THE PSYCHIATRY LETTER

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1 THE PSYCHIATRY LETTER Table of Contents Special article: Adult ADD examined Classic study of the month: The NCS study of adult ADD prevalence and predictors Drug of the month: Atomoxetine Case of the month: Treating adult ADD by stopping amphetamines Curbside consults: Questions from you NEW CONTINUING MEDICAL EDUCATION (CME) CREDITS AVAILABLE! Beginning January 2016, receive 1 CME or CEU credit per issue Available to physicians, nurses, and psychologists Subscribe at Questions, comments, cases? Write us at info@psychiatryletter.org The ADD controversy - Part II This issue continues with the theme of Attention Deficit Disorder (ADD), which was also the theme of the last issue of PL, in October The prior issue focused on ADD in childhood. This issue turns to the topic of ADD in adulthood. The special article provides our overall summary of the ADD concept in adults. We examine its diagnostic validity in particular. The classic study of the month examines a widely cited study regarding the prevalence and validity of adult ADD: the National Comorbidity Survey (NCS). PL raises the question of whether the very high co-occurrence of mood illness with reported adult ADD reflects the constant coexistence of two separate diseases, or the presence of concentration impairment caused by mood illness. The drug of the month is atomoxetine, the first agent FDAindicated for adult ADD. The case of the month examines a case of apparent adult ADD, with comorbid depression, that did not improve with amphetamines and antidepressants. As usual citations and references can be found on the web version of the newsletter. As noted in the side bar, PL is pleased to announce that we can begin to offer CME and CEU credits to physicians and nurses and psychologists beginning with the January 2016 issue. We hope this will provide our readers with another reason to continue reading PL. We are coming up on our one year anniversary with the January issue, and your subscription will be up for renewal soon or in the coming year. We hope you renew and take advantage of CME/CEU credits through your reading. Nassir Ghaemi MD, Editor New truths begin as heresies and end as superstitions - T. H. Huxley The Psychiatry Letter Volume 1, Issue 11 1

2 Last month s special article focused on childhood ADD. We come now to adult ADD. It is worth noting that the concept hardly existed before Eli Lilly marketed the drug Strattera (atomoxetine) for it about a decade ago. Before then, the general consensus of researchers was that ADD did not persist into adulthood in the vast majority of persons. 9 prospective studies were conducted before Strattera came to the US market in 2003; in a total of 718 persons followed for years from childhood into adulthood, from a mean of age 10 to age 25, the prevalence of ADD fell by 90%. In other words, only 10% of children with ADD continued to have it in their mid 20s. This observation contrasts with the common opinion these days that the majority of children with ADD will continue to have it as adults. Post-strattera research, often funded by pharmaceutical companies marketing adult ADD, report higher rates of persistence into adulthood, but even then, the full ADD syndrome is reported to be present in only about 40% of children followed to age In other words, the majority still lose the diagnosis by early adulthood. Now the claim is made that despite syndromic remission, ADD symptoms still persist and cause functional impairment. But, even if so, it is worth noting that all studies show that the majority of children with ADD have syndromal remission by about age 18: they no longer meet ADD criteria. Again, the question of treatment comes up. In general, in these studies, some children are treated and some are not, and the studies do not assess outcomes based on treatment in any systematic fashion, nor are they randomized. Thus Special article: Adult ADD examined Why it s normal to be inattentive Why should pneumonia always happen with fever disorder? they cannot answer this question, but since a good number of the study subjects are untreated, it cannot be assumed that the results are the effect of treatment. Natural history still remains an important possible interpretation of the results. The most cited recent data represent the National Comorbidity Sur vey (NCS) epidemiological study in the US, which found that about 3% of adults are diagnosable with ADD, which means that they meet criteria as adults in a current cross-sectional assessment as part of the NCS study, and that they retrospectively met those criteria as children. The classic article of the month in this issue examines that study in detail. The key aspect discussed there is the finding that 45% of those who met adult ADD criteria also met bipolar disorder criteria and 39% of those who met adult ADD criteria also met major depressive disorder (MDD) criteria. In other words, 84% of those who can be diagnosed with current adult ADD are also diagnosable with current bipolar disorder or MDD. Here is the question: What causes what? Are they just unlucky, and every time they have one disease they have two diseases? Or does the ADD cause depression, as many ADD experts assume? Does ADD also cause recurrent manic episodes? This would seem biologically implausible. At least in the case of bipolar illness, the proponents of the adult ADD diagnosis haven t explained why almost half those patients also have manic episodes. They haven t explained why we should believe they have two diseases, when one disease could explain all the symptoms, since a The Psychiatry Letter Volume 1, Issue 11 2

3 cardinal feature of mania is distractibility. Why should pneumonia always happen with fever disorder? ADD at age 41 One of the most interesting studies (RG Klein et al, Archives Gen Psych Dec 2012, 69: ) that can add to this literature was a recent publication that represents the longest prospective outcome of ADD: a 33 year outcome study following children diagnosed with ADD at age 8, and compared with matched controls who did not have ADD. They were all followed to age 41. Here is an interesting observation: ADD was diagnosable in the control group in 5% as adults. These were children who were NOT assessed to have ADD as children, but simply chosen at random from matched controls, and then they met the criteria 30 years later. NCS study for adults who had persistence of childhood ADD. Here is one potential explanation: the 5% who did not have ADD in childhood but met adult criteria are simply adults who have statistically abnormal attention spans. They don't have a disease, and they don't have a developmental delay of the maturing brain; they are just at an extreme of the normal curve for the cognitive trait for attention. Recall that most psychological and biological traits are distributed on a normal curve in the general population, as shown in the figure. Most of us are at or near the 50th percentile. At 2 standard deviations from the middle of the curve, on each end, there is about 2% of the population. This is not disease, and it is not disorder. Some people are short, some are tall; some are skinny, some are not; some are shy, some are extroverted; How is this possible? This is not adult ADD, because the diagnosis is supposed to reflect persistence of childhood ADD, but this group did not have childhood ADD, and yet it is almost twice as large as the prevalence claimed in the some are hyper focused in attention, some are distractible. 4-5% in fact. So what is adult ADD? Could it just be the extreme of the psychological trait of attention, which is not a bad thing. The Psychiatry Letter Volume 1, Issue 11 3

4 Too much attention disorder If we think about attention as a cognitive trait with a normal curve, you might ask the question: Are we humans supposed to be highly attentive? Nature seems to have evolved in such a way that many of the symptoms which we treat are in fact quite normal when present to a mild to moderate degree. It s normal to be somewhat anxious. It s normal at times to be sad. It s normal even to be somewhat illogical in our thought processes. These are all proven to be common traits in the normal population. All are distributed as in an inverted U-shaped curve. What about attention? Is it normal to be a little inattentive? Of course it is. What would life be like if you focused on every little thing that crossed your mind? You would have this idea, then that, then another; you would focus on one, then the other, then the next. It is normal to filter sensations and thoughts, and focus on some but not others. Inattention is normal. When we have no filter, and attend too much to all our thoughts and feelings, we are psychotic. That is the nature of the thought disorder of schizophrenia. It is not an accident that amphetamines are used as an animal model of psychosis. Too much attention is psychotic. That s why we are selected to be normally inattentive. And some people are more inattentive than others. That is expected for any normal psychological trait. It s not a disease; it s an extreme of a natural trait. One might say that even if this is the case, inattention should be treated if it is causing functional impairment. This may be defensible, or perhaps not. We treat the extreme of the normal trait of blood pressure, but not because it causes functional impairment. In fact, it is famous for having no symptoms at all, for being silent. We treat high blood pressure because it later causes certain diseases, like coronary arter y disease or stroke. What future diseases does inattention cause? None that we know of. Still, one might argue for treatment for current functional impairment. But as discussed the last PL issue's Classic Study of the Month (the MTA study), even if this is the case, non-medication treatments are as effective as medication treatments for functional improvement of ADD. A final comment: In the 33 year prospective study, 78% of subjects with childhood ADD were no longer diagnosable with it as adults. Again, the older literature seems closer to the truth that the majority of children with ADD (about 80% in this study) will not have it as adults. Clinicians need not feel impelled, as is the case these days, to continue amphetamine medications long-term for decades and decades, on the assumption that once the ADD diagnosis is made, then long-term treatment is entailed. The Psychiatry Letter Volume 1, Issue 11 4

5 Mood temperaments A final important clinical consideration in analyzing apparent adult ADD is the concept of mood temperaments. This concept is highly under appreciated in contemporary psychiatry. The terms dysthymia and cyclothymia are in DSM, and are thus known, but they are misused or not used at all. Most commonly, dysthymia is used as a comorbidity along with MDD or other conditions. In contrast, cyclothymia is not used as a comorbidity, but is thought to be exclusive of the diagnoses of MDD or bipolar illness. The mood temperament of hyperthymia, or mild constant manic symptoms, is not known by most clinicians, mainly because it is not included in DSM. All three terms, described in more detail in the PL website, were originally developed about 100 years ago by Kahlbaum and Kraepelin, and later expanded by Ernst Kretschmer, to reflect biological and genetic variants of the diseases of severe depression or manic-depression. They were present as mild forms of those diseases in relatives of persons who had the full disease. In many persons with the full disease states, those mood temperaments also were present in between the clinical episodes of depression or mania. In other words, they are not comorbidities because mood temperaments are not diseases in themselves; they are personality traits in persons, or their relatives, who have mood diseases. If you are depressed all the time mildly, or manic all the time mildly, or back and forth between mild depression and mild mania all the time, you will not have good concentration. This is because concentration is impaired in both manic and depressive states. Hence it is commonly the case that adult ADD is mistakenl y dia gnosed in persons with hy perthymic personality, or cyclothymic personality, or dysthymia. The affective symptoms are chronic, and hence the attentional impairment is constant. But the causal source may be the affective temperament, not a separate disease of adult ADD. The PL experience is that these patients improve in their affective symptoms, including inattention, with low-dose mood stabilizers whereas amphetamines either provide only partial or inconsistent benefit. The PL Bottom Line Adult ADD likely reflects an extreme of the natural trait of attention. The best evidence that adult ADD is not likely to be a valid independent disease entity is that it almost always occurs with mood illnesses, which themselves cause inattention. In the longest follow up into middle age, similar inattention is seen in adults without past ADD as in adults with childhood ADD. Apparent adult ADD often reflects mood temperaments, like hy perthymia and cyclothymia. Further reading Much of the material presented here is discussed in detail with full citations in D Vergne et al, Adult ADHD and amphetamines: A new paradigm. Acta Neuropsychiatrica, 2011, 1: The Psychiatry Letter Volume 1, Issue 11 5

6 Classic study of the month A widely-cited study doesn't show what the authors claim Patterns and Predictors of Attention-Deficit/Hyperactivity Disorder Persistence into Adulthood: Results from the National Comorbidity Survey Replication. R. C. Kessler et al, Biological Psychiatry 2005;57: Most adult ADD represents mood diagnoses Recently one of the authors of this paper gave a talk about ADD in which he cited this study to support the validity of adult ADD. This paper is an analysis of the National Comorbidity Survey (NCS) epidemiological study. In the NCS project, researchers knocked on doors all across the United States to identify the frequency of various DSM-based psychiatric diagnoses. This is the study that is used for basic citation of frequency of many diagnoses. In this analysis, the NCS lead researchers collaborated with ADD experts to identify the frequency of ADD diagnosis in the young to middle age adult population of the US, based on a sample of 3197 subjects, aged Overall, they found that ADD was diagnosable in 3% of this general population sample. This was defined as persistence of childhood ADD. To clarify, 8.1% of the NCS adult sample was identified a s ha ving been dia gnosable retrospectively with childhood ADD. Of this group, ADD persisted into adulthood in 36.3%. So the overall adult prevalence rate was 2.94%. ADD will not have persistence into adulthood. These days, many clinicians practice as if the majority, or almost all, cases of ADD in children or adolescents will persist into adulthood. It is routine practice to continue amphetamines for childhood ADD into young adulthood. Once the growing child enters college, amphetamines are not stopped. They often are continued well past college, into the decade of the 20s. Yet, this study, so often cited by supporters of the adult ADD diagnosis, shows that the reverse should be the case: In 2/3 of children and adolescents, amphetamines should be stopped before they Most children - namely 2/3 - with ADD will not have persistence into adulthood. reach the age of 18, if such treatment is based on the claim that they will continue to meet the dia gnostic definition of adult ADD. The most important finding in this NCS analysis, though, is one that the authors don t emphasize. The researchers looked at comorbidities of adult ADD, based on the careful identification of other DSM diagnoses, which was the main purpose of the NCS epidemiological study. This study is the basis for many claims. One is the idea that ADD is common in adults, happening in about 3% of the general population. Further, it supports the claim that ADD persists in a substantial portion of children into adulthood, namely about one-third of persons. Note that if we take these results at face value, one could turn the interpretation around and conclude that most children - namely 2/3 - with In this analysis of comorbidities, the NCS study found that persons diagnosable with adult ADD could also be diagnosed at the same time with the following diagnoses in the percentages provided in Table 3 of the paper (page 1447): Major depressive disorder % Bipolar disorder % Dysthymia % The Psychiatry Letter Volume 1, Issue 11 6

7 The absolute frequency of these diagnoses was 15.0% for MDD, 10.4% for bipolar disorder, and 7.6% for dysthymia. We will put off the discussion of dysthymia for now, for later discussion in this article on the subject of mood temperaments. It is notable, though, that over one-half of all cases of apparent adult ADD involved the mood temperament of dysthymia. Since depressive symptoms include poor concentration, this comorbidity becomes a major logical problem. How can you say that people have a chronic cognitive condition of poor attention (the claim of adult ADD) when they have another chronic cognitive condition of poor attention (dysthymia)? Turning to other conditions among the adult ADD subjects, there were high rates of other diagnoses, as well, especially anxiety disorders (49.9%, post- traumatic stress disorder, PTSD; 34.4% generalized anxiety disorder, GAD) and substance abuse (40.2% alcohol abuse, 31.4% other drug abuse). Now one can certainly claim, as the authors do, that these are associations with adult ADD; namely, that if you have the adult ADD diagnosis, you ll also run into other problems, such as abusing dr ugs or alcohol. This is not unreasonable; the same interpretation exists with mood illness, for instance, where many patients abuse substances as a result of having mood illness (often as self-medication). In the list of comorbidities, many overlap with each other; for instance, one can have PTSD and also meet criteria for GAD and dysthymia. But two diagnoses are exclusive; you cannot make one if the other is present: MDD and bipolar disorder. 84% of all subjects with adult ADD also met criteria for either MDD or bipolar disorder.. If we look at those two exclusive mood diagnoses, MDD was present in about 39% and bipolar disorder was present in about 45%. Since they are mutually exclusive, this means that a total of 84% of all subjects with adult ADD also met criteria for either MDD or bipolar disorder. Now, here is the key question: Is this a mere association? There are three possibilities: 1) there is no such thing as adult ADD: almost all the time (84% of cases), it is caused by depression or mania; 2) adult ADD causes depression or mania almost all the time (84% of cases); 3) adult ADD cases are unlucky; almost every time they get the ADD diagnosis (84% of cases), they also get an independent and unrelated disease of depression or mania. The third possibility is biologically implausible. Nature doesn't tend to give two diseases every time to patients who are unlucky enough to get one disease. You don't get diabetes 84% of the time that you get diagnosed with cancer. That leaves the other two causal possibilities: either the mood illnesses cause apparent adult ADD, or adult ADD causes the apparent mood illnesses. The last claim is made by ADD experts, when pressed on this issue. Adult ADD is such a terrible experience, they claim, that patients become depressed a lot, hence the 39% prevalence of apparent MDD. They also become quite anxious about half the time, and have terrible life experiences, hence the 34-50% prevalence of GAD and PTSD. The Psychiatry Letter Volume 1, Issue 11 7

8 Adult ADD explains almost everything - except There is a deep flaw in this rationale: ADD proponents cannot claim that adult ADD causes mania. They cannot explain away the 45% prevalence of bipolar illness, which means that those subjects experienced manic or hypomanic episodes. There is no biological or clinical rationale that can claim that adult ADD causes manic or hypomanic episodes. This leaves only one other possibility. Even if interpreted mostly charitably, about onehalf of apparent cases of adult ADD likely represent manic or hypomanic episodes, i.e., bipolar illness. It is well known that depression and anxiety both are mental states that impair concentration and cognitive function. Thus, if we allow that at least some of those apparent cases of ADD were caused by anxiety or depressive illnesses, as opposed to the reverse, then we can make the following claim: Almost half of all cases apparent adult ADD are caused by bipolar illness, and another subgroup are caused by depressive and anxiety illnesses. This analysis would lead to a conservative interpretation that the majority of cases of claimed adult ADD are caused by either bipolar or depressive or anxiety illnesses. This analysis would lead to a conservative interpretation that the majority of cases of claimed adult ADD are caused by either bipolar or depressive or anxiety illnesses. in the special article, attention is a normal cognitive trait, which, like most physical traits, is distributed on a statistical normal curve. This means that 95% of observations occur within 2 standard deviations in either direction from the 50th percentile. In other words 2.5% of the population will be at one extreme or the other. 1% would be observed at over 2 standard deviations from the mean. This observation would be expected with any normal trait; it doesn't reflect a disease process necessarily. One could take another view. If we accept that anxiety and depressive states cause inattention and cognitive impairment, and we consider those conditions as primary to apparent ADD, then we could say that almost all cases of apparent adult ADD reflect either bipolar illness, depression, or anxiety conditions. In this latter interpretation, adult ADD more or less disappears as a concept. When the PL editor raised the bipolar comorbidity aspect of the NCS study with one of the NCS authors recently, the NCS author wasn't even willing to admit the 45% comorbidity rate. This reaction is an example of how human beings ignore data that conflict with their beliefs. The PL Bottom Line In other words, the 3% prevalence rate of adult ADD is not what it seems. Independent adult ADD, not attributable to another psychiatric cause, would be a minority of that 3% prevalence, perhaps about 1/3 or so, leading to about a 1% true adult ADD prevalence rate. This 1% or so rate would be consistent with the concept of an extreme of a normal trait. As noted About one-half of adult ADD involves cooccurrence with manic/hypomanic states. About 84% of all cases of adult ADD co-occur with either mania or depression. About one-third to one half of cases of adult ADD involve co-occurrence of anxiety conditions (PTSD or GAD). The Psychiatry Letter Volume 1, Issue 11 8

9 The most plausible explanation of these apparent comorbidities is that at least half, and probably the majority, of cases of apparent adult ADD in fact reflect cognitive symptoms of bipolar illness and/or depressive or anxiety states. Over one-half of apparent adult ADD cases occurred in persons with dysthymia, another chronic condition associated with attentional impairment. In short, the claim of an independent ADD disease is not supported by the many other conditions documented in the NCS study which cause attentional impairment. PL Reflection I believe we may safely affirm, that the inexperienced and presumptuous band of medical tyros, let loose upon the world, destroys more of human life in one year, than all the Robinhoods, Cartouches and Mcheaths do in a century...i wish to see a reform, an abandonment of hypothesis for sober facts, the first degree of value set on clinical observation, and the lowest on visionary theories. Thomas Jefferson letter to Dr Caspar Wistar 1807 Clinical Tip of the Month: Diagnose the causes of attentional impairment, not adult ADD When faced with a case of apparent adult ADD, either diagnosed by others or self-diagnosed by the patient, apply the concept of a diagnostic hierarchy. Is a mood illness - a clinical depressive or manic/hypomanic episode - present? If so treat it directly, with a mood stabilizer or monoamine agonist (antidepressant), and see if the attentional symptoms improve. If a mood illness is not present, see if an anxiety condition is present, most commonly generalized anxiety or obsessivecompulsive disease. If present, treat them with anxiolytics, and see if the attentional symptoms improve. If neither mood or anxiety conditions are present, see if a mood temperament is present: dysthymia, cyclothymia, or hyperthymia (mild manic symptoms as part of temperament, see PL website). If they are present, treat with low doses of mood stabilizers or monoamine agonists, and see if attentional symptoms improve. If the above differential diagnosis is applied, very few if any patients will remain who could be claimed to have adult ADD. With the above approach, amphetamines would rarely, if ever, be justified for the sole purpose of treating attentional symptoms occurring in the absence of any other possible causal condition. The Psychiatry Letter Volume 1, Issue 11 9

10 Drug of the Month: Atomoxetine An antidepressant masquerading as an ADD drug This medication is a norepinephrine reuptake inhibitor, initially developed as an antidepressant. It was brought to the market as the first drug for adult ADD, rather than one of the last for depression. It differs notabl y f rom other stimulants though in its mechanism and risks. Clinical efficacy and inefficacy In early clinical trials, this agent was found to be effective in major depressive episodes. It was noted that it shared its basic mechanism of pure norepinephrine effects with desipramine, which had been proven effective in childhood ADD. Eli Lilly, the company which was developing atomoxetine, made an economic decision to shift to ADD, rather than major depressive disorder (MDD), but even in ADD, there were multiple other agents, mostly amphetamines, that were FDA-indicated in children. However, no agents were FDAindicated in adults for ADD. Indeed, the whole concept of adult ADD was not used much, and it was not part of DSM-IV. Side effects and dosing The main side effect of this agent, as with the other pure noradrenergic drug desipramine, is anxiety and feeling agitated or overstimulated. D e s i p r a m i n e, Fast Facts: Atomoxetine (Strattera) Typical dose: mg/d (range: mg/d ) Biological mechanism: Norepinephrine reuptake inhibitor Typical side effects: anxiety, insomnia Less common but important side effects: none Medically important side effects: none Clinically proven efficacy: Treatment of major depressive episodes and ADD which is a t r i c y c l i c antidepressant, was also associated with c a r d i a c arrhythmias, but this has not been the case with atomoxetine. The clinical trials with atomoxetine showed some cases of increased suicidal thoughts with this agent, versus no cases with placebo, which led to a FDA black-box warning in The PL Bottom Line Atomoxetine is an antidepressant masquerading as a stimulant for adult ADD. It is a norepinephrine reuptake inhibitor, like desipramine, which tends to cause anxiety. After obtaining academic support, Eli Lilly convinced the FDA to provide the first indication for ADD in adults. The latter designation was then added to DSM-5. Biological mechanism Atomoxetine blocks reuptake of norepinephrine at the synapse. Unlike other stimulants it does not have direct or indirect agonism of dopamine activity. PL Reflection And what goal could be more sacred than that of caring for a brother in distress, especially when the affliction is distinctly human and therefore more obvious than others, and when it respects neither reason nor rank nor riches? Emil Kraepelin The Psychiatry Letter Volume 1, Issue 11 10

11 Case of the month: Not ADD, not chronic fatigue, not depression A 23 year-old female seeks consultation for unremitting depression and ADD. She had been first diagnosed at age 15 with chronic fatigue syndrome. A medical workup for possible causes of exhaustion was negative. Eventually her doctors decided to treat her with amphetamine stimulants to give her energy. Since age 16, she has taken one amphetamine or another, beginning with methylphenidate, later Concerta, and later Adderall. In the past year, she began to see psychiatrists, who changed her diagnosis from chronic fatigue syndrome to major depressive disorder. They continued Adderall and added various serotonin reuptake inhibitors (duloxetine, fluoxetine, sertraline) without success. She was changed eventually to bupropion. On evaluation, she was taking Adderall 20 mg twice daily plus bupropion SR 150 mg twice daily. Besides exhaustion, her parents report that she has marked insomnia and notable cognitive impairment. Her sleep is quite poor: she stays up very late, and has multiple awakenings in the night, followed by tiredness during the day. Her cognition is poor also, with very impaired working and verbal and short term memory. She has been slowed down in her college studies to the point that despite 5 years of college, she has only completed her sophomore year. She has a great deal of trouble organizing herself for her college work and paying attention in class and in memorizing material for tests. Adderall gives her 30 minutes glimpses of normality. After she takes the medication, she reports that she feels like myself for about half an hour, with improved concentration and energy and mood, but then she goes back into her usual depressed, low energy, poor concentration state. She has these depressive symptoms continually, but 2-3 times per week, she has about 1-2 hours of spontaneous high energy states: I feel elated, happy, like I can convince anyone to do anything. I try to do things, but it doesn't last long enough for me to do anything. My thoughts go fast, I talk a lot, I feel super smart briefly, and then I m back to my usual unhappy slowed down state. She reports repeated suicidal thoughts and wishes she was dead, but she has not tried to harm herself. She and her family deny past manic or hypomanic episodes lasting 4 days or longer. One psychiatrist suggested that she had type II bipolar illness, but he continued Adderall and added lithium 900 mg/d immediately. She stopped lithium after two days due to heart palpitations. Family history provides evidence for a paternal aunt with severe depression that required ECT. All other illness is denied. Medical history is otherwise normal and she has no drug allergies, nor does she abuse alcohol or drugs. She has no trauma history. She has had no psychiatric hospitalizations or suicide attempts or self-harm or dissociative or psychotic states, and no eating disorder symptoms. The PL diagnosis is that she is experiencing current mixed depressive states, as described in the PL February 2015 issue. The broader The Psychiatry Letter Volume 1, Issue 11 11

12 diagnosis is manic-depressive illness, or one might use the term bipolar spectrum illness. These diagnoses reflect brief manic states that occur as part of recurrent depressive episodes. The illness is not pure depression, since manic symptoms are present, nor does it represent classic bipolar illness, since full manic or hypomanic episodes are not present. Hence the concept of bipolar spectrum illness can be used to reflect being in the middle of the spectrum between pure depression and full manic or hypomanic episodes. The PL recommendation was to taper off Adderall and bupropion and to resume lithium again, this time in slow titration and in the absence of any antidepressants/amphetamines. This recommendation is explained below: readers will recall that bupropion is an amphetamine in its pharmacological structure - all the more reason to stop it. This patient s apparent adult ADD had not improved with amphetamines because it was driven by her mixed depression. Until the mixed depression improves, the ADD will not improve. Since amphetamines worsen mixed depression, cognitive ADD-like symptoms persist. Lithium is the best agent to choose partly because of its direct suicide prevention benefit, given that this patient has clear suicidal ideation and notable risk for suicide. Specific PL recommendations were as follows: Readers should keep in mind that all amphetamines are antidepressants. They were introduced as the first class of antidepressants in the 1930s. Thus, like all antidepressants, they can have negative effects in bipolar illness of causing/ worsening mania, or causing/worsening long-term rapid-cycling. In the case of mixed depression, as discussed on the PL website and in the February 2015 issue, antidepressants seem to worsen mixed states, thus causing more depressive and manic symptoms. They especially seem to worsen suicidality and impulsivity. In an analysis of mixed depression as described by Koukopoulos, antidepressants caused three times more suicide attempts in person with mixed depression when compared with those treated without antidepressants. Further, a s mood-destabilizing a gents, amphetamines and antidepressants counteract the benefits of mood stabilizers, like lithium. Thus, it is not enough to just add lithium. Adderall and bupropion need to be stopped also. Further, Reduce Adderall to 20 mg daily for 2 weeks, then 20 mg every other day for 2 weeks, then stopped. Reduce bupropion to 150 mg daily for 2 weeks, then stopped. At the same time, begin lithium at 300 mg at night for 1 week, then 600 mg at night for one week, then 900 mg at night, seeking a level close to 0.8. The PL expectation would be that the patient would get worse before getting better, with amphetamine withdrawal leading to worsened energy and concentration and possible clinical depression. This could be the course for a few months, but then the patient would be expected to improve gradually on lithium alone, possibly with later combination with dopamine blockers and/or other mood- stabilizing anticonvulsants such as lamotrigine. PL Reflection Nearly all men die of their treatments, not their diseases. Moliere (1673) The Psychiatry Letter Volume 1, Issue 11 12

13 Curbside consults: Questions from you Question: What are your thoughts on the common combination of amphetamines and benzodiazepines? This is so very common and even worse in patients with substance abuse. PL: This common combination makes sense, in a rather absurd way. Amphetamines cause anxiety, which is then treated with benzodiazepines. Another relevant reason for the combination is that anxiety states, as discussed above, often cause impaired concentration. Such patients then get mistakenly diagnosed with adult ADD, and treated with amphetamines, which worsen the underlying anxiety that caused the inattention to begin with, hence the addition of benzodiazepines. In short, the effect is mistaken for the cause, and inattention is treated with amphetamines which worsen the causal anxiety, leading to further treatment with benzodiazepines. Both classes of agents are addictive potentially, but at least in animal models, amphetamines appear to produce more addictive behavior than benzodiazepines. Certainly the former have more evidence of neurotoxicity harm, as reviewed in last month s PL issue, than the latter. Thus, the PL perspective is that if a patient has an anxiety condition, that is not due to some other diagnosis like a mood illness, then it is reasonable to treat that anxiety condition with benzodiazepines. If such anxiety states cause poor concentration, then those inattention symptoms should improve with benzodiazepines alone, without the need to add amphetamines. The use of amphetamines in persons with anxiety conditions is self-defeating, as is the case with using those a gents in bipolar illness. Amphetamines worsen anxiety and manic states, hence they worsen anxiety and bipolar illnesses. The only condition which they do not worsen is pure depression, where they had been used for years as primary antidepressants. As reviewed in the classic article above, it is reasonable to conclude that most apparent cases of adult ADD in fact represent inattention symptoms caused by other diseases, most commonly bipolar illness, but also anxiety conditions. Thus, if anxiety diagnoses are made, the PL recommendation is that adult ADD should not be diagnosed, and the anxiety condition be treated, with benzodiazepines or in some cases with serotonin reuptake inhibitors. In most cases, attentional symptoms then resolve with treatment of the underlying cause, without ever needing to use amphetamines. PL Reflection The young physician starts life with twenty drugs for each disease, and the old physician ends life with one drug for twenty diseases. William Osler The Psychiatry Letter Volume 1, Issue 11 13

14 Historical insights Emil Kraepelin looks back at the prior 100 years of psychiatry in Compare his observations with the next 100 years. If we compare the situation of mental patients perfect health. Our treatment probably makes today with the circumstances that prevailed a century ago, the revolution that has been accomplished comes into clear focus.one by one prejudices have been overcome, abuses and cruel practices eliminated, new means found to alleviate mental diseases. Spearheading this advance was the growing body of scientific knowledge relating to the nature and etiology of insanity and deriving from study of data in different fields of investigation and from overall progress of the science of medicine. Unrelenting effort on the part of a large number of alienists gradually transformed the sad lot of the mentally ill, with the result that today we are actually nearing the end of our struggle. To be sure there are still many defects to be remedied and improvements to be made, but we are not being presumptuous in stating that we have discovered the approach to be followed henceforth in psychiatry. Our satisfaction over the progress already made is tinged with regret. When we consider the extraordinary sacrifices made by those responsible for the evolution of psychiatry, we are constrained to lament the fact that all the hopes tied to it can never be fulfilled. We must openly admit that the vast majority of patients placed in our institutions are according to what we know forever lost, that even the best of care can never restore them to life endurable for a vast number of mental cripples whose plight would otherwise be intolerable, but only rarely does it effect a cure. We must therefore ask if there are other, more promising, approaches. The answer is a resounding yes. Most promising is the prevention of insanity The nature of most mental disorders is now obscured. But no one will deny that further research will uncover new facts in so young a science as ours; in this respect the diseases produced by syphilis are an object lesson. It is logical to assume that we shall succeed in uncovering the causes of many other types of insanity that can be prevented - perhaps even cured - though at present we have not the slightest clue; a case in point was cretinism before the discovery of the thyroid treatment. The great war in which we are now engaged has compelled us to recognize the fact that science can forge for us a host of effective weapons for use against a hostile world. Should it be otherwise if we are fighting an internal enemy seeking to destroy the very fabric of our existence? PL comment: Kraepelin, a great late 19th century psychiatric leader, identified the basic distinction between schizophrenia (dementia praecox) and manic-depressive illness. These are his reflections near the end of his career, in Emil Kraepelin, One Hundred Years of Psychiatry, NY, Citadel Press, 1962, pp Nassir Ghaemi MD. All material is copyrighted by Nassir Ghaemi. It can be reproduced with proper attribution to The Psychiatry Letter. The Psychiatry Letter, P. O. Box 69, Arlington MA Editor and Founder: Nassir Ghaemi MD. Managing Editor: Alcides Albuquerque MD. The Editorial Board can be found on A monthly independent newsletter not owned, operated, or affiliated with any organization. It receives no financial support from any source other than subscribers. Disclosures: In the past 12 months, Dr. Ghaemi has received speaking honoraria from Sunovion Pharmaceuticals. In the past 12 months, no relationships with the pharmaceutical industry exist for any other members of the PL Editorial Board. Disclaimer: The medical information provided in this newsletter is information based on general scientific knowledge and/or clinical experience.. It is not specific advice intended for individual treatment of a specific patient as would be provided in an in-person professional consultation. If users need specific medical advice for specific treatment decisions, they should consult an appropriate medical professional. No warranties are given in relation to the medical information supplied. The Psychiatry Letter Volume 1, Issue 11 14