverge initially from placebo but ultimately parallel the rate of decline of untreated patients. When withdrawn from treatment, within weeks patients who initially benefited perform no better than the placebo group. Thus, the effect is beneficial but palliative. In contrast, disease-modifying agents would either arrest or slow the progressive loss in quality of life. The result is an altered slope or velocity of decline which diverges at an acute angle from placebo. The larger the effect, the greater the divergence and the sooner the benefits become clinically apparent. Smaller effects may be reliably detected only after prolonged treatment. With the introduction of diagnostic tests to identify at-risk people prior to the onset of illness, disease modifiers may also be preventive.2

 

It is the mechanism of action that distinguishes symptomatic from modifying therapy. The present medications for mild, moderate, or severe Alzheimer’s disease either enhance cognitive performance or retard cognitive decline through the manipulation of neurotransmitter systems. They either boost the signal between cholinergic neurons or reduce the background noise from excessive neuronal excitation. Although the signal is enhanced, the receiver continues to fail at the same rate. In disease modification, the pathology being modified is upstream from events leading to the loss of neurons and neurotransmitters. Both the neurotransmitter signals and receivers continue to decline, though less rapidly. Disease modification does not imply that function will be restored permanently to premorbid levels. Hence, unless the modification occurs prior to neurotransmitter deficits, symptomatic agents would still have a role to play. By analogy, analgesics may be necessary both before and after an osteoarthritic joint is replaced with a mechanical prosthesis. Similarly, cholesterol-lowering agents are indicated both before and after myocardial infarction. Indeed, statin therapy is one possible model of disease modification in both coronary artery disease as well as Alzheimer’s dementia.1

 

How Would Disease Modification Be Measured?

The development of measures for disease modification in dementia has involved at least three elements. First, a human biomarker at or near the cause of the illness needed to be identified. Second, an animal model of the illness in which the biomarker could be experimentally manipulated needed to be developed. Third, agents which reduce the pathogenic effects of the biomarker in animals need to show the same or similar actions in humans but with clinical significance. It is clinical significance which has to be defined if the agent is to be prescribed. However, the definition of meaningful clinical significance is not straightforward. Although FDA-approved medications for dementia reliably demonstrate cognitive benefits superior to placebo, a significant minority of treated patients experience no benefit. These agents may delay the emergence of behavioral problems, but their capacity to reduce them once present is unreliable.3,4 Further, a significant minority of providers find the benefits neither socially meaningful nor economically valuable.5,6

Based on analyses of medical expenditures and the increase in life expectancy between 1960 and 2000 in the United States, Cutler and colleagues7 found that the value extracted from dollars spent was substantial. However, further expenditures are expected to yield decreasing value, meaning that increased spending will likely be accompanied by smaller and smaller increases in the life span. Thus, the quality of existence in the latter part of life takes on greater importance. If disease modification can extend the quality of life (eg, independence, productivity) for the patient and family caregivers, increased life span need not be the measure by which value is determined. Indeed, pushing dementia-related disability to the end of the life span would be nearly as desirable as the more distant goal of outright prevention. Complicating the equation is the amount of time necessary to demonstrate a reduction in the slope of cognitive decline or quality of life that must be demonstrated to argue for the presence of modification. As a result, an accounting of the social and economic benefits will follow at some distance from the expense of initiating disease modification.

 

Unanticipated Consequences

Post and Whitehouse’s8 cautionary examples of dementia treatment following the introduction of donepezil at first reading appear not to apply to disease-modifying therapies. In the cases cited, improved cognition following cholinesterase therapy was accompanied by a return of obsessive worry, agitation, painful and unwelcome insight, and awareness of limitations. For the patients’ caregivers, burden increased rather than declined and the quality of life for both parties was degraded rather than enhanced. In an accompanying editorial, Sachs9 advised that while the vignettes cited by Post and Whitehouse8 are exceptions rather than the norm, they are nonetheless familiar to physicians who treat patients and their families coping with dementia. The cases highlight the need to communicate clear, realistic goals of treatment. If symptomatic improvement in one domain is associated by symptom exacerbation in another, the balance of harm and benefit may not favor continued treatment. Because the cholinesterase inhibitors are not thought to increase the life span of people with dementia, they are not seen as prolonging their disability or exacerbating suffering except in the rare cases cited by Post and Whitehouse.8

However, if disease modification does indeed prolong life by delaying cognitive decline, the expected delay in loss of independence and emergence of behavioral disturbances may not result in a lesser duration of dependency and discomfort. Thus, the question remains of when to stop treatment whether it is merely symptomatic or genuinely disease modifying. Similarly, once the process of neuronal death is well underway there may be little gained from modification agents even if they were to arrest the process entirely. Again, the goals of care must be made explicit to insure that modified disease means more than prolonged dependency.

 

Disease Modification and Diagnosis With Biomarkers

Symptomatic treatment is recommended across the array of common dementias including Alzheimer’s, mixed (Alzheimer’s disease with vascular components), and Parkinson’s dementia.10 However, for disease modification to be effective, particularly for prevention, precise diagnosis is needed to distinguish Alzheimer’s disease from the prevalent but less frequent vascular and Parkinson’s dementias. Dubois and colleagues11 recommend new research diagnostic criteria for Alzheimer’s disease which would require the presence of significant impairment in episodic memory plus at least one abnormal biomarker as detected by either structural neuroimaging with magnetic resonance imaging, functional imaging with positron emission tomography, cerebrospinal fluid analyses of b-amyloid, or hyperphosphorylated tau proteins. If any of the agents currently in clinical trials demonstrate clinically significant disease modification as well as favorable alteration in biomarkers, the research criteria proposed by Fillit and colleagues10 may well take their place in standard clinical practice. Biomarkers sensitive to early effects or lack thereof from disease modifiers would also be useful for the determination of treatment failure. Because disease modification will require long-term treatment, minimizing the expense and disappointment when the treatment fails is critical.

A breakthrough in risk identification through personal genomics12 might justify the prescription of disease-modification agents prior to any phenotypic evidence of illness. However, a statistically significant association between a personal genetic variation and an illness does not mean that it is clinically significant. Simply knowing about one’s risk status does not always lead to better health decisions. Some patients may over-interpret a relative increase in risk as absolute certainty that disease will follow. Others, finding they are at relatively less risk than expected, may forego health-promoting behaviors. As a result, patient education coupled with provider counseling would be required to ethically address the uncertainties of risk and benefit. The costs of a personal genome, even if current prices fall precipitously, will add expense and inevitable concerns about inequities in care and insurance coverage. Finally, at what threshold of risk should medication be started? Further, what evidence will physicians use to declare a disease-modifying treatment is ineffective or has lost efficacy after initial benefit? These are scientific questions of probability but the emotional weight attached to them will be personal to the patient. Thus, tact, time, and counseling will be necessary to help patients and their families make informed, personalized decisions.

 

Conclusion

Advances in preclinical diagnosis may transform disease modification into disease prevention. However, in the interim, disease modification, if shown to be efficacious, will impose substantial burdens before the desired benefits are evident. Disease-modifying agents may fail to demonstrate their full potential unless they are incorporated into a model of disease-modifying care. The collaborative model is supported by several randomized controlled trials but is not the current standard.13-15 Nonetheless, if disease-modifying agents delay the onset of dementia-related disability until the end of the life span, the economic value would be substantial even if they cannot cure or prevent the disease. In summary, enthusiasm for the next-generation medications should be tempered by an awareness of the implications of disease modification for dementia care. PP

 

References

1. Grossberg GT, Pejovic V, Miller ML. Current strategies for the treatment and prevention of Alzheimer’s disease. Primary Psychiatry. 2007;14(8):39-54.
2. Christensen DD. Changing the course of Alzheimer’s disease: anti-amyloid disease-modifying treatments on the horizon. Prim Care Companion J Clin Psychiatry. 2007;9(1):32-41.
3. Howard RJ, Juszczak E, Ballard CG, et al. Donepezil for the treatment of agitation in Alzheimer’s disease. N Eng J Med. 2007;357(14):1382-1392.
4. Yaffe K. Treatment of neuropsychiatric symptoms in patients with dementia. N Engl J Med. 2007;357(14):1441-1443.
5. Birks JS, Harvey R. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev. 2003;(3):CD001190.
6. Kmietowicz Z. NICE proposes to withdraw Alzheimer’s drugs from NHS. BMJ. 2005;330(7490):495.
7. Cutler DM, Rosen AB, Vijan S. The value of medical spending in the United States, 1960-2000. N Engl J Med. 2006;355(9):920-927.
8. Post SG, Whitehouse PJ. Emerging antidementia drugs: a preliminary ethical view. J Am Geriatr Soc. 1998;46(6):784-787.
9. Sachs GA. Dementia and the goals of care. J Am Geriatr Soc. 1998;46(6):782-783.
10. Fillit HM, Doody RS, Binaso K, et al. Recommendation for best practices in the treatment of Alzheimer’s disease in managed care. Am J Geriatr Pharmacother. 2006;4(suppl A):S9-S24.
11. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6(8):734-746.
12. McGuire AL, Cho MK, McGuire SE, Caulfield T. The future of personal genomics. Science. 2007;317(5845):1687.
13. Callahan CM, Boustani MA, Unverzagt FW, et al. Effectiveness of collaborative care for older adults with Alzheimer disease in primary care: a randomized controlled trial. JAMA. 2006;295(18):2148-2157.
14. Vickrey BG, Mittman BS, Connor KI, et al. The effect of a disease management intervention on quality and outcomes of dementia care: a randomized controlled trial. Ann Intern Med. 2006;145(10):713-726.
15. Mittelman MS, Roth DL, Clay OJ, Haley WE. Preserving health of Alzheimer caregivers: impact of a spouse caregiver intervention. Am J Geriatr Psychaitry. 2007;15(9):780-789.

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Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.

Disclosure: Dr. Kennedy reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Division of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.


 

Criteria for Alzheimer’s disease and preclinical dementia have been proposed recently, which include potential biomarkers of the illness. Nonetheless, the etiology of the illness remains uncertain despite consistent associations described for cerebral amyloid and hyperphosphorylated tau pathologies. As a result, further progress toward understanding age-related changes in cognition that are not related to dementia is critical both to characterize healthy aging but also to develop interventions that will sustain cognitive performance. This will be the case even if proposed biomarkers become powerful predictors of the presence of disease.

Introduction

Preliminary criteria for diagnosis of Alzheimer’s disease in both its clinical and pre-clinical forms have appeared in the proposed Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,1,2 and subsequently by work groups convened by the National Institute on Aging and the Alzheimer’s Association.3-5 Both suggest that bio-markers related to amyloid or the microtubule protein tau soon may be incorporated into the diagnostic process. The appeal of putative biomarkers of dementia is their promise of signaling the presence of a disease process before cognition or brain topography become noticeably impaired. In addition to anteceding the onset of symptoms, biomarkers might be less subject to variations seen in healthy cognitive performance related to education, vocation, or innate intelligence. The proponents of biomarker research assume that amyloid is the signal event in Alzheimer’s disease. Amyloid and hyperphosporylated tau are pathology consistently associated with Alzheimer’s disease. But how distal are these pathologies from the pathoetiology of the illness?

Uncertainty about the primary pathophysiology of Alzheimer’s disease has raised skepticism about the use of biomarkers.6 Yet, interventions applied once synaptic atrophy and neuronal death are manifest as cognitive impairment may be too late to be effective. Further, intervention trials to test the amyloid hypothesis among patients selected on the basis of these preliminary criteria could take a decade to complete. Even if the spread of amlyoid in the brain can be reduced or reversed, the demonstration of preserved or improved cognition will be required to establish efficacy. As a result, attention to progress in the characterization age-related changes in cognition is critical to refining criteria for preclinical dementia. The study of working memory and executive function now underway in the Research Domain Criteria initiative of the National Institute of Mental Health7,8 may further advance the assessment of cognitive processes and neural circuits sensitive to the earliest signs of Alzheimer’s disease.

Cognitive Constructs and Aging

Cognitive constructs refer to mental processes which have both scientific and clinical utility yet are approximations of reality based on observation and theory. Functional imaging has revealed age-related changes relevant to the theoretical constructs, but no unified phenomenon which might represent a simple theory of aged cognition has emerged. Nonetheless, awareness of these constructs and how they are changed for better or worse with age will have clinical implications when genuinely therapeutic agents arrive for the treatment of dementia. Prominent constructs recently reviewed by Reuter-Lorenz and Park9 appear in bold followed by descriptions.

Working memory, that component of the cognitive system which retains information for immediate use, is an area of intense interest for clinicians caring with older adults but for neuroscientists as well. Memory screening tests most often rely on working memory by requiring the patient to register, retain (learn), and recall (remember) new information such as a recited list of words or set of image presentations. Older adults perform as well as younger provided the memory load does not exceed four items or require marked executive function to inhibit, reorder, or refresh the list. Thus, when older adults are asked to select from the assortment of recently learned memories or to alternate categories of items, working memory becomes fatigued. Unlike consolidated memory, which seems to have infinite shelf space, working memory is volume dependent and vulnerable to overload. As the memory load increases, both younger and older adults recruit prefrontal cortical areas to manage the load. Older adults reach overload sooner and show a drop in prefrontal activation, suggesting the system has met its limit.

Inhibitory control deficits appear when older adults are given memory tasks in which distractors are also presented. In comparison to a younger adult, the older person is less likely to ignore, screen out, or delete irrelevant stimuli. When instructed to remember a sequence of words or images followed by items to be ignored, older adults show greater brain activation for the latter than do younger adults. When instructed to generate a list of words starting with the letter “S” followed by an instruction to list words starting with the letter “A,” older adults are more likely to insert S-words into the A-word list. Thus, age-related inhibitory dysfunction mediated by prefrontal processes results in impairments in the initial stage of information processing, placing further limits on working memory capacity and efficiency.

Processing speed decrements are the most widely accepted explanation for decline in cognitive processes during late life. Changes in white matter structure and integrity are largely responsible. It is as though age and cardiovascular illness fray the insulation in neural circuits. However, the effects are not uniform. Some neural circuits and the cognitive processes they serve may be more intact and more capable of compensating for those with less integrity. As a result, slowed processing speed is not considered a sufficient explanation for cognitive decline during aging.

Long-term memory deficits have been ascribed to a number of age-related changes in brain structure and cognitive function. Older adults are less effective at encoding new information for memory tests. However, when given contextual or categorical cues associated with the memory item, their performance improves. Such tests of episodic memory are also sensitive to loss of volume and under-activation of the hippocampus and parahippocampus, two areas affected early in Alzheimer’s disease. Implicit, automatic, or procedural memory functions out of awareness and is related to previously learned material that can be applied to current tasks with little conscious effort. This form of effortless recall, particularly when associated with semantic processing, involves left inferior prefrontal regions and is relatively preserved in older people.

Constructs from Imaging Studies of Brain Regions and Neural Circuitry

Functional imaging studies with positron emission tomography or functional magnetic resonance imaging scans have provided a number of discoveries about regional differences in the aging brain. For example, compared to younger people, older adults will activate a greater number of brain regions to meet the same cognitive challenge. Hemispheric dominance, whether for verbal processing on the left or spatial processing on the right, is diminished such that functional asymmetry and localization are reduced. Over-activation is also seen in both posterior and anterior regions of cortex accompanied by a general posterior to anterior shift in activation. The phenomenon is thought not to be a result simply of cerebrovascular aging. Over-activation may be associated with superior cognitive performance and represent compensatory enhancement of neural circuitry. However compensation has its price.

The medial prefrontal, medial, and lateral parietal brain areas are known as the default network. These regions are highly interconnected, more active at rest than during purposeful activity, and associated with internal rather than external stimuli. The default network manages ongoing attention to the environment, self-focus, and reflective memories. However, with advancing age, the network loses interconnectivity and over-reacts to external stimuli. As a result, frontal areas are recruited to compensate, causing loss of efficiency and accuracy.

De-differentiation is the result of lost topographic specificity and decline in neural plasticity. Additional regions of cortex have to be recruited, not to reach a new equilibrium, but rather to respond to loss of specialization. For example, face recognition is specific to the ventral visual cortex, but as this area loses functionality with age, prefrontal areas are recruited to manage the work load placed on working memory. There is a general posterior to anterior activation in the cortex with the medial, lateral, and anterior prefrontal cortex being over-activated to compensate for under-activation in the medial temporal lobe and ventral visual cortex.

Frontal over-activation makes older adults vulnerable to age- and illness-related prefrontal deficits. In addition, there is an increased noise to signal ratio. As dopamine levels decline with age, the strength of synaptic signaling falls while the background neural noise does not.

Older adults are also more likely to exhibit difficulties with proactive versus reactive cognitive control. Because of changes in executive function and prefrontal structures, older adults are less able to benefit from cues and context that might precede a sequence of stimuli. Rather, they rely more than younger people on cognitive procedures that occur during stimulus presentation. This reduces processing speed as well as the stimulus load that can be successfully processed. Thus, their executive function is more reactive than proactive or anticipatory. They multi-task with difficulty.

From “CRUNCH” to “STAC”

How, then, do we explain the increasing proportion of older adults who maintain sufficient cognitive function to remain independent into late life?”10 Reuter-Lorenz and Park9 present two hypothetical mechanisms to account for the maintenance of cognitive performance in late life, shown in the Figure. The Compensation-Related Utilization of Neural Circuits hypothesis suggests that cognitive processes become rerouted to new or additional circuits as age and illness wear the brain down. As one area of mental hardware deteriorates, another is recruited to take its place. A virtual scaffold gradually emerges and is made possible by the distribution of cognitive processes to frontal and other areas, including both hemispheres, and to new neurons via neurogenesis. The Scaffolding Theory of Aging and Cognition adds the notion that the brain’s software may be enhanced at the same time that the circuitry is being upgraded. The scaffold is enhanced by learning, physical exercise, cognitive stimulation, and social engagement. The impact on cognitive performance will vary as a result of both the quality of the structure of the scaffold and personal behavior. In this way, not only do age and illness affect cognition, but so do personal history, ongoing mental activity, and the environment.

 

 

Conclusion

Advances in cognitive neuroscience buttressed by interest in dementia biomarkers and functional imaging techniques promise to increase the measurement of risk for the development of Alzheimer’s disease. However, equally important are insights into compensatory mechanisms and the plasticity of neural circuitry that may argue for interventions which might sustain if not improve cognitive performance to the end of the life span.11 This will be particularly important when treatments emerge to modify the disease process and slow the rate of decline among people with dementia. An understanding of how biomarkers might predict dementia will not obviate the need to advance our understanding of aging and cognition in healthy active older adults. PP

References

1. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association. In press.
2. Kennedy GJ. Proposed revisions for the diagnostic categories of dementia in the DSM-5. Primary Psychiatry. 2010;17(5):26-28.
3. Alz.org. Proposed criteria for Alzheimer’s disease dementia. Available at: www.alz.org/research/diagnostic_criteria/dementia_recommendations.pdf. Accessed August 10, 2010.
4. Alz.org. Proposed criteria for mild cognitive impairment due to Alzheimer’s disease. Available at: www.alz.org/research/diagnostic_criteria/mci_reccomendations.pdf. Accessed August 10, 2010.
5. Alz.org. Proposed criteria for preclinical Alzheimer’s disease. Available at: www.alz.org/research/diagnostic_criteria/preclinical_recommendations.pdf. Accessed August 10, 2010.
6. Kolata G. In Alzheimer’s research, hope for prevention. The New York Times. August 5, 2010: A18.
7. Insel T, Cuthbert B, Garvey M, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167(7):748-751.
8. NIMH Research Domain Criteria (RDoC). Available at: www.nimh.nih.gov/research-funding/nimh-research-domain-criteria-rdoc.shtml. Accessed August 12, 2010.
9. Reuter-Lorenz PA, Park DC. Human neuroscience and the aging mind: a new look at old problems. Journal of Gerontology: Psychological Sciences. 2010;65B(4):405-415.
10. Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med. 1980;303(3):130-135.
11. Rae MJ, Butler RN, Campisi J, et al. The demographic and biomedical case for late-life interventions in aging. Sci Transl Med. 2010;2(40):40cm21.

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This interview took place on June 10, 2010 and was conducted by Norman Sussman, MD.

Disclosure: Dr. Holt reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

If you would like to access this interview online, please visit www.primarypsychiatry.com.


Are we at a point where neuroimaging or neural biomarkers of psychiatric illness can help us identify and even start treating diseases early in their development?

One central goal in neuroimaging research in psychiatric illness is to define the neural correlates of particular psychiatric illnesses so that they can be used as biomarkers of the illness. The basic assumption is that at least some of the brain abnormalities found in people with an illness should also be seen in people who are at risk for that illness but not yet ill. These neural abnormalities could be used as biomarkers of risk; they could work just like stress tests, Papanicolaou smears, or other methods used for early risk detection by other fields of medicine. Then, these biomarkers would allow us to treat people at risk in a targeted, cost-effective way with preventive interventions.

Neuroimaging research in psychiatry is still a relatively young field. It started in the mid-1970s, with the development of computerised tomography scan. The high-resolution magnetic resonance imaging (MRI)-based methods that we use now have only been used since the mid- to late-90s. We have only been conducting this kind of research for the past 10–15 years. The spatial and temporal resolution of these methods are still improving. We have come a long way in identifying neural correlates of psychiatric illness, but we still have a way to go.

Does evaluating multiple aspects of illness in addition to neuroimaging provide a better prediction tool?

Yes. The key may be to use multiple methods in combination to develop a risk signature of psychiatric illnesses. However, it is challenging because a lot of the neural correlates of illness turn out to be somewhat nonspecific. They often overlap with what is seen in healthy people. Also, the different illnesses can show similar abnormalities. This may say more about our diagnostic and classification systems than the biology of the illnesses we study.

There has been a recent set of breakthroughs that will help push forward this line of research. There have been recent studies showing that certain treatments, like cognitive-behavioral therapy1,2 and fish oil,3 may actually prevent the development of certain major mental illnesses, such as schizophrenia and depression.

Can neural dysfunction predict who in combat might experience posttraumatic stress disorder (PTSD)?

PTSD has been associated with a set of abnormalities in brain function, including impaired function of the medial prefrontal cortex (PFC), exaggerated amygdala responses, and dysfunctional connections between the medial PFC and the amygdala. Risk for PTSD has been studied extensively by a group at Massachusetts General Hospital in Boston led by Roger K. Pitman, MD, using various neuroimaging methods including functional MRI (fMRI) as well as psychophysiologic techniques.4,5 They have measured skin conductance responses in response to emotional stimuli and during fear conditioning. They have used these methods to study brain function of combat veterans who do or do not have PTSD. The elegant aspect of their design is that each of the combat veterans they have studied also has an identical twin brother who has not been exposed to combat. The idea is that any abnormalities they find in the veterans with PTSD that they also find in those veterans’ twin brothers could be related to risk for PTSD.

They found several abnormalities in the veterans with PTSD and their twins, such as elevated dorsal anterior cingulate gyrus activity and an enlargement of a space in the middle of the brain called the cavum septum pellucidum. Now that they have found these abnormalities that could be related to risk, they can examine them prospectively in soldiers before they go into combat, to see if these actually are risk markers for PTSD.

Is it true that when patients with neuronal loss in areas like the hippocampus are effectively treated with an antidepressant, neuronal sprouting occurs because of an increase in brain-derived neurotropic factor?

The rat model of the effects of stress on the hippocampus differs from what we see in humans to some extent. Still, there is a lot of evidence for the effects of neurotrophic factors on brain regions affected in psychiatric illness and that antidepressants increase the release of these factors and possibly affect medial temporal lobe volume and neurogenesis. This is an active area of study right now, in research dedicated to developing novel treatments for depression and schizophrenia.

Addictive disorders are common. What do we know about reward circuitry responses?

There has been much research on the reward system of the brain, both in rats and monkeys as well as in humans. Research in humans has mostly been conducted using fMRI and positron emission tomography. There is a network of regions which includes the ventral striatum, orbital frontal cortex, dorsal lateral PFC, and dopaminergic cell groups of the midbrain, which are involved in the pursuit of reward and the experience, and anticipation of rewarding stimuli—all aspects of reward-related responses.

Addiction, major depressive disorder, and schizophrenia have each been associated with a different type of abnormality in the circuitry. For example, addiction may be most related to an impairment in what we call “top-down control” by the PFC of the function of subcortical reward circuitry. Schizophrenia, particularly the negative symptoms of the disorder,  may be related to an impairment in the anticipation, or memory, of rewarding experiences, which may have a slightly different mechanism. We are still in the process of understanding what the specific neural correlates are of these behavioral abnormalities associated with the reward system. Luckily, this system has been very well-characterized in animal models.

If it really turns out to be the case that addiction is associated with a reduction in the top-down control of reward-related responses, there may be a way to augment the activity of the PFC and its modulation of subcortical activity in the striatum and other centers that may be dysregulated in these patients.

Have you done any work on understanding delusions of schizophrenia from a neural point of view?

Yes. Our model comes from several lines of converging evidence that suggest that delusions result from an abnormality in emotional learning and memory.

The idea is that we have a somewhat flexible neural system that tells us whether something in the environment is important, dangerous, or relevant to us in some way. It actually appears that we have two interacting systems that evaluate the emotional meaning of information in the environment. There is a fast, sometimes inaccurate system, and then a slow but more detail-oriented and precise system. Sometimes the fast system misfires, even in healthy non-delusional people. Then, the second more accurate system kicks in to correct these errors.

When people develop delusional ideas, the system misfires frequently, telling the person that something in his or her environment is important, relevant, or dangerous. Yet, there is no mechanism that comes in to correct these misperceptions.

Our lab, among others, has found neuroimaging evidence to support this hypothesis. We have found that delusions are associated with misfiring of certain regions of the brain, such as the cingulate gyrus, in response to information that is not personally relevant or emotionally significant for most people.6-8

Is there a correlation between treatment, elimination of delusions, and changes in these areas?

Neuroimaging studies that conduct this type of within-subject comparison represent the best approach to testing this model of delusions, but it is difficult to do this kind of study well. If you are not careful, there will be several things that are changing at the same time, like doses of medication and symptom severity. We are conducting a study like this right now to see if we can tease out the effects of treatment on delusions and the associated changes in brain function.

Is quantitative electroencephalogram (EEG) valuable in your work?

I have done some event-related potential (ERP) work and I think it is extremely valuable. It can be a very good companion to fMRI because it has very good temporal resolution. However, the spatial resolution is not very good, while fMRI has the opposite set of strengths.

fMRI essentially measures blood flow by taking advantage of the fact that the  deoxygenated hemoglobin (deoxyhemoglobin) is paramagnetic. Because deoxyhemoglobin is paramagnetic, we can measure where it is going in the brain because it disrupts the MRI signal in a predictable way.

EEG measures electrical activity of pyramidal neurons. Because it is directly measuring neuronal activity, the electrical discharge of neurons, it is very accurate temporally, on the order of milliseconds. However, because it can only measure activity that is near the surface of the scalp, it can only measure activity of neurons that are near the cortical surface; it cannot provide the sort of spatial resolution that we have with MRI-based methods.

Has there been work on the circuits involved with anxiety disorders?

This brings up a current question in psychiatric neuroimaging research that many are grappling with, which is whether to continue to use the Diagnostic and Statistical Manual of Mental Disorders classification schemes in our research, since these classifications may not reflect unique biologic or neurophysiologic characteristics. For example, social anxiety disorder may be difficult to distinguish neurophysiologically from generalized anxiety disorder or other types of phobias.

Obsessive-compulsive disorder (OCD), however, appears to have a neural signature that is somewhat distinct in comparison to other anxiety disorders. It seems to be associated with more prominent orbital frontal-striatal abnormalities. This is interesting because it is consistent with the impression of many clinicians, that the clinical features of OCD are somewhat distinct from the clinical features of other anxiety disorders. This is in the line with the general idea that the DSM-IV-TR may have it right in some cases but not in others.

What is the major message for our clinical audience at this point?

I believe that we are slowly moving closer to being able to use neuroimaging as a clinical tool to identify people at risk and to measure effects of treatment. A large benefit of neuroimaging research that we have already seen clinically is that it has contributed to the reduction of the stigma associated with psychiatric disorders. It is really helpful for patients to understand that we have identified abnormalities of the brain associated with these disorders. These are medical disorders, which you can see evidence of, in research studies, on an MRI scan.

Have there been any major findings related to the PFC?

The frontal lobe is the part of the cerebral cortex that is most relevant for psychiatric illness. It is the control center of the brain. The dorsal and lateral PFC are involved in decision-making, planning, and task switching—any process that involves conscious choice. The medial and ventral portions of the PFC are involved in emotional perception, introspective activity, and integrating internal states with incoming sensory information. Many psychiatric disorders appear to be associated with abnormalities of the PFC, including schizophrenia, bipolar disorder, major depression, and PTSD.

Are there other brain areas of interest that you would like to comment on?

Neuroimaging researchers are very interested currently in understanding what the midline cortical network does and whether there are abnormalities in the functioning of this network in psychiatric disorders. This network includes the medial PFC and posterior cingulate gyrus. These regions show elevated activity during what people call “stimulus-independent thought,” which you have during times when you are not really engaged in thinking about anything going on in your surrounding environment. Instead, you may be daydreaming or thinking about the past or future. This network is of interest to psychiatric researchers because certain psychiatric disorders are associated with abnormal introspective thinking—either too much or too little of it. So far, it has been shown that this network functions abnormally in schizophrenia and depression.

What have we learned from the research on the neuropsychology of epilepsy?

It is interesting that medial temporal lobe epilepsy is sometimes associated with psychotic symptoms. Abnormalities in the medial temporal lobe are likely involved in the psychosis associated with schizophrenia too.9 A lot of evidence now supports this possibility. There has been some recent evidence showing abnormally elevated activity in a part of the hippocampus, which is within the medial temporal lobe, in people who have schizophrenia, as well as in people who are at risk for schizophrenia and later develop it.10

Epilepsy is an interesting model in that in some cases it has a very specific neuroanatomical correlate associated with psychiatric symptoms. It suggests that we are on the right track and that, at some point, we will understand psychiatric illnesses just as well as neurologists understand epilepsy. PP

References

1.    Morrison AP, French P, Walford L, et al. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomised controlled trial. Br J Psychiatry. 2004;185:291-297.
2.    Garber J, Clarke GN, Weersing VR, et al. Prevention of depression in at-risk adolescents: a randomized controlled trial. JAMA. 2009;301(21):2215-2224.
3.    Amminger GP, Schafer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146-154.
4.    Pitman RK, Gilbertson MW, Gurvits TV, et al. Clarifying the origin of biological abnormalities in PTSD through the study of identical twins discordant for combat exposure. Ann N Y Acad Sci. 2006;1071:242-254.
5.    Shin LM, Lasko NB, Macklin ML, et al. Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Arch Gen Psychiatry. 2009;66(10):1099-1107.
6.    Holt DJ, Titone D, Long LS, et al. The misattribution of salience in delusional patients with schizophrenia. Schizophr Res. 2006;83(2-3):247-256.
7.    Holt DJ, Lebron-Milad K, Milad MR, et al. Extinction memory is impaired in schizophrenia. Biol Psychiatry. 2009;65(6):455-463.
8.    Holt DJ, Lakshmanan B, Freudenreich O, Goff DC, Rauch SL, Kuperberg GR. Dysfunction of a cortical midline network during emotional appraisals in schizophrenia. Schizophr Bull. In press.
9.    Holt DJ, Phillips ML. The human amygdala in schizophrenia. In: Phelps EA, Whalen PJ, eds. The Human Amygdala. New York, NY: Guilford; 2009:344-361.
10.    Schobel SA, Lewandowski NM, Corcoran CM, et al. Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders. Arch Gen Psychiatry. 2009;66(9):938-946.

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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, such as multiple sclerosis; 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 a previous column in Primary Psychiatry, psychiatric issues in stroke were reviewed.3 In this issue, psychiatric issues related to Parkinson’s disease and multiple sclerosis are reviewed.

 

Parkinson’s Disease

Parkinson’s disease is an idiopathic degenerative disorder characterized by tremor, rigidity, and bradykinesia. Its estimated prevalence is 10–20 cases per 100,000 and its incidence increases with age. While it is thought of as primarily a disease of the elderly, Parkinson’s disease occurs even in adolescents, albeit rarely. Resting tremor (especially “pill-rolling” tremor) is the most obvious feature of Parkinson’s disease and is found in 75% of patients. However, bradykinesia is the most common initial sign, with insidious onset, and is therefore easily misdiagnosed as depression or apathy; bradykinesia is ultimately the most disabling feature. “Cogwheeling” is the result of tremor superimposed on rigidity. Postural instability due to rigidity as Parkinson’s disease progresses results in increased risk for falls. Abnormal involuntary movements are a result both of Parkinson’s disease and of dopaminergic therapy. Freezing of movement is particularly distressing to patients. In addition to the classic motor symptoms, other common manifestations of Parkinson’s disease include autonomic dysfunction (particularly orthostatic hypotension, bladder and gastrointestinal dysfunction), cognitive dysfunction, depression, and other psychiatric symptoms.

 

Psychosis

Parkinson’s disease is accompanied by dementia in a substantial minority of cases, and the boundary between Parkinson’s disease with dementia (PD-D) and dementia with Lewy bodies (DLB) is not a clear one. Psychotic symptoms (hallucinations and delusions) occur in 50% to 75% of patients with DLB, 30% to 50% with PD-D, and 5% to 15% of patients with Parkinson’s disease without dementia.1 Hallucinations are usually visual and delusions are most often paranoid. While limited psychotic symptoms with retained insight in Parkinson’s disease have been regarded as benign, a recent study suggests this is not the case and that most individuals’ psychotic symptoms progress over a period of years.4

In the early days of L-dopa treatment, adverse psychiatric reactions, particularly psychotic symptoms, were frequent after initiation of therapy and reported in up to 50% of patients after several years of treatment.1 The addition of carbidopa to L-dopa made this much less common. Psychotic symptoms have been reported as adverse reactions to other dopaminergic drugs in Parkinson’s disease, including bromocriptine, pramipexole, and ropinirole, but have not been clearly related to dose or length of exposure. Anticholinergic drugs are beneficial for Parkinsonian symptoms but pose the risk of aggravating cognitive dysfunction if dementia is also present. Anticholinerigc drugs also may cause psychotic symptoms as part of delirium, whereas the hallucinations and delusions induced by dopaminergic drugs are usually isolated psychotic symptoms unaccompanied by delirium.

Typical neuroleptics, especially high-potency ones, are contraindicated in Parkinson’s disease because they exacerbate symptoms and block the effect of dopaminergic drugs. Clozapine is the only antipsychotic shown in a randomized controlled trial (that also included olanzapine and risperidone) to be effective against psychosis, without aggravation of Parkinson’s disease.5 Quetiapine appeared beneficial for psychotic symptoms without worsening Parkinson’s disease in an open trial,6 but two small randomized controlled trials were negative. Despite its mixed dopamine agonist-antagonist profile, open trials of aripiprazole have not supported its use for psychosis in Parkinson’s disease.7 While there are case reports of psychotic symptoms responding to cholinesterase inhibitors in patients who have PD-D, without aggravating Parkinson’s disease,8 others have reported they caused significant worsening of Parkinson’s disease motor symptoms (which is not surprising since anticholinergic drugs reduce Parkinson’s disease motor symptoms).

 

Depression

Depression is very common in Parkinson’s disease, with a prevalence of up to 40% to 50%.1 Depression may antedate the development of motor symptoms in Parkinson’s disease and is associated with cognitive dysfunction.9,10 Depression and other psychological factors interact to affect the course and outcome of Parkinson’s disease, with depression resulting in impairment of functional capacity and quality of life, but not motor function in Parkinson’s disease.9 It is not known to what extent depression results from brain pathology as opposed the psychological consequences of the progressive disabling nature of Parkinson’s disease. Early in the course of unrecognized Parkinson’s disease, depression may be misdiagnosed because of the patient’s lack of facial expression and motor slowing. Later in Parkinson’s disease, the diagnosis of depression may be missed when fatigue, psychomotor slowing, impaired attention, poor sleep, and sexual dysfunction—all of which can be caused by Parkinson’s disease—are attributed to Parkinson’s disease. The presence of psychological symptoms of depression (eg, dysphoric mood, anhedonia, negativism, guilt) that are out of proportion to the degree of disability in Parkinson’s disease, and of course suicidal ideation, support the diagnosis of major depressive disorder (MDD).11 Mood lability (both unipolar and bipolar) has been described during the late-stage fluctuations known as on-off phenomena that occur after years of L-dopa therapy.1

For treatment of depression in Parkinson’s disease, tricyclic antidepressants (TCAs) may have the side benefit of reducing Parkinson’s disease motor symptoms because of their anticholinergic effects, but this must be balanced against the risk of their aggravating cognitive or autonomic dysfunction. Selective serotonin reuptake inhibitors (SSRIs) have occasionally been reported to exacerbate Parkinson’s disease motor symptoms and rarely have caused extrapyramidal side effects in patients without Parkinson’s disease. Mirtazapine may be a good choice for depression in Parkinson’s disease and may even reduce symptoms of Parkinson’s disease.12 Finally, dopamine agonists like pramipexole may be an alternative to antidepressants in Parkinson’s disease.13

Electroconvulsive therapy (ECT) may produce simultaneous remission of comorbid depression and Parkinson’s disease. Case reports, case series, and one sham-ECT controlled trial indicate that ECT is effective for depression in Parkinson’s disease and may also improve motor function.14 Many patients will experience improvement in motor symptoms but the magnitude (sometimes dramatic) and duration (sometimes many months) of benefit are variable and unpredictable. Maintenance ECT has also been used to extend the motor benefits. The potential benefits of ECT in patients with Parkinson’s disease and depression must be balanced against the common side effects of delirium and treatment-emergent dyskinesia.

 

Anxiety

Anxiety is very common in Parkinson’s disease,15 particularly as the disease progresses with anticipatory anxiety about motor freezing. Whether antiparkinsonian medications themselves contribute to anxiety is not clear. Treatment with antidepressants and cognitive-behavioral therapy (CBT), particularly if delivered along with physical therapy, can be helpful, and benzodiazepines sometimes may be required. However, the optimal pharmacologic treatment for anxiety in patients with Parkinson’s disease has not been established.1,15

 

Multiple Sclerosis

Multiple sclerosis is the most prevalent chronic disabling central nervous system disease in young adults, with a variable and unpredictable course. Common symptoms include motor and sensory dysfunction, visual loss, incontinence, and fatigue as well as cognitive impairment and mood symptoms. Psychiatric symptoms are common in multiple sclerosis and have significant effects on patients’ lives. (A more detailed review of psychiatric aspects of multiple sclerosis can be found elsewhere.16)

 

Depression

MDD occurs in patients with multiple sclerosis at approximately double the prevalence in the general population of comparable gender and age mix, and subsyndromal depressive symptoms are even more common. Between 25% and 50% of multiple sclerosis patients will have MDD sometime in their lives. However, depression remains underdiagnosed and undertreated in patient with multiple sclerosis. Suicide usually preceded by depression is not uncommon in multiple sclerosis, with one study estimating it may account for as many as 15% of deaths in patients with multiple sclerosis.17 Research to date has not clearly established whether the likelihood of depression is proportional to the degree of neurologic disability or duration of multiple sclerosis. As in stroke, there has been an attempt to differentiate “biologic” depression from “reactive” depression and to link the former to specific brain lesion sites. However, the literature remains unclear as to whether the risk of depression in multiple sclerosis can be related to lesions in specific brain areas.1,16

In patients with multiple sclerosis, depression causes greater cognitive dysfunction, poorer health-related quality of life and functional status, disruption of social networks, and reduced adherence with treatment. Such effects have been found in many other chronic diseases and it has not been demonstrated that depression affects the demyelination pathophysiology of multiple sclerosis, although depression may increase and its treatment decrease production of pro-inflammatory cytokines.18 The study of depression as an independent risk factor affecting the onset or course of multiple sclerosis is challenging because depression may also be a direct physiologically mediated consequence of the disease, a psychological reaction to the illness, or a complication of pharmacotherapy.19 Depression is especially difficult to study in multiple sclerosis because of its uncertain relationship to the multiple sclerosis-fatigue syndrome (discussed below).20

Both psychotherapy and pharmacotherapy appear to be effective for decreasing depressive symptoms in patients with multiple sclerosis,21 but studies to date have been few and small. In those studies, response rates to CBT have been equal to or better than than with antidepressant pharmacotherapy.

 

Bipolar Disorder

It has been long recognized that multiple sclerosis sometimes presented with mania, at times before other neurologic signs. However, some reported cases of bipolar disorder caused by multiple sclerosis may have been due to corticosteroid treatment, and some have represented other types of emotional lability caused by multiple sclerosis, such as emotional incontinence (see below). A limited epidemiologic literature has indicated that multiple sclerosis and bipolar disorder occur together at more than twice the expected rate based on their prevalence in the general population, but there have been no large, population-based epidemiologic studies of the prevalence of bipolar disorder in multiple sclerosis patients.16

 

Emotional Incontinence

Emotional incontinence (also referred to as pathologic crying or laughing, emotional diarrhea, emotional lability, pseudobulbar affect, or, more recently, involuntary emotional expression disorder [IEED]22) is a syndrome of uncontrollable episodes of emotional expression that occurs in up to 10% of multiple sclerosis patients23 and in a variety of other neurologic conditions including stroke.3 IEED is characterized by episodes of crying or laughing that are unrelated to or disproportionate to the patient’s actual emotional state. The crying and/or laughing are disinhibited and experienced by the patient as ego-dystonic and a struggle to stop. This form of emotional lability has been theorized to result from damage to inhibitory neurons projecting from the frontal lobes to limbic areas. Pathologic crying or laughing can have a significant impact on individuals’ social functioning and their relationships with others. Unpredictable and uncontrollable outbursts of affect often cause severe embarrassment and avoidance of social interactions and may result in subsequent agoraphobia. Treatment has usually been with TCAs or SSRIs, but dopamine agonists and a combination of dextromethorphan and quinidine have also been reported to be helpful.24

 

Anxiety

While anxiety symptoms and disorders are common in multiple sclerosis, as with most chronic medical illnesses they have received much less study than depression. Clinically significant current anxiety has been reported in 25% to 40% of multiple sclerosis patients, and the lifetime risk of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,25 anxiety disorders is approximately 50% greater than in the general population.16,26 Like depression, anxiety disorders are underrecognized and undertreated in multiple sclerosis.

 

Cognitive Dysfunction

Cognitive impairment may ultimately affect 50% of all patients with multiple sclerosis, with the deficits reflecting the subcortical location of the demyelination, including impairment of attention, speed of processing, and executive functions.1 Disorders of working memory may be prominent, and a minority of patients become frankly demented. However, cognitive impairment in multiple sclerosis may also be due to fatigue, depression, anxiety, or medication side effects. Neuropsychological assessment in multiple sclerosis patients with cognitive dysfunction can be helpful in this differential diagnosis as well as prognosis.

 

Fatigue

Fatigue is the most common symptom in multiple sclerosis, affecting 80% of patients and ranging from mild to disabling. While it is aggravated by heat and exertion, it is not eliminated by their avoidance. It should be distinguished from depression,20 medication side effects, and physical exhaustion and deconditioning attributable to motor impairment, though such distinctions are usually difficult and many patients have more than one of these contributing to their fatigue. The cause of multiple sclerosis-fatigue is unknown. Pharmacologic treatments include amantadine (100 mg twice daily), amphetamines and related stimulants (including pemoline, which is no longer available in the United States), SSRIs, and most recently modafinil,27 which is Food and Drug Administration-approved for the treatment of multiple sclerosis-related fatigue. A very gradually progressive exercise program, as in chronic-fatigue syndrome,28 can also be very helpful in multiple sclerosis.29

 

Pain

Both acute and chronic pain are common in multiple sclerosis and can be disabling. One study found that 25% of a large community-based sample of people with multiple sclerosis had severe chronic pain.30 Mechanisms may include dysesthesia, altered cognitive function, and other multiple sclerosis complications such as spasticity. Of the acute pain syndromes, trigeminal neuralgia is the most common and usually responds to carbamazepine.31 Widespread chronic pain is more common and harder to manage. Dysesthetic limb pain is particularly troublesome and treatment is usually with amitriptyline or gabapentin.

 

Psychiatric Side Effects of Treatment

Pharmacotherapy for multiple sclerosis may include corticosteroids, interferon, and other drugs. Corticosteroids have dose-related psychiatric adverse effects, including mania, depression, mixed states, psychosis, anxiety, insomnia, and delirium. A previous psychiatric reaction to corticosteroids does not necessarily predict recurrent reactions with subsequent steroids. The onset of psychiatric symptoms is typically within the first 2 weeks of treatment. Mild psychiatric side effects include insomnia, hyperexcitability, mood lability, mild euphoria, irritability, anxiety, agitation, and racing thoughts. Mood disorders are the most common psychiatric reaction to corticosteroids. Mania is also common and patients may experience both mania and depression during a single course of corticosteroid therapy. Affective symptoms are often accompanied by psychotic symptoms. Delirium and psychosis (without mood symptoms) are less common. Cognitive dysfunction also has been reported.

There are two types of interferon (IFN)-β used for the treatment of multiple sclerosis (IFN-β 1a and IFN-β 1b). While IFN-β commonly cause some of the same side effects as IFN-α (eg, flu-like symptoms), in contrast to IFN-α there is no clear evidence that IFN-β increase the risk for depression in patients with multiple sclerosis. Other drugs used to treat multiple sclerosis, including glatiramer acetate, mitoxantrone, and natalizumab, have not been reported to have neuropsychiatric side effects (except with the very rare cases of progressive multifocal leukoencephalopathy that occurred after natalizumab).16 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 I: stroke. Primary Psychiatry. 2007;14(9):37-40.
4. Goetz CG, Fan W, Leurgans S, Bernard B, Stebbins GT. The malignant course of “benign hallucinations” in Parkinson disease. Arch Neurol. 2006;63(5):713-716.
5. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. The Parkinson Study Group. N Engl J Med. 1999;340(10):757-763.
6. Mancini F, Tassorelli C, Martignoni E, Moglia A, Nappi G, Cristina S, Pacchetti C. Long-term evaluation of the effect of quetiapine on hallucinations, delusions and motor function in advanced Parkinson disease. Clin Neuropharmacol. 2004;27(1):33-37.
7. Friedman JH, Berman RM, Goetz CG, et al. Open-label flexible-dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson’s disease. Mov Disord. 2006;21(12):2078-2081.
8. Sobow T. Parkinson’s disease-related visual hallucinations unresponsive to atypical antipsychotics treated with cholinesterase inhibitors: a case series. Neurol Neurochir Pol. 2007;41(3):276-279
9. Holroyd S, Currie LJ, Wooten GF. Depression is associated with impairment of ADL, not motor function in Parkinson disease. Neurology. 2005;64;2134-2135.
10. Errea JM, Ara JR. Depression and Parkinson disease [Spanish]. Rev Neurol. 1999;28(7);694-698.
11. Brooks DJ, Doder M. Depression in Parkinson’s disease. Curr Opin Neurol. 2001;14:465-470.
12. Pact V, Giduz T. Mirtazapine treats resting tremor, essential tremor, and levodopa-induced dyskinesias.Neurology. 1999; 22;53(5):1154.
13. Barone P, Scarzella L, Marconi R, et al. Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease: a national multicenter parallel-group randomized study. J Neurol. 2006;253(5):601-607.
14. Rasmussen KG, Rummans TA, Tsang TSM, Barnes RD. Electroconvulsive therapy. In: Levenson JL, ed. American Psychiatric Publishing Textbook of Psychosomatic Medicine. Washington, DC: American Psychiatric Publishing; 2005:957-978.
15. Richard IH. Anxiety disorders in Parkinson’s disease. Adv Neurol. 2005;96:42-55.
16. Chwastiak LA, Ehde DM. Psychiatric issues in multiple sclerosis. Psych Clin N Am. In press.
17. Sadovnick AD, Eisen K, Ebers GC, Paty DW. Cause of death in patients attending multiple sclerosis clinics. Neurology. 1991;41(8):1193-1196.
18. Gold SM and Irwin MR. Depression and immunity: inflammation and depressive symptoms in multiple sclerosis. Neurol Clin. 2006;24(3):507-519.
19. Zorzon M, de Masi R, Nasuelli D, et al. Depression and anxiety in multiple sclerosis. A clinical and MRI study in 95 subjects. J Neurol. 2001;248(5):416-421
20. Bakshi R, Shaikh ZA, Miletich RS, et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult Scler. 2000;6(3):181-185.
21. Mohr DC, Goodkin DE. Treatment of depression in multiple sclerosis: review and meta-analysis. Clinical Psychology: Science and Practice. 1999;6:1-9.
22. Cummings JL, Arciniegas DB, Brooks BR, et al. Defining and diagnosing involuntary emotional expression disorder. CNS Spectr. 2006;11(6):1-7.
23. Feinstein A, Feinstein K, Gray T, O’Connor P. Prevalence and neurobehavioral correlates of pathological laughing and crying in multiple sclerosis. Arch Neurol. 1997;54(9):1116-1121.
24. Brooks BR. Involuntary emotional expression disorder: treating the untreated. CNS Spectr. 2007;12(4 suppl 5):23-27.
25. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
26. Korostil M, Feinstein A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Mult Scler. 2007;13(1):67-72.
27. Stankoff B, Waubant E, Confavreux C, et al. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology. 2005;64(7):1139-1143.
28. Powell P, Bentall RP, Nye FJ, Edwards RH. Randomised controlled trial of patient education to encourage graded exercise in chronic fatigue syndrome. BMJ. 2001;322(7283):387-390.
29. Petajan JH, Gappmaier E, White AT, Spencer MK, Mino L, Hicks RW. Impact of aerobic training on fitness and quality of life in multiple sclerosis. Ann Neurol. 1996;39(4):432-433.
30. Ehde DM, Gibbons LE, Chwastiak L, Bombardier CH, Sullivan MD, Kraft GH. Chronic pain in a large community sample of persons with multiple sclerosis. Mult Scler. 2003;9(6):605-611.
31. Thompson AJ. Symptomatic treatment in multiple sclerosis. Curr Opin Neurol. 1998;11(4):305-309.

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Dr. Haridas is a final year resident, Dr. Oluwabusi is a Child Fellow, and Dr. Gurmu is Chief resident in the Psychiatry Program at Drexel University College of Medicine in Philadelphia. Dr. Kushon is Clinical Associate Professor of Psychiatry at Drexel University College of Medicine and Medical Director of the Psychiatric-Medical Care Unit at Hahnemann University Hospital in Philadelphia, Pennsylvania.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Off-label disclosure: This article includes discussion of investigational treatments for major depression.

Please direct all correspondence to: Arun Haridas, MD, MRCPsych, Drexel University College of Medicine, Department of Psychiatry, 1427 Vine St, 8th Floor, Philadelphia, PA 19107; Tel: 215-762-6660; Fax: 215-762-6673; E-mail: aharidas@drexelmed.edu.


Focus Points

• Several case reports point to quetiapine’s abuse potential on the black market.
• Oral, intravenous, and intranasal routes of abuse have been reported.
• The inhalational method of quetiapine abuse is novel and counter-intuitive.
• Polysubstance abuse history may bring combinations of abuse, eg, quetiapine with cocaine-“Q” ball, quetiapine with marijuana “Maq ball.”

 

Abstract

Quetiapine abuse has been a cause for increased concern among clinicians. Several reports have highlighted this in the past. Reports of quetiapine abuse have varied in their routes of administration. The authors have had experience in managing several patients who have admitted to the use of quetiapine outside of prescription settings. This article examines the case of a recent patient on the authors’ inpatient unit who admitted to a novel route of abuse. While quetiapine’s abuse potential in the black market is well known, motivations for the abuse of quetiapine have varied in the past. Anxiety and insomnia has been amongst the reported motivations. Combination abuse of quetiapine with cocaine, called “Q ball,” have been reported previously. Quetiapine serves as a substitute for heroin when used in this combination. This article highlights a previously unreported combination of quetiapine with marijuana used in the inhalational route in what is termed a “Maq ball.”

Introduction

Quetiapine has been cited in several recent reports of being abused, especially in prison settings under the name “baby heroin” and “quell.”1,2  Reports of quetiapine abuse have varied in their routes of administration from the intravenous,1 intranasal,3,4 and oral.5 The authors have had experience in managing numerous patients in the in-patient unit who have admitted to obtaining and using quetiapine outside of prescription settings. A recent patient in an in-patient unit is highlighted below, illustrating this worrisome trend.

Case Report

A 27-year-old Hispanic male was admitted to the in-patient unit with a history of worsening depressed mood with suicidal ideation. He described polysubstance abuse involving marijuana, crack cocaine, alprazolam, and quetiapine; his preferred drug of choice was marijuana. He described smoking 1 oz. of marijuana daily. Approximately 1–2 times per week, he smoked crushed quetiapine tablets mixed with one ounce of marijuana. In addition, he smoked crack cocaine 3 times/week and alprazolam 5–10 mg/day orally up to 5 times/week.

Efforts to stop his quetiapine on this admission were unsuccessful on the unit, though he agreed to a tapered discharge dosage of quetiapine 100 mg/day. He requested to be discharged to a local drug and alcohol recovery house. Examination of prior admission records revealed that 5 months earlier, he had admitted to using quetiapine from the black market. At the time, he abused quetiapine orally, taking ~2–3 pills of quetiapine 100 mg/day, in addition to being prescribed quetiapine 100 mg BID by his primary care physician for his mood symptoms.

Discussion

Quetiapine is a drug of known value on the black market of antipsychotics.6 Its use is motivated by anxiety and insomnia.4 Quetiapine, amongst olanzapine, anticholinergics, and tricyclic antidepressants, have been a favored method to “zone out” or “take the edge off” amongst buyers in the black market.6 This may be related to the fact that quetiapine is associated with a better subjective response than its conventional antipsychotic counterparts.7

Quetiapine, crushed and mixed with cocaine and water, and taken intravenously, has been previously recorded in the literature as a “Q ball.”8 The strategy aims to mitigate the dysphoria associated with cocaine withdrawal through the sedative and anxiolytic effects of quetiapine. Quetiapine in the described case served as a substitute for heroin and the more classic cocaine and heroin “speed ball” combination.8

Conclusion

There have been no reports of quetiapine  combined with marijuana and serving as what we term a “Maq ball.” Unlike combining cocaine and quetiapine, which carries the risk for QT prolongation,8 lethal side effects are unlikely with this combination. However, it once again draws attention to this worrying trend of quetiapine becoming an increasing favorite for novel and hitherto unknown methods of abuse. Clinicians would do well to keep this fact in mind when deciding on an appropriate antipsychotic for individuals with comorbid substance use disorders. PP

References

1.    Hussain MZ, Waheed W, Hussain S. Intravenous quetiapine abuse. Am J Psychiatry. 2005;162(9):1755-1756.
2.    Del Paggio D. Psychotropic medication abuse in correctional facilities. The Bay Area Psychopharmacology Newsletter. 2005;8(1):5.
3.    Morin AK. Possible intranasal quetiapine misuse. Am J Health Syst Pharm. 2007;64(7):723-725.
4.    Pierre JM, Shnayder I, Wirshing DA, Wirshing WC. Intranasal quetiapine abuse. Am J Psychiatry. 2004;161(9):1718.
5.    Reeves RR, Brister JC. Additional evidence for the abuse potential of quetiapine. South Med J. 2007;100(8):834-836.
6.    Tarasoff G, Osti K. Black market value of antipsychotics, antidepressants and hypnotics in Las Vegas, Nevada. Am J Psychiatry. 2007;164(2):350.
7.    Voruganti L, Cortese L, Oyewumi L, Cernovsky Z, Zirul S, Award A. Comparative evaluation of conventional and novel antipsychotic drugs with reference to their subjective tolerability, side effects profile and impact on quality of life. Schizophr Res. 2000;43(2-3):135-145.
8.    Waters BM, Joshi KG. Intravenous Quetiapine-Cocaine Use (“Q- Ball”). Am J Psychiatry. 2007;164(1):173-174.

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Dr. Sidhu is staff psychiatrist in Department of Psychiatry at the Community Health Network in Indianapolis, Indiana. Dr. Saggu is Child and Adolescent Psychiatry Fellow at Wayne State University/Detroit Medical Center in Michigan. Dr. Lachover is clinical assistant professor in the Department of Psychiatry and Behavioral Neuroscience at Wayne State University College of Medicine. Dr. Dziuba is Chief of Psychiatry at Sinai Grace Hospital and assistant professor in the Department of Psychiatry and Behavioral Neurosciences at Wayne State University College of Medicine.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Kanwaldeep Sidhu, MD, Staff Psychiatrist, Community Health Network, 7165 Clear Vista Way, Indianapolis, IN 46256; Tel: 317-626-4422; Fax: 317-621-2218; E-mail: kansid@yahoo.com.


 

Abstract

Skin rash is listed by the manufacturer as one of the adverse events that may be associated with risperidone long-acting injection (RLAI). An erythematous rash is described as an infrequent occurrence. The following is a case of a 26-year-old male who developed a diffuse erythematous and maculopapular skin rash on both arms after initiation of RLAI treatment. Previous exposure to oral risperidone was uneventful. Photographs of the rash are included. RLAI treatment was discontinued and diphenhydramine was prescribed. The rash responded to these interventions and was completely gone in 3 weeks. A re-challenge with oral risperidone produced no rash and was clinically effective. A literature review reveals few cases of RLAI treatment with rash and none including an uneventful oral risperidone re-challenge. A consideration of etiologies must include a reaction to an ingredient within the solute or delivery system and becomes an important clinical consideration in treatment planning.


Focus Points

• Risperidone long-acting injection (RLAI) is a common antipsychotic treatment used in clinical practice.
• Skin rash is an adverse effect with RLAI.
• Adverse effects may occur not only with chemical salts in medication but potentially with other ingredients in the solute and delivery system.
• Care should be taken when investigating adverse effects to medications.

 

Introduction

Risperidone is a benzisoxazole derivative and is available in oral and injectable forms. Risperdal long-acting injection (RLAI) is a combination of extended-release microspheres for injection and diluent for parenteral use. The extended-release microspheres formulation is a white to off-white, free-flowing powder. Risperidone is micro-encapsulated in 7525 polylactide-co-glycolide at a concentration of 381 mg risperidone per gram of microspheres. It is provided with a diluent for parenteral use, which is a clear, colorless solution. The diluent is composed of polysorbate 20, sodium carboxymethyl cellulose, disodium hydrogen phosphate dihydrate, citric acid anhydrous, sodium chloride, sodium hydroxide, and water for injection. The microspheres are suspended in the diluent prior to injection.1 RLAI has been shown in multiple studies to be useful in non-compliant schizophrenia spectrum disorders and is generally used on a biweekly basis.2 The following is a case of a 26-year-old male who developed an erythematous, maculopapular skin rash on both his arms after he was started on RLAI.

 

Case Report

Mr. A is a 26-year-old male who was seen at the authors’ outpatient psychiatry clinic with a history of psychosis for 1 year. He reported hearing voices calling him “stupid” and he talked back to the voices. He was also observed to have paranoia, and thought that “people are up to something” and wanted to hurt him. His grandmother reported that he had trouble keeping up with his grooming and hygiene. The patient’s previous psychiatric history included two hospitalizations in the previous year for paranoia and disorganized thoughts. His medications included trials of quetiapine and haloperidol at another clinic. He was reported to be noncompliant with the treatment.

On mental status examination, Mr. A appeared his stated age, exhibited fair grooming and hygiene, and was guarded but cooperative. He did not display any abnormal movements or tremors. His gait and posture were normal. The patient spoke in a monotone voice and described his mood as “composed.” His affect was significantly flat, though he did display inappropriate smiling. He denied the presence of any hallucinations during the interview but he had significant delay of his thought processes without the evidence of any delusional content. He was alert and oriented to time, place, and person. He had intact attention, concentration, remote, recent, and immediate recall. He had fair abstract thinking, insight, and judgment.

A general health assessment was conducted during the evaluation, and no active medical problems were noted. He was on no medical medications. He did not report any known food or drug allergies. The patient’s body mass index and vital signs were found to be within normal limits. Lipid panel and electrolytes, including fasting blood sugar, were ordered and found to be within normal limits as well. A urine drug screen was also negative. A diagnosis of schizophrenia, chronic paranoid type, was made.

A detailed treatment plan was discussed with the patient and his family that included medications, individual supportive therapy, group therapy, and case management. Medication side effects and alternative treatment approaches were discussed. Mr. A agreed to the plan and was started on oral risperidone. The dose was gradually titrated to 3 mg BID. He responded well to this plan with a reduction in psychotic symptoms but within months he became inconsistent with appointments and taking his medication. His family was involved again and Mr. A agreed to be started on RLAI to ensure compliance. Side effects were again discussed. Mr. A was started on RLAI 25 mg injections, intramuscular, every 2 weeks. The dose was increased to 37.5 mg after 8 weeks (four injections) due to reduced but continued symptoms. He had a positive response to this treatment and his psychotic symptoms were extinguished. After the sixth dose of the injection, Mr. A began to develop generalized rash on both of his arms. Initially, the rash was mild and not reported to or seen by the physician. The rash gradually worsened over time as he continued treatment. It was identified at the time of the tenth injection. The rash had become erythematous, maculopapular, and diffuse. It had spread to bilateral hands, forearms, and arms. It was not localized to the site of injection. Photographs were taken at that time (Figure). The patient reported that he had denied these physical symptoms in previous appointments because the rash had not concerned him. He said after the rash developed, it had worsened after each injection. The patient had no other physical symptoms. Another discussion was held with the patient regarding medication side effects and a possible association of the rash with the intramuscular medication. The RLAI was discontinued and diphenhydramine 25 mg TID was begun. Mr. A was monitored regularly for rash and symptomatology. He was switched to haloperidol 2 mg BID and titrated to 5 mg BID.

After 2 weeks of regular observation, Mr. A’s rash began to disappear. It completely resolved by the end of the third week. Diphenhydramine was then stopped.

 

Follow Up and Re-Challenge on Oral Risperidone

The patient’s psychotic symptoms did not return with the haloperidol; however, he did develop medication side effects. These included psychomotor retardation, increased salivation, and further blunting of affect. These occurred within 8 weeks of medication use. He was reluctant to continue oral haloperidol.

Treatment options were again discussed with Mr. A and a decision was made to re-challenge with oral risperidone. Risks, benefits, and potential side effects were again discussed. He was cross-titrated to oral risperidone with frequent monitoring for emergence of any rash and symptoms of psychosis. In 2 weeks, he was on oral risperidone 2 mg in the morning and 4 mg at bedtime. At this point, haloperidol was discontinued.

Mr. A reported continued resolution of the positive symptoms of schizophrenia and was also found to be more engaging and spontaneous. He did not report any side effects and none were noted. Vital signs remained normal, and laboratory results did not show significant change in lipid profile or Hba1c. There was widening of affect. He did not have psychomotor retardation or agitation. Motivation level improved. No rash was observed after 16 weeks of oral risperidone treatment. Mr. A became more regular with individual and group therapy appointments and has joined classes to get his general  equivalency  diploma.

 

Discussion

Mr. A developed an erythematous, maculopapular rash while on RLAI. The rash was observed on both upper limbs and emerged within 12 weeks of initiating medication. The rash was diffuse and not localized to the injection site. It gradually disappeared after the medication was stopped and diphenhydramine was prescribed. It had completely resolved in 3 weeks. When re-challenged with oral preparation of risperidone, the patient tolerated the medication well. He did not have any rash after 16 weeks following the restart of the medication.

Antipsychotics are known to cause adverse cutaneous reactions in ~5% of the individuals for whom they are prescribed. The reported cutaneous adverse effects of antipsychotics include: exanthematous eruptions, skin pigmentation changes, photosensitivity, urticaria, and pruritus.3-5 There have been reports of skin reactions with conventional antipsychotics.6-9 Although the prevalence of skin reactions with atypical antipsychotics is reported to be lower than with typical antipsychotics,10 newer reports linking skin reactions to olanzapine,11-13 clozapine,14-17 and other atypical antipsychotics are emerging. A recent case report18 found risperidone oral solution to be responsible for facial flushing, rash, and skin desquamation in a patient with bipolar I disorder. Skin rash is listed in the manufacturer’s brochure as one of the adverse events associated with long-acting risperidone injection. Erythematous skin rash, on the other hand, is listed as infrequent. One study19 described an occurrence of injection site pain and non-specific skin reactions associated with RLAI. The authors’ literature search also revealed a case of an allergic reaction to RLAI following oral risperidone use. No oral re-challenge occurred.20

 

Conclusion

In this case study, the etiology of the maculopapular rash is not definitive. It does, however, raise important clinical issues. The appearance of the rash, after initiation of RLAI treatment, suggests that further inquiry into a causal relationship between the two is warranted. The lack of rash during oral risperidone therapy suggests the role of the diluent or medication delivery system in the reaction. A re-challenge of RLAI would have provided useful information in this regard; however, clinical risk-benefit and safety concerns prevented this trial. Other explanations of the rash must also be considered. These include exposure to environmental irritants, shampoo, soap, or laundry detergent; over-the counter medication; or an undiagnosed medical condition. Additional investigation is required. Nonetheless, an awareness of this case within the clinical community should aid the physician in treatment planning and evaluation of skin rashes in patients receiving RLAI. This case also highlights the need for continued diligence in monitoring for adverse events while a patient is on medication. It underscores the phenomenon that patients may minimize, ignore, or deny symptoms they deem unimportant; direct questioning and observation are important tools to address this concern. PP

 

References

1. PDR Psychotropic Prescribing Guide. Montvale, NJ: Physicians’ Desk Reference Inc; 2009:395-409.
2. Emsley R, Oosthuizen P, Koen L, Niehaus DJ, Medori R, Rabinowitz J. Remission in patients with first-episode schizophrenia receiving assured antipsychotic medication: a study with risperidone long-acting injection. Int Clin Psychopharmacol. 2008;23(6):325-331.
3. Kane JM, Eerdekens M, Lindenmayer JP, Keith SJ, Lesem M, Karcher K. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antispsychotic. Am J Psychiatry. 2003;160(6):1125-1132.
4. Chue P, Eerdekens M, Augustyns I, et al. Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets. Eur Neuropsychopharmacol. 2005;15(1):111-117.
5. Warnock JK, Morris DW. Adverse cutaneous reactions to antipsychotics. Am J Clin Dermatol. 2002;3(9):629-636.
6. Garenfeld W, Wilting I. Oculotoxic and dermatotoxic side effects of phenothiazines. Tijdschr Psychiatr. 2007;49(4):251-255.
7. Lepp U, Schlaak M, Schulz KH. Contact dermatitis to chlorprothixene. Allergy. 1998;53(7):718-719.
8. Lal S, Bloom D, Silver B, et al. Replacement of chlorpromazine with other neuroleptics: effect on abnormal skin pigmentation and ocular changes. J Psychiatry Neurosci. 1993;18(4):173-177.
9. Srebrnik A, Hes JP, Brenner S. Adverse cutaneous reactions to psychotropic drugs. Acta Derm Venereol. 1991;158(suppl):1-12.
10. Murak-Kozanecka E, Rabe-Jablonska J. Prevalence and type of dermatologic disorders in psychiatric patients treated with psychotropic drugs. Psychiatr Pol. 2004;38(3):491-505.
11. Christen S, Gueissaz F, Anex R, Zullino DF. Acute generalized exanthematous pustulosis induced by olanzapine. Acta Medica (Hradec Kralove). 2006;49(1):75-76.
12. Raz A, Bergman R, Eilam O, Yungerman T, Hayek T. A case report of olanzapine-induced hypersensitivity syndrome. Am J Med Sci. 2001;321(2):156-158.
13. Jhirwal OP, Parsad D, Basu D. Skin hyperpigmentation induced by olanzapine, a novel antipsychotic agent. Int J Dermatol. 2004;43(10):778-779.
14. Bhatti MA, Zander J, Reeve E. Clozapine-induced pericarditis, pericardial tamponade, polyserositis, and rash. J Clin Psychiatry. 2005;66(11):1490-1491.
15. Fong SY, Au Yeung KL, Tosh JM, Wing YK. Clozapine-induced toxic hepatitis with skin rash. J Psychopharmacol. 2005;19(1):107.
16. Stanislav SW, Gonzalez-Blanco M. Papular rash and bilateral pleural effusion associated with clozapine. Ann Pharmacother. 1999;33(9):1008-1009.
17. Bosonnet S, Dandurand M, Moati L, Guillot B. Acute generalized exanthematic pustulosis after intake of clozapine (leponex): first case. Ann Dermatol Venereol. 1997;124(8):547-548.
18. Chae BJ, Kang BJ. Rash and desquamation associated with risperidone oral solution. Prim Care Companion J Clin Psychiatry. 2008;10(5):414-415.
19. Lindenmayer JP, Jarboe K, Bossie CA, Zhu Y, Mehnert A, Lasser R. Minimal injection site pain and high patient satisfaction during treatment with long-acting risperidone. Int Clin Psychopharmacol. 2005;20(4):213-221.
20. Reeves RR, Mack JE. Allergic reaction to depot risperidone but not to oral risperidone. J Clin Psychiatry. 2005;66(7):949.
 

 

Dr. Rapport is associate professor of psychiatry and director of the Consultation Liaison Service in the Department of Psychiatry at the University of Toledo College of Medicine in Ohio.

Disclosures: Dr. Rapport reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


To the Editor:             

With the recent press release regarding the changes we can expect to see in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 1 I think it is timely to comment on the rationale for making diagnoses in mood disordered patients. Few would argue that unipolar and bipolar disorders are likely heterogeneous conditions that are often difficult to differentiate in the clinical setting.2 I believe that clinicians would benefit from having a practical model of the pathogenesis of mood disorders that can be applied in the clinical setting that may yield more accurate diagnoses and possibly more effective treatments.

Saggese and colleagues3 suggested that the current DSM-IV-TR4 classification of mood disorders places too great an emphasis on polarity to the detriment of cyclicity in the diagnosis and treatment of mood disorders. They base their conclusions on epidemiologic data and treatment outcomes. Additionally, many would argue that over the decades patients with so called “treatment refractory depression” appear to respond only marginally well to treatments such as medication switching or augmentation strategies. This implies that better diagnostic accuracy might lead to better treatment decisions and hence better outcomes.5

I wish to propose that a well-known pathogenic model might explain cycle frequency and nicely seperates autonomous, cycling from non-cycling mood disorders.6 I believe that non-cycling mood disorders represent true unipolar depressive illness. Such patients meet the DSM-IV-TR criteria for major depressive disorder (MDD). They tend to lack the features of bipolar spectrum disorders as defined by Ghaemi and colleagues.7 Their onset tends to be later in life and characterized by low recurrence rates, partial remission, or a chronic, indolent course. Even when “recovered,” these patients often appear to need more sleep, tolerate work less well, have diminished exercise tolerance, and appear to suffer various types of medical conditions including neurocardiogenic syncope, fibromyalgia, migraine, and chronic fatigue syndrome.8 For such patients, relatively minor emotional stressors may trigger recurrent episodes of depressions. When examined closely, most true unipolar recurrences are not autonomous. In true unipolar depression, antidepressant monotherapy or combinations of antidepressants with psychotherapy or therapy alone may relieve the depression and reduce recurrences. Mood stabilizers may be used but are not essential to prevent relapse. In summary, the onset, family history, course of illness, and response to treatment of true unipolar depression varies substantially from cycling mood disorders.9

The pathogenesis of autonomous, recurrent, or cycling mood disorders appears to be best described by Post’s6 “kindling theory” of bipolar disorder. Kindling theory suggests that patients are born with a stable, balanced neuroendocrine and nervous system. In essence, their limbic system acts as a natural “emotional thermostat.” From birth this “emotional thermostat” is programmed to maintain a reasonably constant emotional tone. When normal and appropriate variations in the environment occur, a normal emotional reaction may follow. These emotional reactions are culturally appropriate in intensity and duration. However, in the genetically vulnerable individual, when a traumatic life event occurs such as abuse or neglect, the stability of the “emotional thermostat” is disrupted. With the severest of traumas, that sense of security, stability, and predictability may be permanently disturbed. The individual may recover, but only partially. Physiologic data from childhood trauma show persistently elevated heart rates, dysregulated cortisol levels, and other changes as a sign of permanently disturbed neuroendocrine function. Subsequent traumas, disappointments, failures to be validated, or significant experiences of neglect can further disrupt the “emotional thermostat” until a sufficient allostatic load finally “breaks” the mechanism altogether. When this occurs, even at rest, the “emotional thermostat” can no longer maintain a reasonable, steady emotional tone. Instead, it perpetually over-shoots or under-shoots the mark. These are the patients that present to our clinics and hospitals as individuals suffering from bipolar disorder, personality disorders, substance abuse disorder, and, commonly, with highly recurrent MDD with or without psychosis. These cases I propose are the end result of “kindling” phenomenon. I propose that autonomous, highly recurrent mood disorders are the result of kindling and should be diagnosed as such based on the concepts set forth by Saggasse and colleagues,3 Post,6 and Ghaemi and colleagues.7

Thase,10 in his article on treatment-resistant depression and the bipolar spectrum, concludes by reiterating that recent evidence indicates that up to 50% of those seeking treatment for depression may have a bipolar spectrum disorder. Therefore, when we see this pattern of high frequency, autonomous mood recurrences, we should consider the addition of mood stabilizing agents and atypical antipsychotics to re-stabilize the “emotional thermostat.”

Sincerely,

Daniel J. Rapport, MD
 

References

1.    Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; In press.
2.    Ghaemi SN. Hippocrates and prozac: the controversy about antidepressants in bipolar disorder. Primary Psychiatry. 2006;13(11):51-58.
3.    Saggese JM, Lieberman DZ, Goodwin FK. The role of recurrence and cyclicity in differentiating mood disorder diagnosis. Primary Psychiatry. 2006;13(11):43-51.
4.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
5.    Shelton RC, Osuntokum O, Heinloth AN, Corya SA. Therapeutic options for treatment-resistant depression. CNS Drugs. 2010;24(2):131-161.
6.    Post RM. Kindling and sensitization as models for affective episode recurrence, cyclicity, and tolerance phenomena. Neurosci Biobehav Rev. 2007;31(6):858-873.
7.    Ghaemi SN, Ko JY, Goodwin FK. “Cade’s disease” and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry. 2002;47(2):125-134.
8.    Bradley LA. Pathophysiological mechanisms of fibromyalgia and its related disorders. J Clin Psychiatry. 2008;69(2):6-13.
9.    Kennedy N, Abbott R, Paykel ES. Remission and recurrence of depression in the maintenance era: long-term outcome in a Cambridge cohort. Psychol Med. 2003;33(5):827-838.
10.    Thase ME. Treatment-resistant depression and the bipolar spectrum: recognition and management. Primary Psychiatry. 2006;13(11):59-67.
Please send letters to the editor to Primary Psychiatry, c/o Norman Sussman, MD, 333 Hudson St., 7th Floor, New York, NY 10013; via the Web: http://mc.manuscriptcentral.com/primarypsy.

 

Dr. Weiss is head of the Provincial ADHD Program and clinical professor at the University of British Columbia Children’s and Women’s Health Centre in Vancouver.

Disclosure: Dr. Weiss is a consultant to and receives grant support from Eli Lilly, Janssen, Purdue, and Shire. She also receives grant support from the Canadian Institutes of Health Research.

Please direct all correspondence to: Margaret D. Weiss, MD, PhD, Head, Provincial ADHD Program, Clinical Professor, University of British Columbia, Children’s and Women’s Health Centre, Box 178, 4500 Oak St, Vancouver, BC V7T 2Y2; Tel: 604-875-2010; Fax: 604-875-2099; E-mail: mweiss@cw.bc.ca.


 

The adult screening diagnostic interview is typically 1 hour. It includes the usual domains of chief complaint, history of the present illness, family psychiatric history, current work and family functioning, mental status, formulation, and diagnosis. Sometimes, but not always, it may also be informed by either a broad-based screening rating scale for psychopathology or a checklist relevant to the disorder being investigated. The question has been asked why adult psychiatrists failed to identify adults with attention-deficit/hyperactivity disorder (ADHD) or even other childhood disorders. The adult interview does not include the key elements that allow childhood disorders to become visible to the clinician.

This is not a minor clinical issue. The majority of childhood disorders do not disappear. These include ADHD, autism, Asperger’s disease, developmental coordination disorder, Tourette syndrome, speech and language problems, and learning disabilities. This column provides adult psychiatrists with the tools to recognize these disorders, understand their implications for adult functioning, and identify why the adult assessment process differs from the child assessment process so that these difficulties may either go unrecognized or reformulated in as adult disorders.

A patient with ADHD who becomes depressed may be seen by an adult psychiatrist as cyclothymic or even bipolar, when hyperactivity is a lifetime pattern. A patient with Asperger’s may be perceived as having “schizotypal personality disorder.” If a patient comes across as articulate but is depressed because they are failing in school, the psychiatrist may miss that the underlying problem is an undiagnosed learning disability. This may be misinterpreted as functional impairment secondary to a mental health condition, rather than an identified learning disability. A patient with a severe nonverbal learning disability and very poor social skills may be seen as having a personality disorder.

This problem of diagnosing childhood developmental disorders within adult psychiatry has become an issue for appropriate delivery of services. For adult patients where the chief complaint is a childhood disorder grown up, it is adult psychiatry that has the mandate to provide service in most centers. There are two problems. First, adult psychiatrists follow an assessment procedure where these disorders are missed. Second, the child psychiatrists and even pediatricians who are trained in such a way so as to be able to conduct a child assessment on an adult patient are not mandated by the service delivery system to see adult patients.

This column reviews each component of a child assessment to identify how and why it allows identification of child disorders, and then discusses how these can be modified to be user-friendly to adult psychiatrists, but also all adult caregivers and general practitions. First, a child assessment includes a developmental history. Table 1 summarizes the key elements of that history that will identify areas of developmental delay or impairment that can provide clues to determine if further assessment is necessary.

This may seem like a lot of childhood information for a 1-hour psychiatric adult interview that is focused on a specific current complaint. This is why my colleagues and I have formatted a patient checklist that can be completed in the waiting room (Table 2).

Without a knowledge of child psychiatric disorders some of the most common psychiatric complaints in adults could be misinterpreted in a way that effects treatment. The second piece of a child assessment that is not typically present in an adult interview is a family interview (includes parent and sibling collateral) and information from a second setting such as a school. Patients with certain disorders make poor self informants. For example, it is not uncommon to have an adult with ADHD say that he does not have any difficulty, or a patient with autism deny that he misses being with other people or has a problem with social cues. Even for adult patients, a hypomanic patient may present saying that, “things have never been so good,” while a second informant might describe them as “a little too good.” This is not unfamiliar to adult psychiatrists. They would never naturally attempt to determine if a schizophrenic patient complaining that his boss hates him and that people at work are “against him” has a diagnosis of paranoid disorder without first obtaining appropriate collateral through the patient.

The reality of adult psychiatry is that it is not always feasible to bring in parents, impossible to contact employers, and (apart from the patient’s spouse) not always reasonable to obtain an informed mental status from a second informant that knows the patient well enough to observe his activities of daily living. In adults, obtaining collateral often requires the patient’s written consent, which may not be forthcoming. It is for this reason that my colleagues and I have developed a simple Diagnostic and Statistical Manual of Menal Disorders, Fourth Edition,1 checklist that covers both adult and child disorders and can be given to other informants to allow the psychiatrist to identify when and if critical information is missing and then follow up accordingly. This also allows for the clinician to work with the parent to compare his perception of his symptoms with those who are close to him.

The last disorder worth mentioning in this column is that of personality disorders. The DSM-IV defines these as adult disorders and the diagnosis is made starting at 18 years of age. However, a childhood history often reveals information about the development of personality formation that is critical to offering the patient insight into alternative methods of relating to others, coping strategies, and some of the background of his difficulties. Lastly, although the diagnosis may be made at 18 years of age, it is also true that personality formation continues through the life cycle. Thus, for adult psychiatrists seeing patients with developmental disorders, understanding the background of temperament and psychosocial factors as well as the history of early personality difficulties can be helpful to treatment.

By the same token, child psychiatrists need to be aware of precursors of adult syndromes when they take a slightly different format. It is easier for adult psychiatrists to obtain information on the past than for child psychiatrists to predict the future. Nonetheless, child psychiatry always has it in mind that a child with conduct disorder runs the risk of antisocial personality, and that children with extremely difficult temperament, stormy relationships, self-injurious behavior, and mood dysregulation may later evolve into having a borderline personality. Anxiety and mood disorders usually present early, and child psychiatrists are typically very familiar with the early stages of these waxing and remitting important Axis I conditions. The same is certainly true for addictions (eg, Internet addiction, subtance abuse) across the life cycle.

The objective of this column is to provide adult psychiatrists with a user-friendly method of identifying critical child-onset disorders and a developmental history through a checklist. The second objective is to assure that child psychiatrists are providing the adult patient with a broad-based screen for DSM-IV conditions that includes childhood disorders.

This issue represents a change in our field. It is now going to be necessary to treat childhood disorders grown up, and to provide early intervention for adult disorders that present at a young age. Since adult psychiatrists receive minimal training in the clinical presentation and current treatment of childhood disorders, and since child psychiatrists may not always be current in the latest literature on identification and treatment of disorders usually treated in adult settings, it is our hope this column and the attached checklist will facilitate clinical skill in this area.

The Weiss Symptom Record (WSR; Table 2, pages 24–28) can be completed by any informant at any age since the patient has the option to check “not applicable” and the language is gender and informant neutral. The WSR is included as a tool to facilitate the identification of disorders across the life cycle by pediatric, adolescent, and adult psychiatrists and clinicians. Although this is written as a DSM-IV checklist, it is essential to understand that in a busy practice it allows the clinician to eyeball where the difficulty is and to be sure not miss a particular disorder. It also allows the clinician to identify critical areas of potential differential diagnosis. As in most such checklists in child psychiatry, there are four anchor points. Most patients, where the disorder is not a significant clinical issue, will either check “not at all” or “somewhat.” A diagnosis becomes clinically signicant when disorders are checked routinely on the the shaded section. “Pretty much” is usually interpreted as having a problem and “very much” is usually interpreted as “this is a problem that gives me great difficulty.” The right-hand columns provide the DSM-IV criteria and codes for easy reference. This is not a “validated” scale; it is not diagnostic. However, its serves the useful purpose identified in this column of allowing adult psychiatrists to identify child disorders and child psychiatrists to identify adult disorders, and of making it “easy” for an adult psychiatrist to give the checklist to patients to obtain collateral information from a significant other.  PP

 

Reference

1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

 

Dr. Sussman is editor of Primary Psychiatry as well as Associate Dean for Post-Graduate Programs and professor of psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please e-mail questions or comments for Dr. Sussman to ns@mblcommunications.com.


 

As a clinician/educator, I am very aware of the limitations of textbooks and industry-sponsored clinical trials in addressing common challenges to treating patients with mental disorders. I am a big fan of the letters to the editor sections of journals and brief case reports. As editor of this journal, I am therefore gratified at the increase in correspondence and unsolicited papers that we have been receiving from readers of Primary Psychiatry. This is reflected in this issue of the journal, where there are no invited articles. The content of this issue addresses the kinds of clinical situations that we may confront in clinical practice.

The selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are known to impair clotting and produce a variety of bleeding abnormalities. While both case reports and reviews of large patient populations have been published over the past decade, many clinicians remain unaware of the increased risk of bleeding events associated with use of these drugs. These abnormalities are the result of impaired platelet function, although platelet count remains normal. In this issue, Ashish Aggarwal, MD, and colleagues present a case of ecchymoses associated with paroxetine 25 mg/day that remitted after a switch to a tricyclic antidepressant. Publication of this report is intended to remind clinicians to remain alert for hematological side effects when these drugs are used. As the authors note, most cases of bleeding involve the gastrointestinal tract. Risk is increased with concomitant use of non-steroid anti-inflammatory drugs and anticoagulant therapy, as well as in patients with liver disease. The authors review theories about the underlying cause of the bleeding abnormalities. Inhibition of the serotonin transporter on the platelet cell membranes, they hypothesize, leads to a depletion of serotonin in the platelets, which in turn decreases coagulation and may lead to a bleeding tendency in vulnerable individuals. Other possible mechanisms include inhibition of nitric oxide synthase, and hyperserotonemia-induced skin and mucous membrane lesions.

Kanwaldeep Sidhu, MD, and colleagues submit a case report of rash associated with risperidone long-acting injection (RLAI). They present a case of a 26-year-old male who developed a diffuse erythematous and maculopapular skin rash on both arms after initiation of RLAI treatment. Previous exposure to oral risperidone was uneventful. In this case, RLAI treatment was discontinued and diphenhydramine was prescribed, resulting in the rash disappearing completely in 3 weeks. A re-challenge with oral risperidone produced no rash and was clinically effective, suggesting that other ingredients in the solute and delivery system were responsible for this adverse effect.

Dopamine agonists have long been used in the treatment of affective disorders, mainly as add-on therapy. Matthew L. Prowler, MD, and Claudia F. Baldassano, MD, report three cases involving the use of pramipexole—a dopamine agonist Food and Drug Administration-approved to treat Parkinson’s disease and restless legs syndrome—to treat rapid cycling bipolar disorder. They cite reports that pramipexole can provide a beneficial role in bipolar depression, but note there have been no studies of this compound for use in rapid cycling bipolar disorder. They present cases of pramipexole augmentation in rapid cyclers with an active depressive episode. They report a positive response to treatment without cycle induction or acceleration. Effective doses were between 1.5–3.0 mg. At a higher dose, there were signs of emergent hypomania in one patient, which resolved with dose reduction.

Anthony T. Ng, MD, and colleagues present a review article on clinical challenges in the pharmacologic management of agitation. No drug is specifically approved as a treatment for agitation. Most treatment guidelines encourage reliance of behavioral intervention, such as verbal de-escalation and seclusion, as the initial approach for management of agitated patients. However, these techniques are often ineffective, and drug treatment becomes necessary. This article reviews the clinical challenges in managing agitation in the emergency setting. The authors observe that no currently available single agent or combination matches the characteristics of an ideal acute intervention for agitation, which include being easy to administer and not traumatic; rapid onset of action and a sufficient duration of action to allow for transport of patients to appropriate services; provision of tranquilization without excessive sedation that may interfere with patient interaction, diagnosis, and selection of additional therapy; and low risk for significant adverse reactions and drug interactions. They call for further study of alternative therapies for acute agitation that address some or all of these limitations.

La Vonne A. Downey, PhD, and colleagues examine the differences in how psychiatric patients come into the emergency department. The purpose of their study was to determine if there is a difference in the type of psychiatric patient transported via emergency medical service (EMS) as compared to police or walk in. A secondary purpose was to determine if staff was injured during EMS transport. They hoped to determine if there is a significant difference between patients transported by EMS as compared to those who were transported by other means. A total of 300 patients were evaluated. The authors report that the EMS system is frequently used to transport intoxicated patients, who do not have a regular psychiatrist, have an admitting diagnosis of drug use, and are later discharged from the emergency department (ED). These findings could be used to alert ED staff that the psychiatric patient brought in by EMS or police present differently than the majority of psychiatric patients who walk in or are brought by family members. This information could be used further to develop a treatment protocol to assist the ED staff addressing the needs of these patients.

In a letter to the editor, Daniel J. Rapport, MD, anticipates upcoming changes in the classification and diagnostic criteria for mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.1 He proposes a pathogenic model of cycle frequency that distinguishes cycling from non-cycling mood disorders. More specifically, he reiterates a widely held view that spontaneous, highly recurrent mood disorders are the result of kindling and should be diagnosed as such based on the concepts. He concludes that when we see this pattern of high-frequency, spontaneous mood recurrences we should consider the addition of mood stabilers and atypical antipsychotics to re-stabilize the “emotional thermostat.”  PP

 

Reference

1.    Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; In press.