Rif S. El-mallakh, MD

[[{"type":"media","view_mode":"media_crop","fid":"13920","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_3528999163116","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"652","media_crop_rotate":"0","media_crop_scale_h":"118","media_crop_scale_w":"160","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]The aggregation of psychiatric diagnoses in individual psychiatric patients, ie, the presence of multiple disorders in one individual, is a curious and sometimes disturbing observation in psychiatry. Several explanations have been put forward to explain this, including the clustering of different disorders in some unlucky individuals, overlap in symptomatic expression of different disorders, inadequate or inaccurate diagnostic criteria, incompetent diagnosticians, and shared biological underpinnings. Now comes evidence that there may indeed be shared risk factors across multiple psychiatric disorders.

Cross-Disorder Group of the Psychiatric Genomics Consortium

, led by Jordan Smoller, MD, performed a meta-analysis of multiple genetic data sets that encompass 33,332 psychiatric patients and 27,888 non-psychiatric controls.

 Patients who were in the sample had diagnoses of bipolar disorder (BPD), schizophrenia, MDD (unipolar depression), autism spectrum disorders, and ADHD. The researchers applied multinomial logistic regression analyses to the association of single nucleotide polymorphism (SNP, pronounced “snip”) markers across the entire genome (genome-wide analysis). They found that 4 areas of the human genome on the short of chromosome 3 (3p21) and the long arm of chromosome 10 (10q24), and SNPs within 2 calcium channel genes (

) had some association with all 5 disorders. The results have multiple implications.

The findings suggest that psychiatric diagnoses may have symptomatic and syndromal overlap because they share the same pathoetiologic genes. In other words, the reason a psychiatric patient has 2 or 3 different diagnoses may be because of a single genetic contribution, or a small set of shared genetic contributions. This would go a long way to explain why so many psychiatric patients have so many psychiatric comorbidities.

One of the most important contributions of this report is the idea of 

 Pleiotropy is the ability of different abnormalities of the same gene to cause different clinical manifestations in different conditions. The best example of this is the L-type voltage-dependent calcium channel (

), which has been associated with BPD, schizophrenia, MDD, and Timothy syndrome.

 Abnormalities in the CACNA1C protein coding are also associated with hypertension, arrhythmias and sudden cardiac death, and seizure disorders.

 Thus, pleiotropy may also help explain the increased presence of associated medical illnesses in psychiatric disorders. Pleiotropy certainly complicates the understanding of pathogenic processes, but it is an important concept. The introduction of the concept of pleiotropy into our search for causes of psychiatric disorders is a huge step forward.

However, one needs to also be aware of the limitations of these data. First, it is important to understand the design. The study used unique markers in the genome to determine which 

 of the chromosome is related to illness. Thus, in addition to the 2 calcium channel genes that may have pleiotropic actions, the data suggest that a gene or group of genes, close to 4 nonspecific markers, on chromosomes 3 and 10 are related to the 5 psychiatric diseases studied. Given that genes tend to reside in clusters that are related to their function, it could very well be that there are independent genes for each one of these conditions that all reside in the same general area. If this were true, the data would still explain why comorbid diagnoses exist, since sections of DNA tend to travel together. The study does not reveal what the genes on chromosomes 3 and 10 might be, or what they might do. Those investigations would occur in the future if this finding was replicated.

One of the most important limitations of this study is that it reports an

. There are many phenomena that are associated with but not caused by each other. For example, a 

specific SNP that has been related to bipolar illness

 was found to have no functional significance when investigated further.

 In other words, associations must always be confirmed by experiments that examine the potential causal connection between the gene and the associated condition. This limitation seriously constrains the conclusions that can be drawn from the study.

The most important finding of genetic studies is the documentation of the extent of assortative 

. Random mating may be how Gregor Mendel uncovered some of the principles of heredity, but it is not the rule in human mating behavior.

 Rather, human mating is not at all random. Among people with BPD, the likelihood of pairing with an individual with a family history of a mood disorder is approximately 70%.

Assortative mating occurs with all psychiatric conditions. What that means is within any population, genes from people with mood disorders are continuously concentrated from one generation to the next. This is true for all genes, not just ones responsible for causing the illness. Thus, when you perform a study that relies only on finding an association between the illness and a gene, you can expect to find many false leads. Since this study used only people from Europe, a small continent where this phenomenon of in-breeding has been happening for thousands of generations, the likelihood of false leads increases. So one must be careful with the conclusions drawn, even with exciting studies such as this one.

The promise of molecular psychiatry is great. Ongoing work will clarify diagnoses and pathophysiology and will focus treatment. This study has raised the fascinating possibility that many psychiatric disorders share the same genes, but that these genes may cause different phenotypes under different circumstances to produce a wide array of interrelated signs and symptoms.

Dr El-Mallakh is Professor and Director of the Mood Disorders Clinical and Research Program, and Dr Tasman is Professor and Chairman in the department of psychiatry and behavioral sciences at the University of Louisville School of Medicine, Louisville, Ky. They report no conflicts of interest concerning the subject matter of this article.

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Articles

The aggregation of psychiatric diagnoses in individual psychiatric patients, ie, the presence of multiple disorders in one individual, is a curious and sometimes disturbing observation in psychiatry. 

Shared Risk Factors in Multiple Psychiatric Disorders

Bipolar disorder is a clinically challenging condition. In addition to the multiple mood states that patients can experience, the illness is frequently associated with multiple comorbid medical and psychiatric conditions. Bipolar disorder can best be understood as a family of related disorders that share core features of mood or affective variation, impulsivity, propensity toward substance abuse, and predisposition to other psychiatric conditions.

 Most patients who have bipolar disorder have a coexisting anxiety disorder.

 These include generalized anxiety disorder (GAD), social phobia, panic disorder, and PTSD.

 Anxiety disorders, by themselves or in combination with a mood disorder, are associated with an increased risk of suicide and psychosocial dysfunction.

The prevalence of comorbid bipolar and anxiety disorders (with the exception of simple phobias) is high in youths. For example, it is at least twice as high as comorbid anxiety and disruptive behavior disorders. GAD and separation anxiety are the anxiety disorders most commonly associated with bipolar disorder. In children with type I bipolar disorder, comorbid anxiety predicted greater dysfunction, manifested by earlier onset of bipolar disorder and more frequent psychiatric hospitalizations.

A comorbid anxiety disorder in bipolar patients greatly complicates the presentation, the interpretation of symptoms, and the treatment of bipolar disorder, and it negatively alters the prognosis.

Anxiety disorders comorbid with bipolar disorder

 In the Epidemiologic Catchment Area (ECA) study of the early 1990s, 21% of patients with bipolar disorder had comorbid panic disorder. This is a 26-fold higher incidence than in the general population.

 Panic disorder and bipolar disorder may share a special relationship with each other. A study of bipolar probands and their siblings found that panic disorder travels with bipolar disorder exclusively and rarely occurs independently of bipolar disorder.

This unique relationship may be mediated by a genetic predisposition that resides in chromosome 18.

 In both the ECA study and the more recent National Comorbidity Survey, the incidence of OCD was 10-fold greater in bipolar patients than the general population.

 The risk of OCD is greater in family members of bipolar probands, which suggests a familial or genetic association. However, episodic obsessive-compulsive symptoms may simply be a variant of how bipolar disorder is expressed and not a true comorbidity. Either way, the relationship between bipolar disorder and OCD frequently has its origins in childhood and yields a greater burden of anxiety symptoms.

 PTSD may have a special relationship with bipolar disorder because both mania and depression may be perceived as traumatic or because events in the course of the illness may increase the risk of severe traumatic events.

 Consequently, PTSD may be over 6 times more likely to occur in bipolar patients than in the general population.

 The co-occurrence of PTSD with bipolar disorder lowers quality of life, increases rapid cycling and suicide attempts, and reduces the likelihood of remaining well.

 Despite frequent grandiose or expansive behavior during mania, most patients with bipolar disorder actually suffer from social phobia-a potential contributor to dysfunction in bipolar patients.

The combined burden of bipolar and anxiety disorders nearly always has a deleterious effect on outcomes.

 Comorbid illness is associated with marked increases in symptom burden that includes greater risk of psychosis, earlier age at onset of psychiatric symptoms, worse treatment response and more treatment resistance, impaired quality of life, increased suicidal ideation and actions, and increased substance abuse.

 Whether the poor prognosis is due to an interaction between the two conditions or to the additive burden is unknown.

Accurate diagnosis of comorbid anxiety disorder and bipolar disorder is important. The cost of care increases when a bipolar patient is treated exclusively for anxiety because of a misdiagnosis. Once a dual diagnosis has been made, effective treatment may be challenging.

 Serotonergic antidepressants have shown efficacy as acute and prophylactic treatment for all anxiety disorders and are considered first-line agents.

 This is generally true whether the serotonergic effect is alone, is associated with noradrenergic reuptake inhibition, or is obtained by reuptake or monoamine oxidase inhibition.

 Non-serotonergic antidepressants (specifically bupropion) do not appear to be particularly effective.

In bipolar patients, antidepressants have the potential to induce mania, destabilize the course of illness by increasing bouts of mania and depression, and induce a chronic depressive state.

 The risk of these complications is higher if the bipolar patient receives antidepressants during periods of euthymia or over long periods.

 Use of antidepressants specifically for anxiety in bipolar patients would be expected to be associated with more complications. This may account for the observation that pharmacological treatments of comorbidities, such as anxiety disorders, in bipolar patients are generally underused, whereas psychosocial services are used more frequently by patients with coexisting anxiety disorders.

 Second-line pharmacotherapy for anxiety becomes first line in bipolar patients with anxiety disorder. Specifically, studies of atypical antipsychotics such as quetiapine have shown that these agents reduce anxiety in social anxiety disorder and GAD.

 Although the patients recruited for these studies did not have a mood disorder, quetiapine monotherapy (300 to 600 mg/d) significantly reduced anxiety and depressive symptoms in patients with bipolar disorder.

 Quetiapine may be of questionable benefit in patients with PTSD. While open-label, uncontrolled studies support use of this agent for PTSD, there were more early discontinuations with quetiapine than with prazosin and, thus, long-term benefit was lost.

At doses below 4 mg/d, risperidone does not appear to be helpful for the treatment of anxiety symptoms in patients with bipolar disorder.

 Augmentation of mood stabilizer treatment with risperidone was also ineffective.

The olanzapine/fluoxetine combination is approved for the treatment of bipolar depression. It may be useful in the treatment of comorbid anxiety as well. However, olanzapine alone has minimal effect.

 There are no randomized controlled trials that examine the use of anticonvulsants for the anxiety component in bipolar patients. However, anticonvulsants appear to have a small effect in reducing anxiety. In a small open-label study, more than 40% of patients with GAD (without mood disturbance) saw at least a 50% improvement in symptoms with valproate.

 Similarly, modest benefit was seen in a group of patients with PTSD who received divalproex in an open-label study.

 Unfortunately, when the effect size is small in open-label studies, it suggests that results of blinded studies are likely to be negative.

 Gabapentin has been shown to be effective for social phobia in a randomized placebo-controlled trial.

 This effect on anxiety is probably what underlies the early reports of gabapentin efficacy in bipolar disorder. The related anticonvulsant, pregabalin, is also useful in social phobia and GAD at higher doses (approximately 600 mg/d).

 These agents have not been studied in bipolar patients with anxiety but are probably safe to use in this patient population.

Benzodiazepines are clearly effective in many different types of anxiety disorders. However, their use is problematic, and these agents must be prescribed cautiously.

 Psychotherapy may be the treatment of choice for patients with anxiety disorders in general. For example, CBT is as effective as medications in the acute management of panic disorder. Unlike medications, the effect lasts long after treatment has ended.

 However, there are no randomized controlled trials for psychotherapy in bipolar patients who have comorbid anxiety. Nonetheless, therapies such as CBT and relaxation training may be useful in bipolar patients.

Anxiety disorders are commonly comorbid with bipolar disorder and are responsible for much of the morbidity associated with this condition. Treatment of anxiety can be a challenge, since the mainstay of treatment-serotonergic antidepressants-may adversely affect the course of bipolar disorder. Although other agents are available, there is a dearth of information on the outcomes of anxiety treatment for bipolar patients.

Clinicians generally must apply the results of studies performed in patients who have anxiety disorders without mood disturbance to their bipolar patients. This is a reasonable practice, although it is far from ideal. The field needs more high-quality research studies to define the best practice options in treating patients with comorbid anxiety and bipolar disorders.

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 Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication [published correction appears in 

 Chen YW, Dilsaver SC. Comorbidity of panic disorder in bipolar illness: evidence from the Epidemiologic Catchment Area Survey. 

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 MacKinnon DF, Xu J, McMahon FJ, et al. Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data. 

 Chen YW, Dilsaver SC. Comorbidity for obsessive-compulsive disorder in bipolar and unipolar disorders. 

 Goldberg JF, Garno JL. Development of posttraumatic stress disorder in adult bipolar patients with histories of severe childhood abuse. 

 Quarantini LC, Miranda-Scippa A, Nery-Fernandes F, et al. The impact of comorbid posttraumatic stress disorder on bipolar disorder patients. 

 El-Mallakh RS, Hollifield M. Comorbid anxiety in bipolar disorder alters treatment and prognosis. 

 Hollifield M, Mackey A, Davidson J. Integrating therapies for anxiety disorders. 

 El-Mallakh RS, Karippot A. Chronic depression in bipolar disorder. 

 Lembke A, Miklowitz DJ, Otto MW, et al; STEP-BD Investigators. Psychosocial service utilization by patients with bipolar disorders: data from the first 500 participants in the Systematic Treatment Enhancement Program. 

 Bandelow B, Chouinard G, Bobes J, et al. Extended-release quetiapine fumarate (quetiapine XR): a once-daily monotherapy effective in generalized anxiety disorder. Data from a randomized, double-blind, placebo- and active-controlled study. 

 Lydiard RB, Culpepper L, SchiÃ¶ler H, et al. Quetiapine monotherapy as treatment for anxiety symptoms in patients with bipolar depression: a pooled analysis of results from 2 double-blind, randomized, placebo-controlled studies. 

 Hamner MB, Deitsch SE, Brodrick PS, et al. Quetiapine treatment in patients with posttraumatic stress disorder: an open trial of adjunctive therapy. 

 Byers MG, Allison KM, Wendel CS, Lee JK. Prazosin versus quetiapine for nighttime posttraumatic stress disorder symptoms in veterans: an assessment of long-term comparative effectiveness and safety. 

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 Tohen M, Calabrese J, Vieta E, et al. Effect of comorbid anxiety on treatment response in bipolar depression. 

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 Clark RD, CaÃ±ive JM, Calais LA, et al. Divalproex in posttraumatic stress disorder: an open-label clinical trial. 

 Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. 

 Kasper S, Herman B, Nivoli G, et al. Efficacy of pregabalin and venlafaxine-XR in generalized anxiety disorder: results of a double-blind, placebo-controlled 8-week trial. 

 Hollon SD, Stewart MO, Strunk D. Enduring effects for cognitive behavior therapy in the treatment of depression and anxiety. 

 Provencher MD, Hawke LD, Thienot E. Psychotherapies for comorbid anxiety in bipolar spectrum disorders. 

Treatment of anxiety can be a challenge, since the mainstay of treatment may adversely affect the course of bipolar disorder.

The Anxious Bipolar Patient

Major depression is at once simple and complex. At one level, the treatment of this disorder is straightforward. Yet, at a multitude of other levels, it is a complex condition for which available treatments remain suboptimal. Ongoing clinical and translational research in the biology, treatment, and outcome of depression has continued to enlighten the management of this common human affliction. The articles in this special issue highlight the state of the art of depression research and management. Issues as varied as the use of serotonin reuptake inhibitors in pregnancy and the use of imaging to optimize depression outcomes are discussed. In addition to the clinical value of these articles, the reader should note the broad diversity of research being done today.

Studies that have restrictive criteria have been criticized as not being reflective of real-world treatments. This has been labeled the "efficacy-effectiveness gap," or the difference between what studies show and what we see in the clinical setting. For this reason, the NIMH sponsored several large effectiveness studies: STEP-BD, CATIE for schizophrenia, and STAR*D. One of the major lessons these effectiveness studies have taught us is that the restrictive efficacy studies are generally accurate. This is also true when we examine the role of cognitive-behavioral therapy in the treatment of depression as examined in the STAR*D study and analyzed in the cover article of this issue by Edward S. Friedman, MD, 

"Cognitive Therapy: What Is Its Role in Depression Treatment?"

Chronic depression is a growing problem, and yet the definition of chronic depression is not clear. How is chronic depression different from dysthymia? How is chronic depression different from treatment-resistant depression? What is the best approach to the treatment of chronic depression? Research into long-term disorders is difficult to perform. In a field in which so much of our data are generated by industry, finding good information about chronic depression is not easy. That is one of the reasons why "Never-Ending Winter: Chronic Depression" by Francis Mondimore, MD, is an important article.

Research is ultimately an attempt to predict the future. We administer treatments to our patients with the promise that in the near future they will improve. However, we frequently fail and modify our treatment recommendations. Would it not be advantageous if we had tools that would allow us to predict who will respond to which treatment option? Work in major depression is heading in that direction, and the state of the art is described by Jeffrey M. Miller, MD, and Ramin V. Parsey, MD, PhD, in "Can We Predict Response to Antidepressants?"

The placebo effect is frequently invoked when some unexpected improvement occurs. But what is the placebo effect? Is it a reflection of the natural history of an episodic illness? Is it related to the hope or support that naturally occurs when patients come in for treatment? Is it related to the patient's belief that the treatment will help him or her? It is likely all of these and more. We need to understand the placebo effect not only to understand and interpret studies more accurately but also to improve the outcome of our treatments. That is why "Placebo Effects on Pharmacotherapy Outcomes in Major Depression" by Aimee M. Hunter, PhD, is an important article to read.

Nearly 60% of all psychiatric hospital admissions are related to suboptimal adherence to chronic medication regimens. This is a significant problem that may also be an important issue in chronic depression. Factors influencing treatment adherence, and what clinicians can do to improve treatment outcome are discussed in "Adherence to Treatment Regimens in Major Depression: Perspectives, Problems and Progress," by Melvin G. McInniss, MD.

We believe that there is an advance, a progression, from the primitive to the exquisite. However, this is not always absolute. Older treatment options continue to have their utility and their niche. One of our oldest somatic treatments, electroshock therapy, continues to be one of the most effective short-term treatments available. Consequently, it is important to understand how we can use all the tools at our disposal. "

Not Obsolete: Continuing Roles for TCAs and MAOIs

," by J. Alexander Bodkin, MD, and Jessica L. Gören, PharmD, places these older pharmacological options in proper perspective.

Depression has its onset in young adults and is more common in women. Thus, concomitant occurrence of depression and pregnancy may be expected. Given that nearly 60% of pregnancies in the United States are unplanned, information about the effect of antidepressants in pregnancy is very important. The article by Ruta M. Nonacs, MD, PhD, "SSRIs and Pregnancy: Putting the Risks Into Perspective" will help when addressing this issue with your patients.

Research is the future of our field. Thus, examination of these articles can provide a look into our future. The next generation of psychiatrists can expect to have new formulations of medications that can be administered topically, by injection, or even by genetic manipulation. Imaging of brain activity is likely to be more routine. 

The developing field of "personalized medicine" will affect depression treatment. Personalized medicine is based on the belief that specific biological or genetic variants can be predictive of specific treatments. Such a case may already exist for the treatment of alcoholism with naltrexone. A genetic variation of the µ-opioid receptor gene in which the 118th base is occupied by a guanine instead of an adenine, is highly predictive of response to naltrexone. Studies are under way that will lead to routine genotyping before initiation of naltrexone therapy. This may be the case within 2 years.

This is an exciting time for our field. We are confronting the deficiencies in our treatments and learning more about how to address them to improve our patients' lives and to alter the prognosis of a disease that has tortured humanity for thousands of years.

Major depression is at once simple and complex. At one level, the treatment of this disorder is straightforward. Yet, at a multitude of other levels, it is a complex condition for which available treatments remain suboptimal.

Rif S. El-mallakh, MD

Articles

Shared Risk Factors in Multiple Psychiatric Disorders

The Anxious Bipolar Patient

Clinical Depression: Complexities of Diagnosis and Management