This interview took place on February 3, 2009 and was conducted by Norman Sussman, MD.

 

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

Disclosure: Dr. Dubovsky receives research support from Esai, Pfizer, and Sumitomo Pharma.

 

Dr. Dubovsky is professor and chair of the Department of Psychiatry at the University of Buffalo in New York State and adjoint professor of Psychiatry and Medicine at the University of Colorado in Boulder. His research focuses on intracellular signaling in mood disorders, the pathophysiology of psychiatric illness, development of new treatments, and interactions between medical and psychiatric illnesses. Dr. Dubovsky maintains an active clinical practice devoted to mood disorders; complex and difficult clinical problems; and consultation to psychiatrists, other physicians, and other mental health professionals.

 

What is the most appropriate name to describe the newest generation of atypical antipsychotics?

The most appropriate name would be third-generation antipsychotics. The first-generation antipsychotics were the phenothiazines; the second generation was everything else (ie, butyrophenones, thioxanthenes, etc); and the most recent would be the third generation. They are a diverse group but are different enough from the neuroleptics—the first- and second-generation antipsychotics—to warrant their own category.

Are the newer atypical antipsychotics mechanistically different than the older ones?

All antipsychotics act on dopamine (D)2 receptors and have some level of D2 receptor antagonism. They all have a certain amount of serotonin (5-HT)2 blockade as well. The 5-HT2 receptor is linked to a D2 receptor such that when it is stimulated, it makes D2 receptors more sensitive to blockade, and if the D2 receptor is blocked, it mitigates some of the effects of blocking the D2 receptors, especially in the basal ganglia. The older neuroleptics are all 5-HT2 antagonists and D2 antagonists. They have relatively more D2 antagonism than 5-HT2 antagonism. With the newer atypical antipsychotics, the amount of D2 blockade has been turned down and the amount of 5-HT2 blockade turned up.

The major selling point of these newer antipsychotics is that they are more effective in treating negative symptoms than the conventional neuroleptics. Has this been supported by ongoing research?

This observation has not been supported by research. With the exception of clozapine, all of the newer antipsychotics have been studied in industry-sponsored randomized trials where they are compared with a placebo and an active comparator—haloperidol. Haloperidol is very potent in D2 blockade. Blocking this receptor results in many deficits in the ability to generate and coordinate behavior, whether motor behavior, emotional behavior, or thought. Thus, patients taking haloperidol have more bradykinesia and blunted affect. When compared with relatively less D2 blockade, there seem to be fewer negative symptoms from an antipsychotic. Futher, very drug-naive patients enter these randomized trials. Most of these patients have been on a neuroleptic. When switched to one of the third-generation atypical antipsychotics, they get less D2 blockade and less blunting; they seem to brighten up a little bit and their negative symptoms seem to improve. This is because the drug itself is not producing as many negative symptoms.

There are two major flaws in these comparisons. First, they are using higher doses of haloperidol and, therefore, getting more side effects. Thus, the drug being studied is always going to look better than a higher dose of haloperidol. Second, they are not addressing the haloperidol level by blood vessel to see whether it is even the right dose to treat the disorder.

Are the newer antipsychotics more effective in symptom control for schizophrenia?

Of the newer drugs in schizophrenia, the one drug that seems to be more effective than any other for negative cognitive symptoms is clozapine. The newer drugs have less D2 blockade and produce less cognitive Parkinsonism. In comparison to haloperidol, there is less blunting of thought and cognitive functioning is better.

The core cognitive deficit of schizophrenia is a defect in sensory gating (ie, the inability to shut off irrelevant information and to tell the difference between relevant and irrelevant sensory input). Clozapine is the only antipsychotic that is to some extent effective in correcting that deficit. The other thing that corrects the gating deficit is smoking. The defect in sensory gating is due to a malfunctioning gene for a type of acetylcholine receptor called the alpha-7 nicotinic receptor, which nicotine acts on. Thus, acute-inhaled nicotine will correct the gating deficit in schizophrenia. Some research1 suggests that clozapine works better in heavy smokers and that people who respond to clozapine are more likely to stop smoking. This is because clozapine, unlike other antipsychotics, corrects that gating deficit.

Research2 suggests that olanzapine and quetiapine may somewhat help the gating deficit, but they do not benefit as much as clozapine.

Are the newer antipsychotics more effective in symptom control for mood disorders?

All antipsychotics are effective for mania. In equivalent sedative doses, the newer ones are not more effective for mania than the older ones. Benzodiazepines, and before that barbiturates, used to be the mainstay of the treatment of mania years ago. Anything with sedatives, and especially antipsychotic properties, will work acutely for mania.

It is more difficult to determine the effectiveness of maintenance treatment for mood disorders. One must observe how the drug companies have designed their studies. Unlike with schizophrenia, there is no analog of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study for bipolar disorder. The studies are entirely industry sponsored studies.

In the pivotal trial3 for olanzapine monotherapy, slightly <550 patients with bipolar I were treated openly with olanzapine plus lithium. Of that group, ~120 patients over 6 weeks could not stay in the study and were kicked out. The remaining ~430 were felt to be remitted, meaning they had a Young Mania Rating Scale score ≤12 and a Hamilton Rating Scale for Depression score ≤8. Thus, remitted meant 33% to 50% were as symptomatic as they were when they started. Those patients were randomized to ~20 mg olanzapine in decent doses or lithium in a therapeutic dose for 1 year. Investigators found that more olanzapine than lithium patients completed the study (~47% of the olanzapine patients and ~33% of the lithium patients), and there were fewer relapses to mania in the olanzapine study. However, rates of relapse into any affective episode or relapse into a depressive episode were about the same with both drugs.

As with all industry-sponsored studies of bipolar disorder, the sample was enriched: patients who were anticipated to respond in the first place were treated openly, anyone who did not respond openly was kicked out, and the ones who did seem to respond were placed into the randomized trial. At the end of the study, these patients were not well on monotherapy with any of the drugs. They were less symptomatic and had fewer acute episodes, but they were still ill. None of these kinds of studies conduct any measures of functioning or quality of life.

It is also important to note that such studies always exclude patients who are suicidal, are active substance abusers, or have any meaningful comorbidity. However, 80% of people with bipolar disorder are substance abusers. Thus, one cannot extrapolate to real life from these studies.

The same study method is used for the drugs that have now some labeling for maintenance of mood disorders (olanzapine and quetiapine). Quetiapine just had an add-on maintenance study4 published last year. It is the same method with all the studies conducted. The study conductors take patients who respond well acutely, randomize them, and get about the same results with lithium or sometimes divalproex sodium. In an add-on study, they add one of these drugs or a placebo onto lithium or divalproex sodium, and they get less relapse. However, is this the antipsychotic effect of the drug? These are sedating drugs. Is it the fact that patients sleep better and once they sleep better, their moods are better?—or is it that the rating scale scores emphasize insomnia, talking a lot, and agitation, and all of those are going to be better with a sedating drug?

I would like to see a study using diazepam, lorazepam, or clonazepam as a control—the latter two were at one time a mainstay of the treatment of bipolar disorder—and see whether or not there are better results with the antipsychotics.

Is the long-term risk of tardive dyskinesia lower with the new-generation antipsychotics?

First-generation antipsychotics were introduced in the 1950s and tardive dyskinesia was not identified until the late 1970s. Tardive dyskinesia has been reported with all of the atypical antipsychotics, including the newer ones. Though there have been fewer reports with the newer antipsychotics so far, it is yet unclear what long-term experience will show.

Are there any good data on compliance rates other than the CATIE study?

The only other data are in the industry-sponsored studies. There is a relatively low dropout rate with patients on these new-generation antipsychotics compared to historic experience with the neuroleptics or sometimes compared to the comparison neuroleptic. It is hard to know what to make of this because in any of the industry-sponsored studies, there is much effort into keeping patients in those studies and it is nothing like actual clinical practice. The compliance rate is expected to be better in any clinical trial.

The CATIE trial had worse results because they were not putting the massive effort into keeping the patients in the studies that investigators do in these multicenter trials. The reason for it is that investigators do not get paid as much if the patient leaves the study. While the investigators do not get paid for a certain result, they certainly get paid for recruiting and keeping patients in the study.

What drives your choice to prescribe one antipsychotic over another?

Though it is never a first choice, I use clozapine for very refractory schizophrenia. It is difficult to take, but it works better than the other antipsychotics. Most schizophrenic patients who are given clozapine are in a clozapine group, and so there is more effort put into other forms of therapy in addition to the medication that may explain some of the benefit. However, I have seen people who did very poorly on everything except for clozapine.

There were studies5 a number of years ago showing that the combination of a neuroleptic and an antidepressant worked very well for negative symptoms of schizophrenia in schizophrenic patients who were not depressed but who had a family history of depression. This suggested that depression in the family is somehow a marker of response to antidepressants in a patient with negative symptoms but with no real depressive symptoms. Thus, at times I combine an antidepressant with a drug like clozapine.

I also use clozapine for very intractable and severe ultradian cycling in bipolar patients. However, bipolar patients do not tolerate clozapine nearly as well as schizophrenic patients. They have much less patience themselves for the problems taking this medication, and so they are less likely to agree to it. Still, it works well when they need it.

I use molindone hydrochloride tablets in a low dose for patients who should not or do not want to gain weight. It is certainly as good as risperidone and some of the other atypical antipsychotics that have more D2 blockade. There is not a tremendous amount of difference between the amount of D2 blockade or extrapyramidal side effects between risperidone and a drug like molindone hydrochloride, but the latter is much less likely to cause weight gain than risperidone is. I use molindone hydrochloride and loxapine for psychotic depression. I have used all of the newer-generation antipsychotics for psychotic depression as well, almost always in combination with an antidepressant.

I use aripiprazole for some very refractory depression, with or without psychosis, and I find it to be unpredictable. Sometimes I have had very good results with it, but it is very hard to find the right dose. There is a lot of akathisia with it and a lot of blunting if the dose is raised too high. It is very hard to find the right dose with depressed patients, but it is less likely to cause weight gain than some of the others. I use ziprasidone for some severely depressed patients, but it is also unpredictable. Even though it causes less weight gain, it makes a lot of people very jittery and it cannot be combined with other serotonergic drugs easily because it is a selective serotonin reuptake inhibitor. PP

References

1.    McEvoy JP, Freudenreich O, Wilson WH. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol Psychiatry. 1999;46(1):125-129.
2.    Powell SB, Young JW,Ong JC, Caron MG, Geyer MA. Atypical antipsychotics clozapine and quetiapine attenuate prepulse inhibition deficits in dopamine transporter knockout mice. Behav Pharmacol. 2008;19(5-6):562-565.
3.    Tohen M, Calabrese JR, Sachs GS, et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry. 2006;163(2):247-256.
4.    Vieta E, Suppes T, Eggens I, Persson I, Paulsson B, Brecher M. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord. 2008;109(3):251-263.
5.    Rummel C, Kissling W, Leucht S. Antidepressants for the negative symptoms of schizophrenia. Cochrane Database Syst Rev. 2006 Jul 19;3:CD005581.

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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 is a consultant to Myriad; is on the speaker’s bureaus of Forest and Pfizer; and has received grant support from Forest, Myriad, Novartis, Pfizer, and Takeda.

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.


 

Parkinson’s disease affects as many as 1 million Americans and with advanced age is complicated by dementia in a majority of cases. However, the recognition of cognitive impairment in Parkinson’s disease is made complicated by the predominance of motor symptoms and a neuropsychiatric profile that differs from the more common dementia of the Alzheimer’s type. Differentiating the decline in personal and social activities due to cognitive impairment rather than preexisting movement disorder is difficult. Several expert bodies have addressed the use of cholinesterase inhibitors for the dementia of Parkinson’s disease, but the evidence base is far less substantial than that which exists for Alzheimer’s disease. Although most patients with Parkinson’s disease dementia should be offered a trial of anti-cholinesterase therapy, particularly those experiencing hallucinations, dramatic benefits are not common. Temporary symptomatic relief rather than disease modification is the most that can be expected. As a result, treatment should be presented as an option rather than an imperative.

Introduction

Parkinson’s disease has a mean age of onset of 57 years and a prevalence of 1% to 2% among adults ≥60 years of age. There may be as many as 1 million Americans with the illness.1 It is manifested by bradykinesia, rigidity, resting tremor, postural instability, frozen gait disorder, and flexed posture. The progression and severity of Parkinson’s disease varies widely and the associated motor disability may be substantially reduced by numerous medications singly or in combination. The goal is an increase in brain dopamine through either enhanced production or reduced breakdown of the molecule.2 The disease begins as a movement disorder, but with advancing age is complicated by dementia in as many as 80% of patients. The characteristic frozen facial expression, slowed cognition (bradyphrenia), fluctuation in attention, and motor impairment compounded by depression and hallucinations make the assessment of possible dementia challenging. In addition, dopaminergic medications precipitate hallucinations with recognized frequency. Although medication to treat the dementia of Parkinson’s disease is most often modestly effective for patients in aggregate, failure to recognize dementia means that the minority of individuals who might receive substantial benefit will not be offered a therapeutic trial. As a result, practitioners need guidance to efficiently assess cognitive decline among people with Parkinson’s disease as well as realistic expectations for the benefits of dementia treatment. 

      
Similarities and Differences with Other Dementias

Loss of dopaminergic neurons in the substantia nigra is the hallmark of Parkinson’s disease and the basis for the use of dopamine agonists. In contrast, neuronal dropout in the entorhinal cortex and hippocampus are seen in Alzheimer’s disease. Yet, similar to Alzheimer’s disease, cholinergic deficits are common in Parkinson’s disease and parallel the decline in cognition. Hematoxilyn and eosin staining neuronal inclusions known as Lewy bodies occur in both Parkinson’s and Lewy body dementia but not in Alzheimer’s disease. However, amyloid plaques and neurofibrillary tangles thought to be the signature pathology of Alzheimer’s disease commonly occur in both Parkinson’s disease and Lewy body dementia as well, though less extensively. Differences between Alzheimer’s disease and the dementia of Parkinson’s and Lewy body disease detected by imaging studies, whether structural (magnetic resonance imaging [MRI], computerized axial tomography) or metabolic (positron emission tomography, single photon emission computed tomography, functional MRI), are too subtle for use in clinical diagnosis.   

Clinical features of Alzheimer’s, Parkinson’s, and Lewy body dementia overlap as severity progresses but significant differences are apparent in the early stages (Table 1).3-5 In Alzheimer’s disease, memory impairment is prominent with executive dysfunction, aphasia, apraxia, and anomia often present but less obvious. Apathy is more common than depression, but one or the other will be present in ~25% of affected individuals. Hallucinations occur in 10% of cases most often at the mid- to later stage of the disease.6 Severe motor impairments in gait, balance, muscle strength, and swallowing occur in the later stages. In Parkinson’s dementia, the movement disorder precedes the onset of cognitive impairment. Inattention, executive dysfunction, bradyphrenia, and visuospatial deficits may be more noticeable than impaired memory. Hallucinations are four times more frequent and depressive symptoms somewhat less so than in Alzheimer’s disease. Irritability, anger, aggression, and delusions may be more prominent in Alzheimer’s disease. More severe postural instability and gait disorder predict the onset of dementia among people with Parkinson’s disease. Incident hallucinations also predict the subsequent emergence of dementia.3

 

Hallucinations are also a distinguishing feature of Lewy body dementia. Marked fluctuations in attentiveness and mild impairment in memory—both of which precede the appearance of rigidity, tremor, postural instability and gait disorder—distinguish Lewy body dementia from that of Parkinson’s disease. Unanticipated sensitivity to neuroleptic-induced extrapyramidal symptoms also indicates that Lewy body dementia, rather than Alzheimer’s disease with hallucinations, is the correct diagnosis.

Efficient Screening Procedures 

Not every older adult should be screened for cognitive impairment. Screening in clinical practice is predicated on the recognition of cognitive decline interfering with personal or social activities by the patient, family, or clinician. However, Parkinson’s disease often impacts social and personal activities as a result of motor impairment. Thus, personal responsibilities may already have been abandoned before impaired cognition could have made noticeable contribution. Given the elevated frequency with which dementia emerges in Parkinson’s disease, the practitioner’s concern for impairment should be heightened. When hallucinations, apathy, or excessive daytime drowsiness appear after a period of stable treatment, dementia should be suspected.

In a 2007 review7 on the diagnosis and treatment of Parkinson’s disease dementia, the Movement Disorders Society’s taskforce recommended the Mini-Mental State Examination (MMSE) as a global measure of cognitive performance in which a score <26 indicates impairment. They also suggested a number of screening procedures to detect impairments in specific cognitive domains. These included domains of attention, visuo-constructive ability, executive function, and memory. Parkinson’s disease patients with impairments in more than one domain associated with deterioration in personal care or social activities would meet the criteria for dementia. Attention would be assessed with the serial seven subtraction task from the MMSE or by asking the patient to list months of the year in reverse order. In either test, two errors or omissions is considered evidence of impairment. For executive dysfunction, impairment is defined as failure to recite nine examples from the lexical category of words starting with the letter “S” in one minute or inability to draw a clock with the time set at 10 past 2. Visuo-constructional impairment is defined by inability to copy two intersecting pentagons from the MMSE. Impairment in memory is defined by failure to recall all three words from the MMSE’s registration and recall task. The review also provides a comprehensive listing of neuropsychological instruments that have been used to assess cognition among people with Parkinson’s disease.

However, busy practitioners may find the copyrighted MMSE and clock drawing cumbersome. As an alternative, the Memory Impairment Screen and the oral version of the Trail Making Test for executive function do not require paper and pencil, may be administered by phone, and are quite brief. Both have been validated as screening measures for use in population assessments of dementia.8 For the Memory Impairment Screen, the subject is tasked to repeat and remember four words (eg, apple, table, penny, spoon) given in sequence at 1-second intervals and then asked to recall each when prompted with a category cue (eg, fruit, furniture, money, utensil). The registration phase may be repeated up to five times before moving to the next test. Next, the subject is asked to recite the alphabet from “A to Z” and then to count from 1–25. The person is then asked to continue the sequence, which the examiner starts with “One A, Two B, Three C, Four ?” Subjects making two errors as they reach “M 13” are considered to exhibit executive impairment. Following the Trail Making test, the examiner returns to the Memory Impairment Screen by asking the subject to recall the four words that were previously rehearsed. Allowing 1 minute for free recall the examiner then provides the category cue for each word not remembered spontaneously. Words recalled freely receive a score of 2; those that required the cue for recall receive a score of 1. A total score of 4 is predictive of dementia. A free demonstration of the Trail Making Test, clock-drawing test, and other measures of executive dysfunction can be accessed on the Internet.6 Baseline assessment of cognition with simple screening procedures following the diagnosis of Parkinson’s disease will set the stage for detection of genuine impairment should warning signs of dementia emerge.

Responsiveness to Cholinesterase Inhibitors

The evidence base regarding the efficacy of pharmacotherapy for Parkinson’s disease dementia is limited9 but more extensive if one considers the illness to be part of a spectrum including dementia with Lewy bodies.10 In the largest randomized controlled trial to date, Emre and colleagues11 conducted a pivotal study of 541 people whose Parkinson’s disease was accompanied by mild-to-moderate dementia defined by MMSE score of 10–24. Patients were allocated to rivastigmine or placebo in a 2:1 ratio. Rivastigmine 1.5 mg was introduced and titrated to a maximum tolerated dose or 12 mg over 16 weeks. Exclusion criteria included a history of major depressive disorder, use of cholinesterase inhibitor or anticholinergic drug, or change in Parkinson’s disease medication within 4 weeks of enrollment. The initiation of a psychotropic medication during the study with the exception of an antipsychotic for an acute episode of psychosis was forbidden. The mean age of study participants was slightly >72 years and 66% were men. Forty percent were diagnosed with a mental disorder in addition to dementia.

Greater than 25% of participants were taking an antipsychotic at baseline, 25% were on an antidepressant, 20% were on a benzodiazepine or sedative hypnotic, and 95% were taking levodopa. The two primary efficacy measures were the Alzheimer’s Disease Assessment Scale (ADAS-cog) and the Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change (ADCS-CGIC). Each were separately assessed by trained raters blind to the assessment outcome. The ADAS-cog is a 70-point measure of cognitive performance. The ADCS-CGIC is a 7-point categorical scale anchored at baseline where “1” equals marked improvement, “7” equals marked worsening, and “4” denotes no change. Detectable changes that were not clinically meaningful were defined as minimal; changes associated with obvious clinical improvement were defined as moderate. Secondary efficacy measures included the ADCS measure of activities of daily living, the Neuropsychiatric Inventory, the MMSE, tests of attention and reaction time, and tests of executive function as measured by letter-category verbal fluency and clock-drawing.

At the end of dose titration, >50% of treated participants were taking rivastigmine 9–12 mg/day. Of those completing the study, 72% were in the rivastigmine group and 82% in placebo. Adverse events accounted for most of the premature withdrawals in both groups. Nausea (29%), vomiting (16.6%), and worsening tremor (10.2%) were significantly more frequent among the rivastigmine group. Of the efficacy measures comparing rivastigmine to placebo, at 24 weeks all were statistically significant. There was an 11.7% difference in cognitive performance (ADAS-cog) between drug and placebo groups. Clinically meaningful (marked to moderate) improvement was seen in 14.5% of placebo and 19.8% of the rivastigmine group. Clinically meaningful deterioration was seen in 23.1% of placebo and 13.0% of the rivastigmine group. Among the secondary measures of disability, neuropsychiatric symptoms, cognition, and executive functions all showed improvement with rivastigmine and decline with placebo with the differences being statistically significant. Of note, 34.6% of placebo and 45.4% of the rivastigmine group exhibited a ≥30% improvement in neuropsychiatric symptoms. Hallucinations disruptive enough to be considered adverse events occurred in 9.5% of placebo and 4.7% of rivastigmine participants, and the difference was significant.

Emre and colleagues11 conclude that their findings among patients with Parkinson’s disease and dementia are similar to those seen in studies of cholinesterase inhibitors for Alzheimer’s disease. Benefits are modest, representing a 6-month reprieve in the course of symptoms without genuine disease modification. However, close to one in five patients will show dramatic benefit obvious to the family and the clinician alike. Indeed, Press12 advocates the family’s impression of benefit over formal neuropsychological measures to assess the effectiveness of treatment. Given that benefits if apparent at all emerge within the first weeks of treatment, the most realistic expectation for patient and family is a 60–90-day trial of therapy rather than an open-ended course. Also noteworthy were the relatively more substantial benefits of rivastigmine for neuropsychiatric symptoms, including hallucinations, a finding similar to McKeith and colleagues’10 rivastigmine study of 120 patients with Lewy body dementia. The number of study participants receiving a neuroleptic during the Emre and colleagues11 study was considerable. Low doses of atypical antipsychotics such as olanzapine, quetiapine, and clozapine were initially used to control levodopa-induced hallucinations because they were less likely than typical antipsychotics to induce extrapyramidal symptoms.12

However, the 2005 Food and Drug Administration warning of increased mortality when prescribed to patients with dementia11 amplified by more recent reports14,15 raise the threshold at which these agents may be considered for psychosis in dementia nearly out of reach. Clearly, a trial of cholinesterase therapy should be recommended to reduce hallucinations of dementia in Parkinson’s disease before a neuroleptic is offered. The transdermal rivastigmine patch with less frequent gastrointestinal effects, not available at the time of Emre’s11 study, is an added advantage.16 It should be added that other cholinesterase inhibitors may be efficacious for the dementia of Parkinson’s disease but have not been subjected to large-scale trials. Nonetheless, the Cochrane Review and other sources17-20 find at least minimal evidence to support the use of donepezil as well (Table 2).

 

 

Conclusion

Dementia is such a frequent complication that every older patient with Parkinson’s disease should be screened for memory impairment and executive dysfunction, particularly if hallucinations emerge in the context of stable dopaminergic treatment. The impact of cholinesterase inhibitor therapy on cognition and activities of daily living will be obvious in only one patient in five. However, the reduction in hallucinations may be more robust. Consistent reports of elevated mortality associated with antipsychotics prescribed to people with dementia make cholinesterase inhibitor therapy preferable when hallucinations emerge. A 60–90-day trial of a cholinesterase inhibitor should be adequate to give the patient, family, and practitioner sufficient evidence on which to base a decision for ongoing treatment. In equivocal cases, the medication can be reinstituted if visible decline is observed following discontinuation.8 With adverse reactions and lack of efficacy taken into account, 40% to 60% of treated patients would withdraw from cholinesterase inhibitor therapy. However, lacking predictors of treatment responsiveness and balancing in the safety of cholinesterase inhibitor therapy, most patients with Parkinson’s disease dementia should be offered a trial of treatment. Practitioners’ zeal for treatment must be tempered by the realization that temporary symptomatic relief rather than disease modification is the most that can be expected. As a result, treatment should be presented as an option rather than an imperative. PP

References

1. Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of Parkinson’s disease. Mov Disord. 2002;18(1):19-31.
2. LeWitt PA. Levodopa for the treatment of Parkinson’s disease. N Engl J Med. 2008;359(23):2468-2476.
3. Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with parkinson’s disease movement disorders. Mov Disord. 2007;22(12):1689-1707.
4. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
5. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65(12):1863-1872. Erratum in: Neurology. 2005 ;65(12):1992.
6. Lyketsos CG, Sheppard JM, Steinberg M, et al. Neuropychiatric disturbance in Alzheimer’s disease clusters into three groups: the Cache County study. Int J Geriat Psychiatry. 2001;16(11):1043-1053.
7. Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson’s disease dementia: recommendations from the Movement Disorder Society Task Force. Mov Disord. 2007;22(16);2314-2324.
8. Kennedy GJ, Smyth CA. Screening older adults for executive dysfunction: an essential refinement in the assessment of cognitive impairment. American Journal of Nursing. 2008;108(12):60-69.
9. Poewe W, Gauthier S, Aarsland, et al. Diagnosis and management of Parkinson’s disease dementia. Int J Clin Pract. 2008;62(10);1581-1587.
10. McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomized, double blind, placebo controlled international study. Lancet. 2000;356(9247):2031-2036.
11. Emre M, Aarsland, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Eng J Med. 2004;351(24):2509-2518.
12. Press DZ. Parkinson’s disease dementia–A first step? N Engl J Med. 2004;351:(24)2547-2549.
13. Kennedy GJ. Caution vs. closure: the use of atypical antipsychotics for the treatment of behavioral disturbances in dementia. Primary Psychiatry. 2005;12(9):16-19.
14. Ballard C,  Hanney ML, Theodoulou M, et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol.  2009;8(2):151-157.
15. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Eng J Med. 2009;360(3):225-235.
16. Lefèvre G, Pommier F, Sedek G, et al. Pharmacokinetics and bioavailability of the novel rivastigmine transdermal patch versus rivastigmine oral solution in healthy elderly subjects. J Clin Pharmacol. 2008;48(2):246-252.
17. Maidment I, Fox C, Boustani M. Cholinesterase inhibitors for Parkinson’s disease dementia. Cochrane Database Syst Rev. 2006;(1):CD004747.
18. Ravina B, Putt M, Siderowf A, et al. Donepezil for dementia in Parkinson’s disease: a randomised, double blind, placebo controlled crossover study. J Neurol Neurosurg Psychiatry. 2005;76(7):934-939.
19. Aarsland D, Laake K, Larsen JP, Janvin C. Donepezil for cognitive impairment in Parkinson’s disease: a randomised controlled study. J Neurol Neurosurg Psychiatry. 2002;72(6):708-712.
20. Leroi I, Brandt J, Reich SG, et al. Randomized placebo-controlled trial of donepezil in cognitive impairment in Parkinson’s disease. Int J Geriatr Psychiatry. 2004;19(1):1-8.

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Dr. Raby is assistant clinical professor of psychiatry at Columbia University in New York City.

Disclosure: Dr. Raby reports no affiliation with or financial interest in any organization that may pose a conflict of interest.
Off-label disclosure: This article includes discussion of the following unapproved medications for co-occurring marijuana abuse or dependence and psychotic disorders: bupropion, dronabinol, and nefazodone.

Please direct all correspondence to: Wilfrid Noël Raby, MD, PhD, Division on Substance Abuse, Unit 66, New York State Psychiatric Institute, 1051 Riverside Dr, New York, NY, 10032;
Tel: 212-923-3031; Fax: 212-568-3832; E-mail: rabywil@pi.cpmc.columbia.edu.


 

Focus Points

• Cannabis use before 15 years of age increases the risk of serious mental illness, especially psychotic illness later in life.
• A family history of psychiatric illness may increase the risk of cannabis-induced psychosis.
• Clinicians need to investigate not only the use of cannabis by patients, but also its effect, in order to determine vulnerability to mental illness from its ongoing use.
 

Abstract

Marijuana abuse can lead to transient psychosis, but can it cause or worsen psychotic disorders like schizophrenia? This article reviews the evidence from key research reports, leading to the conclusion that marijuana use, especially in early adolescence, can lead to psychotic disorders in adulthood, such as schizophrenia. There is a want of treatment approaches for marijuana use in individuals with schizophrenia, or for emerging psychosis in patients dependent on marijuana. Second-generation antipsychotics, especially clozapine, appear to be the best approach to treatment for psychosis co-occurring with—and often secondary to—marijuana abuse. More research is needed to develop appropriate and effective treatments for marijuana dependence, both alone as well as in conjunction with psychosis and psychotic disorders.

Introduction

Is marijuana dangerous? With an estimated 150 million people worldwide smoking or eating marijuana leaves annually,1 the question is pertinent. Marijuana is perceived as an innocuous drug in many circles due to its association with cultural and religious rituals, and with the fact that unlike alcohol, cocaine, or heroin, it rarely brings individuals to the brink of destitution. However, this perception is changing. In 1997, Tanda and colleagues2 reported that marijuana, like most drugs of abuse, increases dopamine release in the nucleus accumbens. Moreover, the increasing potency of available marijuana has led to the recognition of a withdrawal syndrome, characterized by irritability, restlessness, insomnia, anorexia, and aggressivity, which may last up to several weeks after stopping marijuana.3 Marijuana, like tobacco smoking, also increases the risk of lung cancer in young adults.4 With respect to mental health, marijuana smoking is reported to elicit psychotic disorders in individuals at risk5 as well as worsen psychotic symptoms in patients with psychotic disorders. This last point will be the focus of this article, which will review of the evidence, discuss clinical symptoms that may indicate an enhanced risk of psychosis stemming from marijuana, and present available treatment options.

Review of the Evidence Linking Marijuana to Psychosis

Marijuana use appears to be beginning at an increasingly early age. Based on the Substance Abuse and Mental Health Service Administration (SAMHSA) 2002–2003 survey, 90.8 million adults in the United States (42.9%) ≥18 years of age had used marijuana at least once in their lifetime. Among them, 2.1% had reported a first use before12 years of age, 52.7% between 12–17 years of age, and 45.2% at ≥18 years of age.6 In the same survey, 12.5% of individuals >18 years of age who reported lifetime use of marijuana were classified as having a serious mental illness in the past year. Furthermore, 21% of adults who first used marijuana before 12 years of age were classified as having a serious mental illness in the past year, as opposed to 10.5% of adults who had first used at ≥18 years of age. Strictly with respect to psychosis, results from the US National Epidemiological Catchment Area Study7 highlight that daily marijuana smokers were 2.4 times more likely to report psychotic symptoms than non-daily users, even after adjusting for psychiatric conditions and sociodemographic factors.8 Data like these have created the suspicion that marijuana may not be as innocuous as it has been previously thought.

Before inquiring about psychotic disorders, this article evaluates how prone marijuana users are to experience some form of psychosis. As early as 1972, marijuana use was stated to possibly cause acute psychosis.9 Usually, the effects of marijuana are dose related. Mild intoxication causes drowsiness, euphoria, and heightened sensory perception, while severe intoxication leads to motor incoordination, lethargy, and postural hypotension.10 Psychosis is not considered a usual manifestation of marijuana use. Cross-sectional studies have attempted to look at the types of symptoms that might be elicited by marijuana: positive (perceptual anomalies, magical or paranoid ideation), and negative (asociality, anhedonia) in non-clinical samples. While methodologic differences abound in these studies, these studies11-14 imply that marijuana users are more prone to transient positive symptoms of psychosis; one study15 found an association with negative symptoms as well. It is unclear whether these negative symptoms represent true negative symptoms or the so-called “amotivational syndrome” (loss of interests, motivation, impaired occupational performance and achievement), which is described as a subacute, reversible encephalopathy caused by chronic marijuana use.16 A review17 of randomized trials unrelated to mental health assessing the antiemetic effects of cannabis found that 6% of patients receiving cannabis experienced hallucinations and 5% paranoia, effects not seen with the other antiemetic drugs tested. Using a method called Experience Sampling Method, which is a structured daily diary method to investigate subjective experience during daily life in which subjects a prompted every three hours to complete the diary, Verdoux and colleagues18 found that in a given 3-hour period the likelihood of reporting unusual perceptions was increased if marijuana was used in the same 3-hour period, and not if used in the previous three hour period. This finding is consistent with the estimated duration of the pharmacologic effects of marijuana.19 With heavy marijuana use, symptoms of hypomania, agitation, auditory hallucinations, and thought disorder have been reported, which have tended to improve substantially after 5–7 days.20 However, one may ask if the association between marijuana use and psychotic experiences extends to psychotic disorders. National surveys support this association, such as the data from the US National Epidemiological Catchment Area study7 presented earlier. Two other national surveys also concur. The Australian National Survey of Mental Health and Well Being revealed that 12% of those diagnosed with schizophrenia also met International Classification of Diseases and Health Related Problems, Tenth Edition21 criteria for cannabis dependence. After adjusting for other disorders and sociodemographic factors, individuals with cannabis dependence were found to be nearly three times as likely to be diagnosed with schizophrenia as those not diagnosed with cannabis dependence.22 In the Netherlands, marijuana use was more prevalent among individuals with psychosis (15.3%) than those without (7.7%).23 Taken together, these findings support the association of marijuana use not only with transient psychosis, but also with the development of psychotic disorder. However, they cannot answer the question: do we need to worry that marijuana use can cause a psychotic illness?

The issue of causality is a difficult one to answer when it comes to conditions such as psychosis which can have multiple etiologies. To establish causality, three factors must be established: association (presented above), a temporal priority, and a direction of effect.24 The latter two factors can only be scrutinized in prospective studies, where a group is selected for assessment of a risk (marijuana use) and followed over time to evaluate how potent the risk is in causing a particular condition (psychotic disorders).

Two landmark prospective studies will be reviewed: the Swedish Conscript Cohort25,26 and the Dunedin study from New Zealand.27 The Swedish study examined a cohort of 50,087 conscripts and found a dose-response relationship between marijuana use at 18 years of age and a schizophrenia diagnosis. Self-described “heavy marijuana users” (>50 lifetime use) were 2.3 times more likely than non-users to have a schizophrenia diagnosis 15 year later (after controlling for pre-existing psychosis).25 When the analysis was extended to 27 years, heavy users were 6.7 times more likely than non-users to carry a schizophrenia diagnosis, after controlling for drug use other than marijuana, low intelligence quotient, and antisocial personality, among other factors.26 Restricting the analysis to a 5-year window past 18 years of age to examine whether cannabis use might be a result of prodromal psychosis did not change those risks, leading the authors to state that their results were “consistent with a causal relationship between cannabis use and schizophrenia.”26

The prodromal phase of schizophrenia is marked by gradual but profound changes in behavior, perception, and cognition, raising the question as to whether marijuana use may be a consequence of emerging psychosis rather than a cause of it. Although small in contrast to the Swedish study, the Dunedin study27 provided unique insights in this regard, studying a birth cohort of 1,037 individuals born in Dunedin, New Zealand between 1972–1973, with a 96% follow-up rate at 26 years of age. It gathered information on self-reported psychotic experiences at 11 years of age, before the onset of marijuana use, and on self-reported use of marijuana at 15 and 18 years of age. All individuals were assessed to yield Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition28 diagnoses if present at 26 years of age, allowing the investigators to note the presence of psychotic symptoms along a continuum or the presence of a formally diagnosed psychotic disorder. Psychotic symptoms stemming from alcohol or other drugs were ruled out. Cannabis use by 15 and 18 years of age, respectively, led to higher rates of psychosis at age 26 compared to non-users, even after controlling for psychotic experiences preceding marijuana use. Age of first marijuana use was a significant factor: 10.3% of individuals who had used marijuana by 15 years of age were diagnosed with schizophreniform disorder at 26 years of age, compared to 3% of controls. The risk for adult schizophreniform disorder remained elevated after controlling for psychotic experiences at 11 years of age, with an odds ratio of 3.1. Marijuana use by 15 years of age did not predict depression at 26 years of age, and other drug use did not pose a risk for schizophreniform disorder above the one posed by marijuana. Marijuana use begun between ages 15 and 18 was associated with a heightened risk for schizophreniform disorder, but only if preceded by psychotic experiences at 11 years of age. This study corroborated the notion that marijuana use in adolescence is a risk factor for schizophrenia in later life, especially if used at an early age, suggesting both a temporal priority and direction between early marijuana use and schizophrenia. The issue of age may be especially important because at  ≤15 years of age, the developing brain may be especially susceptible to suspected trophic and neurobiologic effects of marijuana exposure, for which there is accumulating evidence.29-31

Since the Dunedin study, other studies and reviews have lent support to its findings. Semple and colleagues32 conducted a meta-analysis in which odds ratio from 2–9 were found between early exposure to marijuana and psychosis, leading them to conclude that early marijuana is an independent risk factor for psychosis and psychotic disorders. Arendt and colleagues33 reported on a cohort of 535 patients who had been diagnosed with marijuana-induced psychotic disorder and found that 47% of the patients received a diagnosis of schizophrenia 1 year later. Ferdinand and colleagues34 concluded, after a 14-year follow-up study of 1,580 individuals 4–16 years of age at study entry, that there was a specific link between marijuana use and psychosis, independent of other forms of psychopathology. In a nationwide population-based sample of 2 million individuals, the authors concluded that marijuana-induced psychosis could be an early sign of schizophrenia rather than a distinct form of psychosis.35 In individuals with prodromal symptoms of schizophrenia, marijuana increased the intensity and frequency of psychotic symptoms, especially hallucinations, and did so during and shortly after marijuana use.36 This lead the authors to ponder whether marijuana could worsen prodromal symptoms and increase the likelihood of developing schizophrenia  in young adolescents at risk. Genetic predisposition may further enhance this risk. In a study of the Dunedin cohort, Caspi and colleagues37 reported that individuals with a functional polymorphism in the catechol-O-methyltransferase (COMT) gene were at increased risk of schizophreniform disorder after use of marijuana during adolescence as compared with those who did not carry this polymorphism. Similar evidence is being found for polymorphisms at the cannabinoid receptor (CB1).38 These genetic factors may influence future risk of schizophrenia by interacting with other potential risk factors. For example, accumulating evidence points to dysregulation of the endogenous cannabinoid anandamide in patients with schizophrenia, with elevation of anandamide levels in blood and cerebrospinal fluid during acute exacerbations of psychosis and resolution after treatment (Figure).10,39-41 Hence, exogenous cannabinoids may worsen preexisting states that could make some individuals more at risk to develop schizophrenia from consuming marijuana.

 

 

 

Faced with this mounting evidence that marijuana use, particularly at an early age, can increase the risk of schizophrenia in adults, what is a clinician to do? The next section will describe an approach that may help in advising patients on the risk inherent to marijuana use and on the risk of developing a psychotic disorder.

Clinical Approaches to Advising Patients

Given the prevalence of marijuana use, psychiatrists and clinicians will encounter patients who smoke marijuana. As a starting point, not only is it important to know which substances have been and are being used (marijuana in this instance), but it is useful to ask the patient about what they experienced when smoking marijuana. Usually, mild intoxication can be followed by drowsiness, euphoria, heightened sensory awareness, and altered time perception. Moderate intoxication may produce memory impairments, depersonalization, and mood alteration. Severe intoxication can lead to decreased motor coordination, lethargy, slurred speech, and postural hypotension. These are the usual symptoms of marijuana use. Individuals who consistently experience these symptoms may have smoked marijuana for many years, with perhaps an ensuing decline in motivation, mental acuity, and a stalling in their personal and professional achievements. These later symptoms are often those that bring these patients to seek treatment. For those other patients who may be unknowingly more at risk of psychosis from marijuana, the experience of consuming marijuana seems to be different.

Clinicians are encouraged to look for any symptoms that might differ from the usual effects of marijuana stated above. After first smoking marijuana, or after some time thereafter, some patients may experience dysphoria, restlessness, generalized anxiety, panic attacks, paranoia, and sometimes hallucinations (Table). In most cases, marijuana-induced psychiatric symptoms, such as panic attacks, agitation, or persecutory delusions, are transient.5,42 Although no literature appears to exist looking at how these early effects of marijuana may portend future risk of mental illness, they may represent a first warning. In this author’s experience, marijuana-smoking patients with these symptoms frequently have a family history of psychiatric illness as well, be it depression, bipolar disorder, anxiety disorders, or schizophrenia. How these familial risks enhance the probability of acquiring a psychotic disorder from marijuana is not yet elucidated. Nonetheless, this author has witnessed patients with these anomalous effects of marijuana go on to develop autonomous psychotic disorders from not stopping their marijuana use in time. In the face of current evidence, the most conservative stance would dictate that patients be told that symptoms contrary to the usual effects of marijuana may signal that continued use of marijuana may possibly and seriously jeopardize their future mental health, although no definite proof of this exists for now. Presently, the state of reimbursement for clinical care forbids ancillary testing that might substantiate this risk, such as genetic testing for polymorphisms in the COMT or CB1 receptor genes.

 

 

Treatment for Marijuana-related Psychosis

Compared to psychosis unrelated to marijuana, marijuana-associated psychosis is emerging as more challenging to treat. In established schizophrenia, marijuana or other drug abuse leads to decreased adherence to treatment43 as well as increases recurrence of symptoms,44 episodes of violence,45 victimization (such as being used as drug “mules” to carry drugs),46 hospitalizations,47 and suicide.48 This underlies the seriousness of the problem, and the importance of developing effective treatments. Before moving on to potential medication treatments, the context of treatment deserves special mention. Programs that integrate counseling for substance abuse, psychosocial support for mental illness, and medication treatment provide the continuity and comprehensiveness that is more likely to make such treatment a success with the severely mentally ill. The inclusion of cognitive-behavioral and motivational interviewing approaches enhances treatment success.44,49-51 Features such as contingency management, where abstinence is rewarded with small prizes, can further increase success.52 For the most recalcitrant patients, long-term residential programs must be considered.53 However, many clinics are not equipped to provide such comprehensive services, and much remains to be overcome to disseminate such services throughout the current mental health network and to a wider population.

There are few guidelines concerning the pharmacologic treatment of co-occurring marijuana abuse or dependence and psychotic disorders. With respect to marijuana dependence itself, the cannabinoid receptor antagonist rimonabant is showing promise in primate trials to alter marijuana-seeking behavior.54 Low dose naltrexone (12 mg) has been reported to reduce the effects of marijuana, an approach that may hold promise in schizophrenia patients.55 Nefazodone, buspirone, and dronabinol show some promise as well in attenuating the manifestations of marijuana withdrawal.56 However, this research is in the preliminary stages, and it is yet to be made clear how these various approaches can be implemented in schizophrenia patients with marijuana dependence. As psychosis must be addressed in any approach to treatment for these patients, antipsychotics have featured prominently in the attempts to treat psychosis and marijuana dependence.

The first-generation antipsychotics appear to have little role in the treatment of other cannabis use disorders, and indeed, there are reports that they may worsen substance abuse.57 Older antipsychotics, especially high-potency dopamine antagonists, may further disrupt an already dysregulated mesocorticolimbic dopamine pathway, a feature common to both schizophrenia58 and drug dependence.59 Marijuana or other drug use may very well transiently relieve core deficits in schizophrenia patients, even though it may worsen psychotic symptoms.60,61 Buckley and colleagues62 reported on a 6-month study with clozapine, showing equal response in individuals for schizophrenia who did and did not use recreational drugs. Outcomes from dual diagnosis programs are of interest as well; for the 36 out of 151 schizophrenia patients on clozapine, remission rates from marijuana and alcohol were reported at 67% to 79%, compared to 34% for the remaining patients on first-generation antipsychotics.63 A 10-year follow-up study of this group showed that schizophrenia patients on clozapine and in remission had an 8% relapse risk in the following year compared to 40% on typical antipsychotics.64 Results have been more equivocal for the other second-generation antipsychotics.65 These antipsychotics, most prominently clozapine, seem to offer the best approach to the treatment of marijuana-associated psychosis, based on the literature available and in the personal experience of the author who has treated many patients with emerging psychosis due to marijuana use. Few treatments for individuals with emerging psychosis from marijuana use can be sifted from the existing literature. This author has found clozapine, olanzapine, and aripiprazole to be most useful in treating such patients that do not yet meet criteria for schizophrenia or other psychotic disorders.

Conclusion

Despite the major public health problems posed by marijuana abuse, the weight of disability imposed by schizophrenia, and the emerging consensus that marijuana use—especially at an early age—can lead to psychotic disorders in adults, treatment approaches to schizophrenia patients with marijuana dependence or for emerging marijuana-related psychosis are still sorely lacking.66 Any medication approach will likely not deliver its promise without the proper supportive and psychotherapeutic environment. Although medications like naltrexone or rimonabant may be applicable to the treatment of marijuana dependence in patients with schizophrenia as these might be less likely to exacerbate psychosis, they remain to be tested. Clozapine offers the best promise thus far among antipsychotics to mitigate both psychosis and marijuana misuse, both in individuals with schizophrenia and in patients with incipient psychosis due to marijuana. The difficulties of using clozapine have reduced its acceptability to patients and still pose a major hurdle to its more widespread use. Alternatives to clozapine that preserve its benefits and shed its severe liabilities are being actively sought after. Much more work is necessary to address the issue of marijuana-related psychosis, especially in light of the risk of serious mental illness posed by marijuana use in adolescents. Intervening early to stop marijuana use, as with overall drug use in the US, must remain a public health priority and may represent a unique and significant preventative measure to preserve good mental health in individuals at risks. PP

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Return

 

This interview took place on January 15, 2010 and was conducted by Norman Sussman, MD.

Disclosure: Dr. Chang is consultant to Bristol-Myers Squibb, Eli Lilly, and GlaxoSmithKline; is on the speaker’s bureaus of Bristol-Myers Squibb, Eli Lilly, and Merck; and receives research support from GlaxoSmithKline, the National Alliance for Research on Schizophrenia and Depression, and the National Institute of Mental Health.


 

Dr. Chang is associate professor of Psychiatry and Behavioral Sciences in the Division of Child Psychiatry at the Stanford University School of Medicine in California. He is director of the Pediatric Bipolar Disorders Clinic and Research Program, where he specializes in pediatric psychopharmacology and treatment of depression and bipolar disorder in children and adolescents. Dr. Chang’s research includes brain imaging, genetics, and medication and psychotherapy trials.

 

How is bipolar disorder diagnosed in children and adolescents?

Unfortunately, we are still using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition1 criteria because that is all we were given. We still do not have a good biological marker to help with early detection and diagnosis. That is the focus of my research, but in the meantime we are left with phenomenology and the DSM-IV. The biggest thing to remember in children is that they are not small adults and that, naturally in their developing brains, they have rapid mood shifts and rapid emotional changes; at each age, what is considered normal in development changes. A 3-year-old child is very normally going to have rapid mood shifts, and an adolescent is going to have fairly rapid mood shifts as well. Clinicians must remember that context when making a diagnosis in youths. In light of these rapid mood shifts, clinicians must realize that much of it is normal. Even if it is an abnormal mood, whether it is depression or mania, the child is not usually going to sit in the mood for the whole 2 weeks for depression or the full 1 week for mania. The crux of the whole diagnostic question always comes down to the episode: Can a child reach a full episode? Youths typically do not meet full episode criteria because their brains are not geared that way.

Since their brains are still developing, the criteria for bipolar disorder do not apply correctly to children. However, clinicians still try to make the diagnosis fit the criteria as much as possible, looking at the overarching episode as a distinct period of change in mood and not necessarily requiring that the child is in that mood state 24 hours a day.

 

How is that diagnostic process different than for an adult?

It is similar in that adults in mania are not necessarily manic 24 hours a day. Their moods do change throughout the day; it is just a predominant mood. However, a child’s mood fluctuation is definitely more extreme than in adults. When that normal developmental context is clear, a clinician can make a more appropriate diagnosis based on what is normal for a child.

The individual symptoms can be different as well, because the symptoms were originally developed for adults. Grandiosity in a 32-year-old does not look the same as grandiosity in a 7-year-old. Again, one has to be aware of what is normal versus abnormal grandiosity in a 7-year-old.

 

Do you think that bipolar disorder has become a default diagnosis in children and adolescents?

Yes, I think it has become one of the diagnoses, along with pervasive developmental disorders in children. A study2 examining the last 10 years in an Health Maintenance Organization sample found a 4,000-fold increase in community diagnoses of bipolar disorders in children. That does not mean that they really have bipolar disorder, rather that there has been a greater diagnosis in the community. I think it is a reflection of the fact that people do not know what it looks like. When behavioral problems occur, a diagnosis of bipolar disorder has become one of the first thoughts that people have. It is good in that at least we are not missing diagnosing children who have real bipolar disorders. However, clearly there are children also being incorrectly diagnosed and overdiagnosed. Thus, it is really important to get the accurate diagnosis.

 

Some people would argue that the increase in diagnosis is because there are now drugs approved for that diagnosis and that such drugs are being promoted.

Without just flat out saying that is complete lunacy, there is some concern about pharmaceuticals’ involvement to the extent where now pharma is reluctant to even market such drugs towards children, regardless of the indications for children, because of the fear of the backlash. If anything, I think that kind of backlash will be negative and that we are going to start missing diagnoses and missing treatment opportunities because people are so fearful that they may be looked upon as agents of the pharmaceutical industry.

Before the last 2 years, nothing was indicated for bipolar disorder in children other than lithium, and that was only down to age 12. There are still children who need treatment. I think it is a little bit of an incorrect kind of accusation.

 

Upon getting a history, even without seeing a child’s or adolescent’s symptoms, what would a clinician look for that would put a youth at high risk for bipolar disorder?

The first thing we always look at is family history. The more loaded the family history for mood disorder, particularly bipolar disorder, and the closer to the child (eg, a first-degree relative, like a sibling or a parent), the greater the risk.

Then, after that, we take a really close look at two main kinds of syndromes. First, unipolar depression: a child with depression who has a strong family history is at very high risk to go on to develop bipolar disorder, ie, possibly 30% to 50%. Second, attention-deficit/hyperactivity disorder (ADHD) plus mood dysregulation: if they have symptoms of ADHD at an early age and then go on to develop more mood problems and they have a family history of bipolar, that also puts them at higher risk.

Those are the two main pathways that my colleagues and I have been investigating in our research. We are pretty sure there are other pathways as well, including anxiety disorders, and even children who present with what we call bipolar not otherwise specified (NOS); the latter opens up a whole other can of worms, but is really important because probably most of these children in the community are being diagnosed with bipolar disorder NOS without really good, firm criteria to back up those diagnoses.

 

Does family history of alcoholism help predict whether there is a higher risk of bipolar disorder?

We have not seen alcoholism per se do that, but whenever we get a family history of alcoholism we examine more closely to see if there is a mood component. With family histories, we will go very closely and try to diagnose by proxy, asking the parents questions about their direct relatives (eg, “Did your brother have this? Did he have a manic episode? Did he have a depressive episode?”) Oftentimes, if the patient had a history of drug abuse or alcoholism, we will find either depression or sometimes even bipolar disorder. However, in the absence of that, we have not really seen a big increase in risk.

 

Do you think bipolar disorder is caught most of the time now, or is there still a ways to go in terms of recognition?

I think there is still a ways to go, depending on where you are. In the United States, certainly in major urban areas, there is probably the tendency towards overdiagnosis, but in other areas it is still being underdiagnosed. Clearly, the increase in incidence is due to better recognition and over-recognition, but it may also be due to an actual increase in incidence due to genetic and environmental reasons. The age of onset appears to be getting lower throughout the generations, so that would indicate that there are more children and adolescents with bipolar disorder now than there were in previous generations.

I think we have a long way to go in terms of catching bipolar disorder. The majority of children diagnosed in the community are diagnosed with NOS, but there are no firm criteria. We have been trying to develop criteria, along with other research institutions across the country so that we can speak the same research language, and that can be translated to better clinical recognition of bipolar NOS.

Currently, the way we are using NOS is that patients have to have the criteria A symptoms for the manic episode—which are elation, euphoria, or irritability—but they need one less criteria B symptom than they normally would, or their episodic duration needs only to be 4 hours rather than 4–7 days. However, during the 4 hours, the symptom has to be something that repeats itself on different occasions and does cause functional impairment.

It is a little controversial, but when this type of criteria is applied to children, many children are found to meet this diagnosis. This has been well-studied in the Course and Outcome of Bipolar Youth study in Pittsburgh.3 Those researchers have found that ~38% of these children with bipolar disorder NOS go on to develop full bipolar I or II disorder over 4 years.

 

Why are early recognition and intervention important in dealing with children and adolescents?

Detecting the manic episode early on is important to not only inform better treatment, but also to prevent future episodes from reoccurring. My colleagues and I are big believers in the kindling hypothesis, which proposes that with each subsequent mood episode, it becomes easier for the brain to flip into that mood episode. Preventing mood episodes is actually preventing recurrence of worse and worse mood episodes that become more difficult to treat.

Thus, it seems prudent to figure out which children are at the highest risk for developing bipolar disorder and intervene even before the first manic episode. Granted, there is much controversy with treating children who have not developed full bipolar disorder; however, as I mentioned, a lot of these states are already problematic, whether it is bipolar disorder NOS, depression, or ADHD plus mood symptoms. They are already usually being treated anyway in the community. If we can tailor that treatment and guide it more towards bipolar disorder prevention, we will be able to hopefully even stave off the first manic episode and prevent a whole life filled with morbidity.

 

Is there any new evidence that confirms or contradicts reports about there being specific polymorphisms associated with bipolar disorder?

What is new is that we are realizing the complexity involved with these genetic polymorphisms. For example, with brain derived neurotrophic factor or with the serotonin transporter gene, it does seem like certain polymorphisms confer perhaps a very small increased risk for developing bipolar disorder. Yet, the complexity we are realizing is that these polymorphisms then affect development of certain brain regions and brain activation patterns that then lead to problems with mood regulation. The future of understanding how these candidate genes help increase risk for major mood disorders, including bipolar disorder, is going to look at their effects on brain structure and function that then lead to these mood episodes. That is an area of research that my colleagues and I are actively engaged in.

 

In treating a child as opposed to a middle-aged adult, are there different considerations when choosing which medication to start with?

Absolutely. We used to base our treatment plans on adult data because there were no childhood data. In the last 4–5 years there has been an explosion of data, so that now we have many positive, placebo-controlled, large-scale trials for acute mania in children down to 10 years of age.

Unfortunately, some of those trials have been negative, as well—for example, with oxcarbazepine and, surprisingly, divalproex. This has somewhat changed the landscape of treatment choices in children in the community and probably also in academia, where now we are gearing a little bit more towards atypical antipsychotics because of their relatively positive data compared to anticonvulsants.

 

You seem to be referring to acute treatment. Does the answer change in regards to maintenance or long-term treatment?

Definitely, again because of our concerns with the side effects from the atypical antipsychotics, whether it be weight gain or metabolic problems. I refer to children who have even more weight gain than adults exposed to these medications. From a long-term standpoint, we are very careful when continuing medication doses at the doses that were used to get them stable.

It becomes a different issue. Unfortunately, there are very little maintenance data in children. There are a couple studies being conducted now in that area, but only with a couple agents, so we need a lot more data before being able to understand what is the best for efficacy. However, for long-term side effects profile, we are concerned about continuing atypical antipsychotics. Thus, we will be very active in treating the acute symptoms. Once we get things under control, we are also very active in trying to pare down the medication regimen so that the children do not have these side effects, because very little is known about the adverse effects on the developing brain and body of these children.

 

Are risks of side effects greater in children, as opposed to adults, taking medications to treat bipolar disorder?

Yes, the risks become much greater when dealing with children. Many are psychological risks because clinicians are afraid to impact children more so than they are afraid to impact adults, as children are in a more vulnerable position. They cannot consent for themselves, but can only give assent. It is a little bit trickier.

Still, when it comes to a major mood disorder like bipolar disorder that carries great morbidity and a great suicide rate, it becomes clear to these families that some of these unknown side effects can be handled down the road. My colleagues and I believe endocrine effects, such as polycystic ovarian syndrome, are somewhat reversible. Maybe not the kidney effects—almost nothing is known about that in children in long term.

The idea is to try to stabilize a child and improve his or her functioning and prevent the suicidality now because that is the most important thing. Then we will worry about the other kinds of side effects down the road after the child has been stabilized.

 

Is there any evidence that the early use of antidepressants or stimulants to treat either depression or ADHD has led to an increase or a worsening of bipolar disorder when used in a vulnerable child?

Clinicians are much more aware of this possibility now than they were 10 years ago. However, time and time again, we still see patients who are exposed to these medications that have manic episodes, and we wonder if it is completely due to these medications or not. We used to be very concerned about stimulants and that they may promote kindling in these vulnerable children, but more and more data have come out that suggest that, overall, stimulants are probably not a problem. In fact, they may be beneficial in some children.

Tillman and Geller4 followed children with ADHD. Approximately 25% of them developed bipolar disorder, eventually experiencing a manic episode. Those children treated with stimulants were less likely to develop mania than children who were not treated with stimulants, almost suggesting that there may be some protective effects of improving a child’s psychosocial and school functioning as well as against developing a mood disorder. Even with stimulants currently, once in a while a child still may have a manic reaction. Of course, that child should probably not be on this class of medications. Still, overall, it appears stimulants may actually be beneficial in these children and not speed up the process of bipolar disorder.

Antidepressants are a different story. A lot of retrospective evidence suggests that antidepressants are much more problematic in causing manic episodes in children who otherwise may not have developed mania. My colleagues and I are examining that area very closely. The conversion from unipolar depression to mania often coincides with giving a child an antidepressant.

Again, we look very carefully at family history and other early signs of hypomania that might indicate that this child really has underlying bipolar brain chemistry, and then in those children we are very careful before starting antidepressants. We still feel that some of them will be fine, but there is a certain proportion—probably significant somewhere on the order of 30% to 40% of children who have strong family histories of bipolar disorder and depression—who may respond adversely to antidepressants. I am very careful before using them, and if we do use them, we start very low and go very slowly, and ask the parents to really closely monitor for any manic symptoms.

The alternatives, though, are the mood stabilizers lithium and lamotrigine, which have not been well studied yet in this population. Some parents will opt to go that direction rather than risk having a manic episode. There are more side effects associated with those medications, so we are very careful to explain all the risks and benefits to the family members.

 

People tend to ask whether there is some kind of imaging or other diagnostic test that will help confirm the diagnosis. What are your thoughts on this?

I tell parents, family members, and patients that right now the general consensus among all researchers in the field is that bipolar disorder or most psychiatric disorders cannot be diagnosed using any kind of brain imaging. In fact, at this point brain imaging does not inform diagnosis or treatment selection, particularly for bipolar disorder.

I do tell them there are private enterprises that use brain imaging more as a clinical gestalt tool because most of their data have not been published and have not been rigorously analyzed to figure out what are signs associated with specific diagnoses or specific treatment response. A clinician involved in such enterprises might see that the last five people treated with a certain medication who had a certain symptom complex did really well on a specific drug. The clinician will then continue that drug. It is almost as if they are using this tool in the same manner, saying, “The last five people we saw with this brain pattern responded well to this medication profile, so we will use this.” Some have received positive results but some have not. I just caution them to be completely aware of the possible pitfalls of that approach.

That is all a long-winded way to say that we really have no idea or evidence that these things work at all. I do not recommend obtaining brain imaging for diagnostic purposes at this time, but it is an excellent research tool, and we are getting close to making it useful clinically.  PP

 

References

1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
2.    Moreno C, Laje G, Blanco C, Jiang H, Schmidt AB, Olfson M. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007;64(9):1032-1039.
3.    Birmaher B, Axelson D, Goldstein B, et al. Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the Course and Outcome of Bipolar Youth (COBY) study. Am J Psychiatry. 2009;166(7):795-804.
4.    Tillman R, Geller B. Controlled study of switching from attention-deficit/hyperactivity disorder to a prepubertal and early adolescent bipolar I disorder phenotype during 6-year prospective follow-up: rate, risk, and predictors. Dev Psychopathol. 2006;18(4):1037-1053.

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Dr. Luo is associate clinical professor in the Department of Psychiatry and Biobehavioral Sciences at the University of California in Los Angeles; past president of the American Association for Technology in Psychiatry (AATP) in New York City; and Gores Informatics Advocacy chair at the AATP.

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


 

Technology has enabled mental health practitioners to have greater reach to their patients with telemedicine, and electronic prescribing systems have made transcribing errors a faint memory. However, the day-to-day practice of medicine still requires many other elements in the office for communication and documentation such as e-mail, scheduling, transcription, and voicemail. Some practices can afford to hire staff full time, whereas others consider part-time and even off-site assistants for cost savings. With today’s more technologically savvy patients who look up their physicians online and review medical information, it is not a far stretch that these same tech-savvy patients want that same convenience with online scheduling and one stop for messages. This month’s column reviews these virtual assistants which can enhance the clinician’s busy practice and save time.


Online Scheduling

It is highly unlikely that a private practice would use an online calendar such as Google Calendar1 to schedule appointments for the office. Although it is free and has options whereby Gmail users can share their calendars, it clearly lacks privacy features and the ability to set appointments. Many electronic health record systems such as Practice Fusion2 and Valant Electronic Medical Record3 offer appointment scheduling entered by providers and administrative staff in realtime on these Web-based systems, typically at the end of an appointment. However, a true time saver would be if patients could independently reschedule or schedule their appointments directly online without staff intervention. Companies such as SCI Solutions’ Schedule Maximizer,4 Appointment Quest,5 NetAppointment,6 and Appointment-Plus7 offer these services. Patients are able to see available times only and do not see appointment times taken by other patients. They can log in at any time and set up how they want to be reminded, such as via e-mail or phone. In addition, these systems can be set up to collect co-pays and other information in advance of the appointment. Many of these systems can export the schedule into Microsoft Outlook or a spreadsheet for offline backup. Finally, many of these systems also provide analysis, which may help providers determine which patients cancel the most often or who change their appointments frequently.

 

Secure Communication

Many healthcare providers utilize e-mail for communication with patients, usually initiated by the patient who finds it convenient for asking for refills or a change an appointment. The 1998 American Medical Informatics Association Guidelines for the Clinical Use of Electronic Mail with Patients recognized that encryption was not widely available, user friendly, or practical, and therefore did not demand its use.8 Although encryption availability in standard e-mail client software still has not become user friendly or practical, there are alternative solutions to ensure that electronic communication between patients and providers is secure enough to maintain privacy. LuxSci9 and 4SecureMail10 are companies that provides Health Insurance Portability and Accountability Act-compliant e-mail solutions. One method is using a a secured ‘escrow’ account where patients and providers go online via an SSL connection to the company e-mail server providing a secured portal as all messages are left there. Alternatively, both companies also offer secured SMTP (simple mail transfer protocol) relaying services so that providers can use an e-mail client such as Microsoft Outlook or Eudora to send encrypted e-mail. RelayHealth provides a secure communication portal where patients can leave specific messages for providers, such as request/cancel appointment, request a lab/test result, request medication refills, send a note to the doctor/office staff, or request a referral.11 It structures the patient queries via specific messaging templates that have fields such as pharmacy and medication request, so that the prescription can be sent via fax directly in the system on the SureScript network. RelayHealth also offers webVisits, where patients can enter specific queries or consultations on non-urgent topics, which are responded to by providers using a template-based reply system to save time. For offices with a single provider and on a limited budget, TeleHealth Connect provides a free secure communication system for providers with their patients using the basic account.12 TeleHealth Connect has partnered with Microsoft’s HealthVault, a personal health record system, so that all secure messages and attachments are stored in HealthVault. These messages are controlled by the patient, who can delete and discontinue them at any time. Patients always use the TeleHealth Connect system at no cost, whether the healthcare provider is in solo practice or part of an enterprise system.

Although there may be some reluctance on the part of patients to entrust their medical information with a large company such as Microsoft, HealthVault was launched in 2007 and was designed to balance privacy features with management of health information. In particular, the privacy protections in HealthVault reflect the privacy principles of the Coalition for Patient Privacy,13 a non-profit health privacy watchdog organization founded in 2004 by Debora C. Peel, MD. Encouraging patients to set up a free account with HealthVault has benefits for healthcare providers as many Internet-based healthcare applications and medical devices interface with HealthVault and store information there. For example, Quest Diagnostics,14 a large national laboratory testing company, can export patient test results directly from their doctor into their HealthVault account upon authorization. In this way, patients can have a copy of their blood tests after reviewing them in the office with their physician. If the physician is using the National ERx initiative software from Allscripts ePrescribe,15 patients can request to have an electronic record of medications, conditions, and allergy information be placed into their HealthVault account. Similarly, patients can have their pharmacy records from CVS16 and Walgreens17 linked to their HealthVault account for management. Personal health records were primarily touted as a way for patients to keep track of their own health information; however, a secondary benefit is that more accurate health information is organized and now available to any physician, which will save valuable time spent sending for records or contacting pharmacies for medication names, dosages, and frequencies.

 

Central Communication

Many physicians carry a pager, check messages on an office voicemail system, receive fax requests for medication refills, and use e-mail for communication. All theses systems are enough to make anyone feel like they need several heads like the hyrda beast to keep up with these systems. A variety of products help tame the information overload in different ways. Google Voice18 provides one phone number to manage all the clinician’s phones. This number is linked to the clinician’s account, not a physical location or a particular device. Voicemail can be heard by dialing in or on the computer while online. Voicemail can even be transcribed and sent either via e-mail or text messages. The Google Voice number can be used to route phone calls to any phone number such as a mobile phone or office phone. One very handy feature is the ability to use a Google Voice number as the caller ID, which preserves the privacy of the mobile device. Innoport19 offers hosted unified communication solutions, which provides similar features as Google Voice, but it includes a hosted PBX that provides directory assistance, customizable greetings, and Internet fax to e-mail as well as e-mail to fax. YouMail20 provides access to voice mail either on phone, online, or via e-mail attachment. It also provides voicemail filtering to avoid telemarketing as well as smart greetings to distinguish between family, friends, and patients. Jott21 offers similar services for voicemail, but also allows voice dictation to send notes and to-dos, set reminders and appointments, send e-mail and text messages, and post to blogs, all with a phone call. These time-saving solutions all work by keeping it simple to respond to different mechanisms of received messages.

 

Conclusion

Although the technologies described above at first seem obvious and mundane, the minutes of time saving and decreased hassle all add up. Unfortunately, one system does not provide everything needed for the office practice, akin to how finding the perfect electronic health record system today is very much an exercise in frustration. There are times when a jack-of-all-trades or unified solution is better than numerous expert or customized system solutions; however, many of these virtual assistants do add up to save clinicians time and frustration. Why not employ one of them now?  PP

 

References

1.    Google Calendar. Available at: http://calendar.google.com. Accessed March 4, 2010.
2.    Practice Fusion. Available at: www.practicefusion.com. Accessed March 4, 2010.
3.    Valant EMR. Available at: www.valentmed.com. Accessed March 4, 2010.
4.    SCI Solutions. Available at: www.scisolutions.com/solutions/schedule-maximizer.asp. Accessed March 4, 2010.
5.    Appointment Quest. Available at: www.appointmentquest.com. Accessed March 4, 2010.
6.    NetAppointment. Available at: www.netappointment.com. Accessed March 4, 2010.
7.    Appointment-Plus. Available at: www.appointment-plus.com. Accessed March 4, 2010.
8.     Kane B, Sands DZ. Guidelines for the clinical use of electronic mail with patients. The AMIA Internet Working Group, Task Force on Guidelines for the Use of Clinic-Patient Electronic Mail. J Am Med Inform Assoc. 1998;5(1):104-111.
9.    LuxSci. Available at: www.luxsci.com. Accessed March 5, 2010.
10.    4SecureMail. Available at: www.4securemail.com. Accessed March 5, 2010.
11.    RelayHealth. Available at: www.relayhealth.com. Accessed March 5, 2010.
12.    TeleHealth Connect. Available at: www.telehealthconnect.com. Accessed March 7, 2010.
13.    Patient Privacy Rights Foundation. Available at: http://patientprivacyrights.org. Accessed March 7, 2010.
14.     Quest Diagnostics Partnership. Available at: www.healthvault.com/websites/QuestDiagnostics-MyCare360.html. Accessed March 7, 2010.
15.     Allscripts ePrescribe Partnership. Available at: www.healthvault.com/websites/allscripts-AllscriptsePrescribe.html. Accessed March 7, 2010.
16.     CVS Partnership. Available at: www.healthvault.com/websites/CVSPharmacy-CVSPharmacy.html. Accessed March 7, 2010.
17.     Walgreen Partnership. Available at: www.healthvault.com/websites/Walgreens-Walgreens.html. Accessed March 7, 2010.
18.    Google Voice. Available at: voice.google.com. Accessed March 9, 2010.
19.    Innoport. Available at: www.innoport.com. Accessed March 9, 2010.
20.    YouMail. Available at: www.youmail.com. Accessed March 9, 2010.
21.    Jott. Available at: www.jott.com. Accessed March 9, 2010.

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Parents Report Inadequate Support in Schools for Behavioral and Emotional Issues

Children with behavioral, emotional, or family problems typically first seek support from school psychologists, counselors, and social workers. Behavioral problems, including attention-deficit/hyperactivity disorder (ADHD), along with emotional and family problems, bullying, and homelessness, can negatively impact children’s academic success.

Approximately 1,100 parents across the United States were surveyed by the C.S. Mott Children’s Hospital National Poll on Children’s Health regarding how well their children’s public schools supported children with behavioral, emotional, or family problems. The poll revealed that 37% of parents surveyed gave an A to primary schools’ support for children with ADHD and other behavioral problems, and 34% gave an A for support for children with emotional or family problems. For secondary schools, 22% of parents surveyed gave an A for support for children with behavioral, emotional, or family problems. For overall education, 52% of parents surveyed gave primary schools an A, whereas 38% gave secondary schools an A.

“Most surprising is the lower parental confidence in secondary schools versus primary schools in public systems, in terms of support for children with emotional, family, or behavioral problems,” said Matthew Davis, MD, MAPP, director of the poll and associate professor of Pediatrics and Internal Medicine at the University of Michigan Medical School in Ann Arbor. “Generally, adolescents are at a greater risk than younger children, in terms of harming themselves and harming others. Therefore, we as a society need to offer more, rather than less, support for them and their emotional struggles.”

Some stakeholders believe that school funding should be limited to educational services due to the economy. If students need special support services, drastic cuts to these areas may interfere with students’ ability to learn and work to their full academic potential.

Dr. Davis said that in the most optimal circumstances, primary care physicians (PCPs) and schools should act together to support children and their families. However, there are many potential obstacles to good teamwork between PCPs and school staff.

“Our results indicate that one major problem is that many parents do not feel that their children’s schools are providing adequate support,” Dr. Davis said. “Based on our findings, I would encourage PCPs to ask parents openly about the amount of support they and their children are receiving from schools. If parents seem discouraged, PCPs should try to help them find other types of support within the community rather than insisting they keep trying to find support within the school setting.”

Funding for this research was provided by the Department of Pediatrics and Communicable Diseases and part of the CHEAR Unit at the University of Michigan Health System. To view the poll, please visit the University of Michigan Health System Website. (www.med.umich.edu/mott/npch/). – JV

 

fMRI Reveals Functioning Behind Stunted Emotional Processing in Generalized Anxiety Disorder

In a recent imaging study, patients with generalized anxiety disorder (GAD) demonstrated inhibited emotional processing. This, according to researchers, was explained by the inability of GAD patients’ brains to regulate the amygdala by engaging the pregenual anterior cingulate.

The investigation, headed by Amit Etkin, MD, PhD, at Stanford University, and colleagues, focused on implicit emotional regulation in GAD.

Etkin and colleagues scanned 17 GAD patients (mean 31.5 years of age, 65% female) and 24 healthy comparison subjects (mean 36.5 years of age, 75% female) with functional magnetic resonance imaging (fMRI) while displaying happy or fearful facial expressions. Each image was overlaid with a “happy” or “fear” caption. Some facial expressions had mismatching captions.

The comparison subjects non-intentionally regulated the emotional conflicts presented by mismatched captions. The GAD group, however, had impaired emotional adaptability and delayed reaction times. fMRI and performance results were so significantly correlated with symptoms that patients could be divided accurately by that sole criterion.

This study was funded by grants from the National Institute of Health and the residencey program of the Veterans Affairs–Palo Alto Health Care System. (Am J Psychiatry. Epub February 1, 2010). – LS

 

Database of Brain Tissue to Advance Research of Major Psychiatric Diseases

Biomarkers, which are biologic footprints left behind by illness, can be found in brain tissue, the most reliable vehicle that contains direct clues to psychiatric and neurologic disorders. Biomarkers can divulge clues regarding the origin of a disorder and the chain of events that cause full-blown disease.

Robert Yolken, MD, a neurovirologist at Johns Hopkins Children’s Center in Baltimore, Maryland, and colleagues from the Stanley Medical Research Institute in Baltimore, have developed a large repository of brain and tissue samples to advance the understanding and treatment of major psychiatric diseases such as bipolar disorder, major depressive disorder (MDD), and schizophrenia. 

“The medications currently used to treat mental illness can have significant side effects and often do not alleviate symptoms,” Dr. Yolken said. “We anticipate that the database will facilitate the identification of molecular pathways that can be targeted for the development of new and improved medications that primary care physicians can use more successfully in their practices.”

During the last 12 years, information from 45 human brains was obtained postmortem from people who were diagnosed with a psychiatric disorder. In total, the database contains 60 human brains, including 15 brains from people diagnosed with schizophrenia, 15 from those with bipolar disorder, 15 from those with MDD, and 15 from unaffected brains. The database also utilizes software that provides powerful analyses of 1,749 neuropathology datasets and several gene expression datasets.

Also available is information regarding other patient-specific factors, including age, sex, duration of illness, brain pH, alcohol, drug use, and smoking. The database also offers blood, lymphocytes, cerebrospinal fluid, and liver and spleen tissue from the same patients. These samples are meant to provide clues to disease activity. Yolken’s laboratory has also conducted research on the role that viral and bacterial infections, such as the human herpes virus, Epstein-Barr virus, toxoplasmosis, and influenza, play in the development of schizophrenia and bipolar disorder.

“We have found that antibody levels against Epstein-Barr virus and human herpes virus type 6 were significantly increased in the serum of patients with bipolar disorder as compared to control subjects,” Dr. Yolken explained. “Moreover, the antibody levels were significantly correlated with the dopamine receptor mRNA levels on the hippocampus of the same subjects. This suggests that exposure to certain viruses may contribute to the risk for developing psychiatric disorders by interacting with or regulating neurotransmitters.”

Funding for this study was provided by the Stanley Medical Research Institute.  (www.stanleyresearch.org/dnn/BrainResearchLaboratorybrBrainCollection/tabid/83/Default.aspx). – JV

Psychiatric dispatches is written by Lonnie Stoltzfoos and Jennifer Verlangieri.

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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.

Email questions or comments to ns@mblcommunications.com


While reading the Wall Street Journal on the morning of March 8, 2010, I came across the following headline under the New Medical Findings section:“Say What? New Risk in Pain-Reliever Use.”1 The brief article, based on a study published in the American Journal of Medicine,2 went on to report the following:

     “Regular use of pain-relief medicine appears to increase men’s risk of hearing loss, especially among middle-aged men, according to an American Journal of Medicine study. Researchers surveyed nearly 27,000 men every two years from 1986 to 2004; about one-fourth of the men said they had been diagnosed with hearing loss. Men who used pain relievers at least twice a week were more likely than non-users to be diagnosed. Aspirin users were 12% more likely, those on ibuprofen-like drugs were 21% more likely and users of acetaminophen, 22% more likely. Men from 45 to 50 years old at the start of the study faced the greatest risk—a 33% increase for aspirin, 61% for ibuprofen and 99% for acetaminophen. Previous nonhuman research has found some substances in pain-relievers can decrease blood flow to the cochlea, the part of the inner ear that converts waves sound into brain signals.”2

This was of particular personal interest to me because in recent years there has been decline in my hearing, along with an increase in tinnitus. It got suddenly worse ~1 year ago. The physicians at my institution gave me the full work up—magnetic resonance imaging, computerized axial tomography scan, and advanced auditory testing—trying to determine why, other than age, there had been such a sudden change. Nothing turned up. However, reading this article made me question whether years of using ibuprofen for various ailments had caused or contributed to my hearing problems. It also caused me to realize how often it is that we only find out about some serious drug adverse effect many years or even decades after it has come into clinical use. This is certainly the case with drugs in all therapeutic areas, including those used to treat mental disorders.

For example, there is growing evidence that use of antidepressants may be associated with an increase in risk for developing diabetes. Two studies3,4 have been published in recent months that strongly suggest that patients treated with these agents be monitored closely for evidence of glucose dysregulation.

One study3 found that use of selective serotonin reuptake inhibitors (SSRIs) was only associated with a significantly reduced risk of developing type 2 diabetes compared to using tricyclic antidepressants (TCAs) alone (37.5% versus 44.2%), but that using TCAs/SSRIs concurrently was associated with an increased risk of type 2 diabetes compared to using a TCA alone (59.8% versus 44.2%). After adjusting for sex, age, number of physician visits, and use of augmentation therapy, only the use of TCAs and SSRIs concurrently was associated with an increased risk of type 2 diabetes compared to using TCAs only. Using multiple antidepressants or SSRI monotherapy was not associated with an increased risk of diabetes compared to using TCAs alone. SSRI use in the study was associated with weight gain during the study. The investigators found that elevated depression inventory scores, which were present in 10.3% of patients on study entry, did not predict whether patients would develop diabetes during the study, but baseline antidepressant use did. When other factors associated with the risk of developing diabetes were controlled, elevated depression scores at baseline or during the study were not associated with diabetes risk in any arm.

As part of the study, some patients were put on metformin, an antidiabetic drug, as prophylactic treatment. The study showed that treatment with metformin did have a protective effect—those participants on antidepressants with metformin did not develop diabetes. Other findings were that antidepressant treatment for shorter periods or with lower daily doses were not associated with an increased risk. Recent use of other antidepressants was associated with an 80% increase in risk of diabetes; however, a dose or duration effect could not be detected, probably because of the rather low number of exposed case and comparison subjects.

Another study found results that are consistent with the data from the randomized Diabetes Prevention Program trial cited above. This article4 reported on a large observational study, which included >160,000 patients with depressive disorder treated with antidepressants for up to 2 years. It was found that recent long-term use of antidepressants in moderate to high daily doses was associated with an 84% increase in risk of diabetes. This association was present for both TCAs and SSRIs. The authors reported that antidepressant treatment for shorter periods or with lower daily doses was not associated with increased risk. Recent use of other antidepressants was associated with an 80% increase in risk of diabetes. However, a dose or duration effect could not be detected, probably because of the low number of exposed case and comparison subjects. There was a four-fold increase in risk of diabetes associated with long-term therapy with paroxetine in daily doses >20 mg/day but not with long-term use of fluoxetine, citalopram, or sertraline. Paroxetine, venlafaxine, fluvoxamine, and amitriptyline were associated with the highest risk.

These two studies3,4 are consistent with a third study, a Canadian review5 of the medical history of 2,400 people who were diagnosed with depression and were taking antidepressants. The investigators set out to determine whether there was a clear correlation between that disease and type 2 diabetes. They found that people with a history of depression had a 30% increased risk of type 2 diabetes. They divided the group into four categories: those taking older antidepressants, using newer treatments, using a combination of both old and new treatments, and who were switching medications. The risk of diabetes almost doubled for the patients who were using two types of therapies at the same time, TCAs and SSRIs. Collectively, these findings suggest a need for regular screening for diabetes in depression, particularly those taking more than one antidepressant.

An obvious question that arises as a result of these findings is whether the growing practice of augmenting antidepressants with second-generation antipsychotic, which have a well-established risk profile for causing cardiometabolic disturbances, will result in an even higher incidence of type 2 diabetes among patients on combination therapy. This issue surely should be on our radar.

I want to thank Brendan T. Carroll, MD, and Francisco Appiani, MD, for serving as guest editors for this issue of Primary Psychiatry. Their guest editorial provides an overview on the articles that focus on this month’s theme—catatonia. I would also urge you to read the case report by Michael M. Messer, MD, and Irina V. Haller, PhD, MS, which describes exciting findings about the effectiveness of ketamine as an antidepressant. In recent years, it has become clear that this anesthetic/recreational drug may pave the way for a new generation of effective antidepressants.  PP

 

References

1.    Singer-Vine J. Say what? New risk in pain-reliever use. Wall Streeet Journal. March 8, 2010. Pg D4.
2.    Curhan SG, Eavey R, Shargorodsky J, Curhan GC. Analgesic use and the risk of hearing loss in men. Am J Med. 2010;123(3):231-237.
3.    Rubin RR, Ma Y, Marrero DG, et al. Elevated depression symptoms, antidepressant medicine use, and risk of developing diabetes during the Diabetes Prevention Program. Diabetes Care. 2008;31(3):420-426.
4.    Andersohn F, Schade R, Suissa S, Garbe E. Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Am J Psychiatry. 2009;166(5):591-598.
5.    Brown LC, Majumdar SR, Johnson JA. Type of antidepressant therapy and risk of type 2 diabetes in people with depression. Diabetes Res Clin Pract. 2008:79(1);61-67.

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Effects of Long-Term Treatment With Topiramate on Mood and Body Weight in Patients With Bipolar Disorders

David B. Marcotte, MD

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Primary Psychiatry. 2003;10(3):63-68

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Fibromyalgia and Psychopathology in a Community Hospital Emergency Room

P. Waverly Davidson III, MD, FACP

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Primary Psychiatry. 2003;10(3):69-73

 

Dr. Davidson is clinical professor of psychiatry and behavioral sciences in the Department of Psychiatry at the University of Southern California School of Medicine, and consulting psychiatrist at the Pacific Hospital of Long Beach Outpatient Psychiatric Clinic, in Long Beach California.

Disclosure: The author reports no financial, academic, or other support was received for this work.

Please direct all correspondence to: P. Waverly Davidson, MD, PO Box 15778; Beverly Hills, CA 90929.



Abstract

Objective: Using a retrospective chart review, the authors investigated the rate of occurrence of primary and posttraumatic fibromyalgia among 204 patients being assessed for pain management at a community hospital emergency room (ER). The presence of psychopathology was investigated as well.

Background: The relevant medical literature was summarized in regard to the comorbidity of fibromyalgia and depressive disorders, the comorbidity of fibromyalgia and somatoform disorders, and the comorbidity of fibromyalgia and other neurologic and medical syndromes.

Methods: This study was conducted at Pacific Hospital of Long Beach, CA. The author reviewed 204 charts of patients with musculoskeletal pains who were assessed in the ER between July 1999 and March 2001, 10 of whom had been previously diagnosed with fibromyalgia.

Results: Although fibromyalgia constitutes 20% to 30% of a typical rheumatologist’s practice, only 5% of the ER patients were diagnosed with the condition. As was summarized in the literature review, there were multiple psychiatric diagnoses in the 10 fibromyalgia patients, as well as disabilities, multiple outpatient psychiatric treatments, and use of analgesics and psychotropic medications. All 10 patients were receiving some form of monetary compensation and none were currently employed.

Conclusion: It would appear that fibromyalgia is a somatoform disorder more aptly described as a “multisomatoform disorder” because of the basic symptoms of widespread musculoskeletal pain, fatigue, tender points on physical examination, and due to its association with victimization attitudes, family history of alcoholism, depression, or somatization, childhood sexual abuse, and association with certain neurologic syndromes such as carpel tunnel syndrome, chronic fatigue syndrome, work absenteeism, and disability.

Discussion: Guidelines to help primary care physicians distinguish which acute fibromyalgia patients are likely to become chronic fibromyalgia patients are presented, followed by guidelines for future investigations into the psychopathology associated with fibromyalgia.

 

Introduction

Fibromyalgia is a common, complex, chronic, and controversial condition of unestablished etiology,1 that is characterized by widespread musculoskeletal pain, multiple tender pressure points, and profound fatigue. Although the condition is distinct from articular joint disease, ironically it is referred to as “rheumatism of the muscles.” The condition may be associated with other syndromes of uncertain etiology such as chronic fatigue syndrome (CFS), irritable bowel syndrome (IBS), and carpel tunnel syndrome (CTS), and is often accompanied by headaches, insomnia, depression, and exhaustion.

This study is a retrospective chart review investigating the occurrence rate of fibromyalgia among patients assessed for pain management in the emergency room (ER) of a general hospital. The study also investigates the comorbid psychopathology of fibromyalgia patients, which can help primary care physicians better treat such patients or know when to refer them to specialists.

 

Background

Ayd2 found that fibromyalgia had an estimated prevalence of 15% to 20% in rheumatology clinics and is the most common cause of widespread chronic pain. The estimated prevalence of fibromyalgia in the general community is 2% for both sexes; 3.4% for women and 0.5% for men.3,4 Marden and colleagues5 pointed out that fibromyalgia is the second most common diagnosis in American rheumatology clinics, while Schultes and colleagues6 indicated that 1% to 7% of the German population suffer from fibromyalgia. According to Hadler,7 20% of Americans awaken frequently with “morning stiffness” lasting as along as 30 minutes and seek no medical attention at all. In pointing out the difficulty of determining the presence of focal “tender points,” Sola and colleagues8 reported that 50% of their patients can be made to be aware of such tender points during a physical exam, especially of the pectoral girtle muscles, and still be in robust good health.

In the past, a wide spectrum of chronic and subchronic musculoskeletal conditions had been commonly called “fibrositis.”9 In 1990, based on a multi-center study,10 the American College of Rheumatology (ACR) set the criteria for the classification and diagnosis for the favored, more descriptive term, “fibromyalgia.” At present, the diagnosis of fibromyalgia must include the finding of widespread, chronic musculoskeletal pain, and mild (or greater) tenderness in at least 11 of 18 specified tender points located by digital palpation.11

In a study by Andersson and colleagues,12 22% of 1,609 Swedes with widespread pain of >3 months’ duration fit the ACR criteria for fibromyalgia. However, the 78% who did not fulfill the fibromyalgia criteria had similar profiles to the group with fibromyalgia in regard to fibromyalgia spectrum of problems, including depression, anxiety, work, absenteeism, and pain intensity.

In terms of prognosis, McFarlane and colleagues13 studied 141 English men and women in Manchester and found that only 35% of their subjects with chronic widespread pain still had pain 2 years later. Thus they speculated that most fibromyalgia patients who do not receive treatment for their symptoms, tend to make spontaneous recoveries. How then, can a primary care physician predict which fibromyalgia patients will improve with little or no treatment and which ones will need specialized rheumatological care?

 

Posttraumatic Fibromyalgia

Before the ACR published their report in 1990, the terms “fibrositis” and “fibromyalgia” were used interchangeably.10 The term “primary fibromyalgia” was introduced when describing a patient without any other medical disorder or disease that could affect fibromyalgia symptoms; the terms “secondary fibromyalgia” or “concomitant fibromyalgia” was used when other medical disorders or diseases were also present. The multicenter committee of the ACR which had devised the two terms, then disavowed the existence of any significant clinical difference between the two. The term “posttraumatic fibromyalgia” (PT fibromyalgia) refers to the fibromyalgia symptoms present which have arisen only after trauma (usually motor vehicular accidents), and are not synonymous with “secondary fibromyalgia.”

Nielsen and Merskey14 reported that the diagnosis of PT fibromyalgia has not been adequately validated and that reports of high rates of PT fibromyalgia among those fibromyalgia patients are not well designed and are often derived from uncontrolled studies. In contrast, Buskila and colleagues,15 in a well-designed study, reported 102 patients with nonspecific soft tissue neck injuries, 90% of whom had classical “whiplash” symptoms, and compared the occurrence of PT fibromyalgia in these patients with the occurrence of PT fibromyalgia in 59 patients with leg fractures. They offered no clear explanation as to why there was a higher prevalence of PT fibromyalgia (21.7%) in the neck injury patients, but only a prevalence of 1.7% of PT fibromyalgia in the more severely injured leg fracture patients, after 12.4 months from the time of injury.

Turk and colleagues16 described three distinct profiles of fibromyalgia patients: dysfunctional, interpersonally distressed, and adaptive copers. In a second study by Turk and colleauges,17 the researchers explored the differences between PT fibromyalgia patients and fibromyalgia patients, with 46 patients in each diagnostic category matched for age and duration of pain. While they found that the PT fibromyalgia patients used more narcotic analgesics, more nerve blocks, more transcutaneous electric nerve stimulator units, more physical therapy, and were more likely to fall into the “dysfunctional” and interpersonally distressed” profiles, the fibromyalgia patients were more often classified as “adaptive copers.” There were no significant differences between the two groups in terms of legal-financial incentive, suggesting that the PT fibromyalgia patients were not merely seeking monetary gains, but perhaps indicating that these PT fibromyalgia patients had more subconscious unmet needs, as in the psychodynamics of somatoform disorders.

 

Comorbidity of Fibromyalgia and Depression

Goldenberg and Don18 administered the Diagnostic Interview Schedule (DIS) to 31 fibromyalgia patients at the Newton-Wellsley Hospital in Boston, using 14 patients with rheumatoid arthritis as controls. In 1989, this was the first time that a structured interview using criteria of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition19 was used with fibromyalgia patients. When the researchers expanded their fibromyalgia patient pool from 31 to 82, they found that 60% had a lifetime history of major depression and 21% had current major depression, in contrast to the current rate of 8.7% in the rheumatoid arthritis group. However, 3 years later, Ahles and colleagues20 and Yunus and colleagues21 made similar studies and did not find significant difference in major depression between groups of patients with fibromyalgia and rheumatoid arthritis.

In a 1999 study22 involving four tertiary care centers in Washington, DC, San Diego, CA, Stonybrook, NY, and Charleston, SC, 73 patients were evaluated for major depression based on criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)23 using the Structured Clinical Interview, the Raad 36-Item Health Survey, and multiple self-report measures. The fibromyalgia patients were found to have a high lifetime prevalence and current incidence of major depression (68% and 22%, respectively). In addition, 16% had a lifetime prevalence of panic disorder as well as a 7% incidence of current panic disorder.

Katz and Krabitz24 evaluated 425 first-degree relatives of 55 females and 5 males with fibromyalgia and concluded that there was a subgroup of fibromyalgia patients with major depression, whose family members had both depression and alcoholism, and who were more likely to have had an abusive childhood as a result of this family dysfunction. This theme of physical and emotional abuse and neglect is also reported by Van Houdenhove and colleagues,25 who showed a higher prevalence of abuse in 96 patients with fibromyalgia and CFS compared with two other control groups—a chronic disease group and a healthy group.

 

Comorbidity of Fibromyalgia and Somatoform Disorders

Kirmayer and colleagues26 studied 20 fibromyalgia patients and 23 rheumatoid arthritis controls and found no significant difference in current or lifetime depression. While they did not conclude, as other investigators did, that fibromyalgia was a type of somatized depression, they did report that the fibromyalgia patients had “more somatic symptoms of obscure origin,” had more numerous somatic complaints, had endured more surgical procedures, and had sought medical help more frequently.

In 1991, Maccrocchi27 reported a case of conversion disorder presenting as fibromyalgia in which he was able to trace the fibromyalgia symptoms to specific psychological trauma. He speculated that his case, unlike those of classical conversion disorder, wherein psychological events lead to neurologic symptoms, had shown that psychological events had led to fibromyalgia symptoms.

Kroenke and colleagues28 have also noted that fibromyalgia patients are not classical cases of somatization disorder, but have proposed that a new disorder be added to the spectrum of DSM-IV somatoform disorders; this new disorder, to be called “multisomatoform disorder,” would fall between “full” and “abridged” somatization criteria, and would include functional impairment, psychiatric comorbidity, family dysfunction, and health care utilization costs. He opined that fibromyalgia would be properly included in this new multisomatoform designation.

McBeth and colleagues29 completed a prospective population-based study of 1,658 adults, using the General Health Questionnaire, the Somatic Symptom Checklist, the Fatigue Questionnaire, and the Illness Attitude Scale. Half of his subjects were pain-free and half had pain symptoms, but not widespread or chronic pain. At 1-year follow-up, 825 subjects with pain were re-evaluated, and it was found that 8% of these individuals, who had displayed many aspects of somatization earlier, were the ones who developed widespread chronic pain, a cardinal symptom of fibromyalgia.

 

Comorbidity of Fibromyalgia and Other Disorders

Sleep disturbances, tension headaches, and migraine headaches occur commonly in fibromyalgia patients. Malt and colleagues30 reported that 27% of 45 female patients studied had lifetime prevalence of panic disorder. Sivri and colleagues31 reported that 42% of IBS patients had fibromyalgia, whereas Veale and colleagues32 reported a much higher occurrence (65%) of fibromyalgia among IBS patients. Yunus and Aldag33 reported restless legs syndrome in 31% of fibromyalgia patients compared to 15% in rheumatoid arthritis patients and 2% in control subjects. Andreu and colleagues34 reported that CTS is common in fibromyalgia patients, but that fibromyalgia was very rare in the 102 CTS patients he studied. Dohrenbusch and Gruterich35 reported an association between fibromyalgia and Sjogren’s syndrome.

 

Method

The purpose of this study was to determine the rates of patients diagnosed with primary fibromyalgia and with PR fibromyalgia occurring in a community hospital ER by use of a retrospective chart review, and to determine the nature of any psychopathology co-occurring in these patients.

Pacific Hospital of Long Beach, CA, is a full-service 171-bed hospital with a 24-hour ER. Between July 1999 and March 2001, 204 individuals presented themselves to the ER with the International Classification of Diseases, Ninth Edition diagnostic code of 729.1.36 This code covers the following categories: unspecified myalgia and myositis, fibromyositis, and fibromyositis not otherwise specified. The charts of these 204 patients were reviewed to determine which among them were diagnosed with fibromyalgia or PT fibromyalgia and to determine if any psychopathology was present in the fibromyalgia and PT fibromyalgia patients.

Many of the 204 patients had made multiple presentations to the ER for treatment of their pain symptoms so that the total number of ER visits was 309.

 

Results

Of the 204 patients, 22 had musculoskeletal chest pains for which cardiac pathology was ruled out. Nevertheless, these 22 charts had been retrieved with the 729.1 diagnostic code. Thirteen patients presented with myositis as a result of a motor vehicular accident or a slip-and-fall accident; 40 patients had musculoskeletal pains or myositis in addition to acute panic episodes with hyperventilation symptoms; 43 patients were acutely intoxicated with alcohol and/or drugs and had minor lacerations in addition to painful musculoskeletal soft tissue injuries or myositis directly related to their intoxication; 76 patients had various types of musculoskeletal pains associated with osteoarthritis, lower back pain, disc disease, migraine headaches, or other forms of myositis, and had previously been diagnosed with a major mental illness such as schizoaffective disorder, schizophrenia, bipolar disorder, or major unipolar depression. Ten patients, representing 5% of the total group, had been previously diagnosed as having fibromyalgia prior to their visits to the ER.

Of the 10 fibromyalgia patients whose charts were retrieved, 8 were female (average age=49 years) and 2 were male (ages 56 and 31). Both males and two of the females had been diagnosed with PT fibromyalgia. Of the six females with primary fibromyalgia, three had comorbid diagnoses for generalized anxiety disorder, four had been also diagnosed with minor depression, and one was diagnosed with current drug addiction and had been previously diagnosed with schizoaffective disorder. Three females had lifetime histories of alcohol or drug addiction; two females had diagnoses of temporomandibular joint syndrome; one female was also diagnosed with IBS.

A careful new chart review of the 10 fibromyalgia patients showed that all patients with PT fibromyalgia (two males and two females) were currently receiving social security disability benefits or workers’ compensation benefits; one of the males had received five epidural blocks for his fibromyalgia during the 21 months of the study. The schizoaffective female had two inpatient psychiatric hospitalizations during the study. Two of the six females with primary fibromyalgia had previous treatments for CTS and four primary fibromyalgia females had been treated for their comorbid psychopathology with a total of 15 outpatient psychiatric clinic visits in addition to their ER visits during the time frame of the study.

All eight females were treated with analgesics for their fibromyalgia or PT fibromyalgia symptoms and psychotropic medications for their psychiatric symptoms; the two males were receiving analgesic medications for their PT fibromyalgia symptoms. In addition to the four patients receiving some form of monetary compensation or benefits on the basis of their PT fibromyalgia symptoms, all of the remaining six primary fibromyalgia females were also recipients of monetary benefits, based not just on primary fibromyalgia alone, but on the totality of their several comorbid diagnoses as well.

 

Discussion

One of the 2-fold purposes of this study was to investigate the rate of occurrence of fibromyalgia among patients assessed for pain management in a community hospital ER. With a retrospective chart review of 204 patients over a 21-month period, 5% had been diagnosed with fibromyalgia. If patients with fibromyalgia constitute 20% to 30% of the clinical practice of some rheumatologists, it would appear that they present themselves to local ER only for pain management and not for diagnoses.

Due to the comorbidity of so many varying neurologic syndromes and psychiatric conditions, one can begin to understand the controversy that often surrounds the validity of the diagnosis of this chronic widespread pain syndrome. It is because of this comorbidity and chronicity that so many fibromyalgia patients seek the emotional support of fibromyalgia self-help groups, fibromyalgia advocacy groups, and more sympathetic rheumatologists.37-41 It can also be speculated that fibromyalgia patients who do not feel that they get adequate management for their symptoms turn to the ERs for pain relief. Many turn to litigation as well, making inadequate medical treatment a financial burden on the population at large; it is estimated that $10 billion is spent annually in America on health care for the 6 million fibromyalgia patients, including litigation costs.42,43

All 10 of the fibromyalgia patients whose charts were reviewed in this study (96 primary fibromyalgia and 4 PT fibromyalgia patients) were receiving monetary benefits.

 

Conclusion

It is clear that a wide range of psychopathology existed in the background of these 10 patients, perhaps in their families as well, and in the multiple neurologic and psychiatric diagnoses most of them have in addition to the fibromyalgia /PT fibromyalgia.

Fibromyalgia was described in the early 1880s but it only recently emerged as a distinct syndrome in 1990 when fibromyositis was renamed by a committee of the American College of Rheumatology. Seven of the 10 patients (70%) reported here who habitually use a local ER for pain flare-ups but who report to rheumatologists or primary care physicians for diagnostic validation of their symptoms, have either a current or lifetime comorbidity for psychiatric diagnoses, mostly depression. This percentage is comparable with that of Goldenberg and Don,11,18 Crook and colleagues,44 and Granges and colleagues.45

There seems to be a subgroup of fibromyalgia patients prone to depression themselves, with family histories of depression, as reported in the studies by Epstein and colleagues22 and Katz and Krabitz.24 There are other fibromyalgia subgroups with CFS, IBS, sleep disturbances, restless legs syndromes, and other disorders.

Since both patients with depression and those with fibromyalgia respond often to antidepressants, there is a tendency to link them in terms of causation. However, most fibromyalgia patients seen in rheumatology clinics do not have treatable major depression nor are they seeking treatment for depression from their rheumatologists. Thus, Ayr2 referred to an Iowa study reporting that “fibromyalgia has been associated with anxiety and depression in 50% to 90% of patients seeking treatment for fibromyalgia.” There is no suggestion that these fibromyalgia patients also sought treatment for their depression, but they may have reported depressive symptoms when asked about their lifetime experience.

The question of somatization is an important one in terms of prognosis, as noted by the studies of Kirmayer and colleagues,26 Macciocchi,27 Kroenke and colleagues,28 and McBeth and Selman,46 which note that the more likely it is that the basic symptoms of fibromyalgia (widespread musculoskeletal pain, fatigues, and tender points) are associated with work, absenteeism, disability, victimization attitudes, psychiatric comorbidity, family history of alcoholism, depression or somatization, childhood sexual abuse, and/or neurological syndromes (such as CTS, degenerative disc disease, or migraine headaches), the more likely it is that those fibromyalgia symptoms will become chronic. This seems to be true for both primary fibromyalgia and PT fibromyalgia.

In addition, it it noted that once the fibromyalgia symptoms have become chronic, it is more likely that those fibromyalgia patients will be referred to rheumatologists. It is also more likely that their symptoms will fit into the multisomatoform disorder (MSD)described by Kroenke and colleagues28 in 1998, when they combined data from two studies (N=1,258) and proposed that MSD was an intermediate diagnosis between the abridged and full somatization disorder. The MSD?diagnosis included a patient’s disabilities, comorbid psychiatric diagnosis, family dysfunction, and use of health care facilities.

Guided by these insights, the primary care physician can more quickly predict which fibromyalgia patients will become pain-free with only the “morning stiffness” that Hadler7 describes, and which patients will require rheumatologists and/or psychiatrists for longer periods of care and pain management.

Future investigators should compare primary and PT fibromyalgia patients being currently treated for their comorbid psychiatric disorders, and those being treated in rheumatology clinics who are not in current psychiatric treatment (even though some psychiatric symptoms may be present), with matched groups of nonpatients in the community who were treated for primary or PT fibromyalgia in the past (including subgroups of patients who had and who did not have psychiatric disorders in the past) but who have completely recovered.

There should also be two distinct control groups: healthy individuals matched for age and gender with the other groups, who have never experienced any treatment for psychiatric symptoms or any pain syndromes, and another group of individuals, also age and gender matched, who currently or in the past have had painful musculoskeletal diseases other than primary fibromyalgia or PT fibromyalgia. Family history, various psychological tests, and pain inventory tests, should be obtained on all groups in such an extensive retrospective and prospective study. PP

 

References

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2. Ayd FJ Jr. 1998 American Psychiatric Association Report. Psychiatr Times. 1998;8:4.

3. Wolfe F, Toss K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromaylgia in the general population. Arthritis Rheum. 1995;1:19-28.

4. Croft P, Schollum J, Silman A. Population study of tender point counts and pain as evidence of fibromyalgia in the general population. BMJ. 1994;6956:696-699.

5. Marden WD, Meenan RF, Felson DT, et al. The present and future adequacy of rheumatology manpower: a study of health care needs and physician supply. Arthritis Rheum. 1991;10:1209-1217.

6. Schultes H, Pirk O, Berger K, Schramm B, Pongratz D. Cost of illness in fibromyalgia: results of a feasibility study. Abstract presented at: 64th Annual Meeting of the American College of Rheumatology; May 2000; Neurenberg, Germany.

7. Hadler NM. Occupational Musculoskeletal Disorders. 2nd ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 1999.

8. Sola AE, Rodenberger ML, Gettys BB. Incidence of hypersensitive areas in posterior shoulder muscles. Am J Phys Med. 1955;34:585-590.

9. Hudson JI, Hudson MS, Pliner LF, Goldenberg DL, Pope HG Jr. Fibromyalgia and major affective disorders: a controlled phenomenology and family history study. Am J Psychiatry. 1985;4:441-446.

10. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia: Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;2:160-172.

11. Goldenberg DL. Fibromyalgia syndrome a decade later: what have we learned? Arch Intern Med. 1999;8:777-785.

12. Andersson H, Ejlertsson G, Leden I, Rosenberg C. Characteristics of subjects with chronic pain, in relation to local and widespread pain reports. Scand J Rheumatol. 1996;3:146-154.

13. MacFarlane GJ, Thomas E, Papageiorgiou AC, Schollum J, Croft PR, Silman AJ. The natural history of chronic pain in the community: a better prognosis than in the clinic? J Rheumatol. 1966;9:1617-1620.

14. Nielsen WR, Merskey H. Psychosocial aspects of fibromyalgia. Curr Pain Headache Rep. 2001;4:330-337.

15. Buskila D, Neumann L, Vaisberg G, Alkalay D, Wolfe F. Increased rates of fibromyalgia following cervical spine injury: a controlled study of 161 cases of traumatic injury. Arthritis Rheum. 1997;3:446-452.

16. Turk DC, Okifuji A, Sinclair JD, Starz TW. Pain, disability, and physical functioning in subgroups of patients with fibromyalgia. J Rheumatol. 1996;7:1255-1262.

17. Turk DC, Okifuji A, Starz TW, Sinclair JD. Effects of type of symptom onset on psychological distress and disability in fibromyalgia syndrome patients. Pain. 1996;2-3:423-430.

18. Goldenberg DL. Psychiatric and Psychological Aspects of the Fibromyalgia Syndrome. Vol 15. Newton, MA: Arthritis-Fibrositis Center, Newton-Wellesley Hospital; 2000:105-114.

19.Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Assocation; 1980.

20. Ahles TA, Khan SA, Yunus MB, Spiegel DA, Masi AT. Psychiatric status of patients with primary fibromyalgia, patients with rheumatoid arthritis, and subjects without pain: a blind comparison of DSM-III diagnoses. Am J Psychiatry. 1991;12:1721-1726.

21. Yunus MB, Ahles TA, Aldag JC, Masi AT. Relationship of clinical features with psychological status in primary fibromyalgia. Arthritis Rheum. 1991;1:15-21.

22. Epstein SA, Kay G, Clauw D, et al. Psychiatric disorders in patients with fibromyalgia: a multicenter investigation. Psychosomatics. 1999;1:57-63.

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

24. Katz RS, Kravitz HM. Fibromyalgia, common depression, and alcoholism: a family history study. J Rheumatol. 1996;1:149-154.

25. Van Houdenhove B, Neerinckx E, Lysens R. Victimization in chronic fatigue syndrome and fibromyalgia patients in tertiary care: a controlled study on prevalence and characteristics. Psychosomatics. 2001;1:21-28.

26. Kirmayer LJ, Robbins JM, Kapusta MA. Somatization and depression in fibromyalgia syndrome. Am J Psychiatry. 1988;8:950-954.

27. Macciocchi SN. Conversion disorder presenting as primary fibromyalgia. Psychosomatics. 1993;3:267-270.

28. Kroenke K, Spitzer RL, deGruy FV, Swindle R. A symptom checklist to screen for somatoform disorders in primary care. Psychosomatics. 1998;3:263-272.

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Successful Concomitant Treatment of Raynaud’s Phenomena, Premenstrual Dysphoric Symptoms, and Bipolar Disorder With Oxcarbazepine and Venlafaxine

Hayne McMeekin, MD

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Primary Psychiatry. 2003;10(3):53-56

 

Dr. McMeekin is in private practice at Piedmont Psychiatric Associates in Rock Hill, South Carolina.

Disclosure: Dr. McMeekin is a regional speaker for Novartis Pharmaceuticals.

Please direct all correspondence to: Hayne McMeekin, MD, Piedmont Psychiatric Associates, PO Box 36024, Rock Hill, SC 29732-0500; Tel: 803-327-6103 ext. 233; Fax: 803-328-5443; E-mail: hmcmeekin@comporium.net.


 

Abstract

Stress in association with depression and anxiety has been increasingly defined in relation to the hypothalamic-pituitary axis, which regulates physical and emotional processes. Thus, is it possible that there are physical as well as emotional consequences to depression and anxiety associated with stress? This case study describes a patient’s psychological and physical findings during the process of successful resolution of the illness. Adiscussion of modulation of the hypothalamic pituitary adrenal axis and the sympathetic nervous system in relation to mood, anxiety, and pharmacotherapy follows.

 

Introduction

Perceived internal or external stress affects organ function via the hypothalamic-pituitary-adrenal axis (HPA) and the sympathetic nervous system. The central nervous system components of these two systems interact with each other on a regular basis.1 Stress causes the release of corticotrophin-releasing-factor (CRF) and subsequently adrenocorticotropic hormone (ACTH), which stimulates the adrenals to release cortisol. Cortisol at first acts to protect neurons from the chemical results of stress. With continued stress the body’s ability to control the HPA axis becomes impaired and with that, levels of cortisol, CRF, and glutamate become elevated. This increases the chance of neuronal toxicity and may be the reason for the hippocampal atrophy seen in chronic depression. Sympathetic activation from the locus ceruleus increases peripheral catecholamines. The circulating glucocorticosteroids and catecholamines (primarily norepinephrine) then act at diverse sites to produce wide-ranging effects across a number of systems.1-3 Many of these changes such as increases in alertness, respirations, and heart rate, and decreases in feeding, digestion, and sexual behavior, result in the fight-or-flight response to threat.1

Glutamate is the major excitatory neurotransmitter in the central nervous system. Mathew and colleagues3 have postulated that glutamate plays an important role in modulating the HPA axis and, therefore, mood and anxiety. Skolnick4 has proposed that tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) may stabilize the HPA axis in two ways. The first would be through the process of reuptake inhibition of norepinephrine and serotonin, thereby promoting the production of protective and growth-enhancing neurochemicals such as brain-derived neurotropic factor (BDNF). BDNF causes stabilization of the neuron’s cell membranes, increased branching and connections between neurons, and reverses the potential overstimulatory and cytotoxic effects of the glutaminergic system by stabilization of glutamate sensitive receptors. This promotes healing of neurons which then improves mood and anxiety. Drugs that modulate the effects of glutamate (such as lamotrigine and oxcarbazepine) may also increase BDNF by protecting neurons from overstimulation.4,5 The anticonvulsant oxcarbazepine modulates sodium channels, calcium channels, reduces glutaminergic transmission, and enhances dopaminergic neurotransmission.6 Oxcarbazepine has been reported effective in bipolar disorders.7

Intense vasospastic phenomena have been noted in anorexia nervosa. Bhanji and Mattingly8 examined an unselected series of 155 anorectics and found acrocyanosis in 32 patients. The patients with intense vasospastic phenomena were judged more ill than their counterparts. The characteristic cyanosis and coldness of the hands and feet in acrocyanosis is caused by constriction of the skin arterioles and venous dilatation.8 Anorexia nervosa, like migraine, has been genetically linked to bipolar disorder.9 Vasospastic phenomena have also been noted in bipolar disorder.

Endicott10 studied 400 patients who fell within the bipolar spectrum. He noted a significant positive correlation with migraine headaches, Raynaud’s “disease,” enuresis, “episodic phenomena,” (which may have been migraine auras), fingernail biting, and learning disorders. Forearm blood flow has been noted to be reduced compared to controls in depersonalization disorder.9

In a study of 186 bipolar I women, Blehar and colleagues11 found that 6% reported regular mood changes in the menstrual or premenstrual phase of their cycles. In addition, 75% described their premenstrual symptoms primarily as increased irritability, anger outbursts, and mood lability; 25% reported that their chief symptom was depression. Only five women reported symptoms as minor, while 20 described them as severe. Other disturbances related to hormonal changes were reported as well. Of those bipolar I women who reported a pregnancy, 45.3% reported experiencing severe emotional problems during pregnancy or within 1 month after childbirth and 19.3% reported increased symptoms during perimenopause or menopause. Blehar and colleagues11 also noted a higher rate of migraine headache in their sample of bipolar women than reported in the general population.

Intense vasospastic and/or vasodilatory phenomena has been reported in anxiety and affective disorders, koro, eating disorders, depersonalization disorder and disorders genetically linked to bipolar disorder, such as migraine, and Raynaud’s phenomenon.8,10,12,13 The following patient presented with severe premenstrual psychiatric symptoms, Raynaud’s phenomenon, and migraine headaches. All resolved or improved following successful concomitant treatment of the patient’s affective syndrome.

 

Case Report

A 42-year old married, white female was referred for anxiety attacks, chronic generalized anxiety, and severe premenstrual symptoms only partially responsive to sertraline.

She had originally noted the onset of distractibility following the birth of her children. Her anxiety began at 32 years of age following a severe case of Bell’s palsy. The anxiety persisted and gradually worsened so that she became increasingly more “on guard” when leaving home, driving, or seeing others outside her home. In retrospect, she also noted during that time the onset of Raynaud’s phenomena in her hands and feet when she was anxious, and a feeling of sporadic sadness sometimes without reason. Three years later she experienced her first panic attack during a business meeting. She noted shortness of breath, feelings of terror, loss of feeling in her arms and legs, and a feeling of being overwhelmed (Table).

This intensified her level of anxiety and she shortly became frightened to drive or to leave her home except to walk next door to the family business and, as a result, became socially isolated. The vasoconstriction in her extremities intensified during her attacks and she began to feel pain in her extremities as though “someone was pouring hot oil over her hands and feet” (while her hands and feet would become “icy cold”). She also noted her nose, ears, and nipples would be affected and that her nipples would become erect and cold, and then excruciatingly painful, as did her hands and feet. These symptoms would reliably occur when she would become frightened, such as when forced to make a sales call or go outside the home to shop. She would also often have an urgent bowel movement accompanied by diarrhea.

None of these autonomic phenomena would be preceded by aura-like phenomena, but were triggered by fear. The pattern of her baseline psychiatric symptoms included problems concentrating due to distractibility, being easily startled, her mind being flooded with thoughts (or, as she described it, “rushing”), a mixture of anxiety and painful awareness (a sensation of being overwhelmed by events, noises, and movement around her), and restlessness. The restlessness could gradually increase to overactivity, agitation, and mild elation with a decreased need for sleep. This was followed by periods of depression, during which she had difficulty falling and staying asleep. These cycles were unpredictable and brief in duration, sometimes lasting only 5 days.

The cycles often began following the patient’s menses. Her premenstrual symptoms were an intensification of her basic mixed anxiety and depressive symptoms and began 7 days prior to her menses as tracked using a calendar. The patient’s gynecologist had prescribed sertraline that helped her depression at a dosage of 50 mg/day, and helped her premenstrual symptoms at a dosage of 100 mg/day 2 days prior to her menses. However, the increased dose of sertraline intensified her anxiety and mood swings at other times. She became severely depressed when the sertraline was discontinued. The patient was referred for psychiatric evaluation.

 

Medical, Social, and Family History

The patient’s medical history was significant for occasional hemicranial migraine headaches that were accompanied by nausea and photophobia. Her aura consisted of nonspecific “vision changes” in her left eye and lessened sensation in her tongue. Computerized axial tomography (CAT) and magnetic resonance imaging (MRI) scans of her brain were read as normal and her neurologist reported her examination as unremarkable. She had not been given an electroencephalogram (EEG). No migraine-specific treatment was required. Her Bell’s palsy was mostly resolved and not noticeable. She was unable to take oral contraceptives as they increased her blood pressure. She was allergic to levofloxacin, trimethoprin and/or sulfamethoxazole, and erythromycin. She had gained 20 pounds since treatment with sertraline began and was unable to reach orgasm. Her two preadolescent children were in good health. She had no accidents, head injuries, operations, or hospitalizations other than for childbirth. She denied a history of fainting or any phenomena reminiscent of seizure activity.

There was a family history of diabetes mellitus, hypertension, cardiovascular disease, and a history of depression in her mother, both sisters, and her maternal aunt. Two family members had been treated successfully with sertraline.

The patient was in a successful second marriage. Both of her children were symptom-free and successful in their academic and social life. The family business was successful. The patient was a college graduate, denied alcohol or drug abuse, and reported no problems with authority figures during her life, but had a difficult relationship with her mother, whom she described as critical and dominating. There was no history of sexual or physical abuse.

 

Mental Status Exam

At initial evaluation the patient presented as an anxious, hyperactive, overstimulated woman who spoke rapidly and whose speech was poorly modulated. She was neatly dressed and of average weight. She tended to become distracted easily and lose her train of thought. Her eyelids were over-retracted and her pupils were 5 mm in diameter and reacted sluggishly to distance and changes in light. Her eyes moved in jerky arcs and she tended to glance quickly about the room as she became distracted.14 Her movements were hesitant and poorly modulated. Her hands, ears, and nose were cool and her hands showed slowed capillary filling after pressure was placed against the skin; they also had a curious pale dusky hue.

She was intelligent, well informed, pleasant, and frustrated by her symptoms. She described herself as easily angered, often losing control of her temper to her later embarrassment and shame. She described herself as being depressed at times but not suicidal, and felt that her main problem was her anxiety. She described her premenstrual symptoms as an intensification of her basic symptom pattern complete with increased irritability and racing of her thoughts. She was unable to stop her anxiety and panic attacks once they started and arranged her life to minimize those activities and situations that she thought triggered the attacks. She described herself as feeling almost constantly “on guard.”

 

Treatment

Due her mood swings, irritability, racing thoughts, and increased anxiety following the increases in her sertraline, a diagnosis of comorbid or primary bipolar disorder was considered and oxcarbazepine 300 mg BID was prescribed with instructions to increase the dose by 300 mg/week to a maximum of 1,200 mg/day. Sertraline was continued and alprazolam 0.5–1.0 mg/day was added as needed to help with panic attacks. At her return in 1 month, she was taking oxcarbazepine 600 mg BID and had noticed improved concentration; her mind had “stopped rushing,” and her extremities (and nipples) were warm and no longer painful. Her premenstrual symptoms had been much improved, but she was still having difficulty sleeping and still felt moderate anxiety in stressful situations.

Her oxcarbazepine dosage was changed to 600 mg in the morning and 900 mg in the evening with remission resulting. The only side effect noted was mild morning sedation. Attempts to decrease the total dosage, or to further decrease the morning dose and increase the evening dose (to maintain the same total daily dose) resulted in an increase in her premenstrual symptoms and a return of her peripheral vasospasm. Returning to her previous dosing schedule brought the patient to her asymptomatic state. Her sedation has gradually abated. Attempts to stop the sertraline to help with weight loss resulted in a return of sustained depressive symptoms. Venlafaxine 37.5 mg BID was substituted with resulting normalization of mood, weight, and sexual functioning. She reported no further need for the alprazolam.

This combination of medications has resulted in a near complete remission of the patient’s affective and depressive psychiatric symptoms, her Raynaud’s phenomenon, and a marked decrease in her migraine headaches. She had earlier noted some “bloating” prior to menses, but has increasingly had no premenstrual symptoms. She is now able to drive about freely and go to public gatherings such as church and shopping malls and has joined her church choir. She has had a decrease in the severity of her allergic reactions to bee, wasp, and fire ant bites. Although she used to required steroid and epinephrine injections, she now responds to diphenhydramine injections alone. Her improvement has been maintained for over 9 months.

 

Discussion

The case patient presented with mixed, rapidly-cycling mania, Raynaud’s phenomenon, peripheral pain accompanying vasoconstriction, migraine, and severe premenstrual discomfort. All these syndromes resolved or improved with treatment, suggesting some commonality of process.

There is evidence of an interaction between the hypothalamic-pituitary-ovarian axis and the HPA axis. Stress can induce amenorrhea and women normally show a hyperresponsiveness of the HPA axis when compared to men.15 Interestingly, when estradiol patches are given to normal men, they then show an increase in plasma cortisol, ACTH, and norepinephrine from baseline when subjected to unexpected stress.16 This patient’s premenstrual symptoms were best described as a cyclical exacerbation of her basic manic process and her panic attacks as a painful, intense exacerbation of the flight-or-flight process causing sensory overload.

In a 10-year study of 135 patients diagnosed with obsessive-compulsive disorder, Perugi and colleagues17 noted that in 27.4% of their patients, symptoms followed an episodic course with periods of remission and exacerbation and that those patients were more likely to respond to mood stabilizers such as lithium. While the patient discussed in this case study did not have periods of remission, her symptoms did vary in intensity and on closer investigation brief cyclical episodes were noted. Perugi and colleagues17 suggested that in some patients obsessive and compulsive symptoms were the “phenotypic expression of an underlying affective genotype.” The case patient’s premenstrual, anxiety, and panic symptoms may well fit that pattern of an affective syndrome mimicking other disorders or making latent syndromes overt.17

In an open case series, Blumer and colleagues18 reported that premenstrual dysphoria responded to a combination of anticonvulsants and antidepressants in both patients diagnosed with and without epilepsy. They noted that chronic epilepsy involving the mesial temporal lobe often results in hippocampal sclerosis and that interictal dysphoria in those patients often results in a syndrome which varies in intensity and presents in a characteristic pleomorphic and intermittent pattern of depressed mood, anergia, irritability, euphoric mood, insomnia, pain, anxiety, and fears. They reported that this syndrome often responded to the addition of modest doses of antidepressants to the optimal antiepileptic regimen. While an EEG was not performed for the case patient, both MRI and CAT scans of her brain were negative and there were no symptoms or history suggestive of a seizure disorder.

 

Conclusion

There is increasing evidence that dysregulation and hyperresponsiveness of the HPA axis plays a role in psychiatric disorders and symptoms.3,19 As the brain structures involved in the HPA are involved in the regulation of physical and emotional equilibrium one might expect to see somatic symptoms as well as emotional distress in such patients’ presentation.1

From the work of Bhanji and Mattingly8 one might suspect that a subgroup of more ill psychiatric patients would show such symptoms. The case patient presented demonstrated or reported mixed, rapid-cycling mania, Raynaud’s phenomena, peripheral pain accompanying vasoconstriction, migraine, severe premenstrual discomfort, and symptoms suggestive of the fight-or-flight process. All these syndromes resolved or improved with treatment. PP

 

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