Nidal Moukaddam, MD, PhD

 I really enjoyed the roundtable discussion. I really enjoyed how thorough everybody was. There were a lot of questions about “Well, how did you make the diagnosis of bipolar I? Give me more details about the mania. Flesh out the case for me.” I would not want to give someone a diagnosis of bipolar I, which is a lifelong disorder, without knowing exactly what they've been through, and I thought that was nice. People talked about dilution of care and how quick encounters where patients are not given the time that they need is not a good thing, and I agree. People also talked about how important it is to educate patients and work with them and establish that nice rapport that makes you know your doctor is on your side. Your doctor is really trying to get you to be functional and happy. I also thought it was interesting that you have people who are willing to start with atypical second-generation antipsychotics and people who are willing to start with lithium, and I'd say the room was evenly split. That probably indicates that the trends in treatment of bipolar disorder are changing throughout our country.

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Dr Moukaddam discusses key takeaways for the management of bipolar disorder.

Takeaways for Bipolar Disorder Management

 In the United States, medications would be approved by the FDA [Food and Drug Administration]. If you were in Europe, they’d be approved by the EMA [European Medicines Agency]. That’s the equivalent of the FDA here. The medications can be approved for the initial stage of bipolar disorder, which is mania. That would be acute treatment, but a medication could also have an approval for maintenance treatment. Obviously, one would want to initially go with treatments that have FDA approval. That being said, when a patient is very sick, sometimes you end up with some off-label prescribing, but that should not be your first step. The field has evolved a lot. As I’ve said, we have a lot of options now. You have your mood stabilizers: lithium, Depakote, carbamazepine, and lamotrigine. You also have your atypical antipsychotics and second-generation antipsychotics. Second-generation antipsychotics are a fascinating drug class because they take what the previous class of antipsychotics have done, which is dopamine agonism, and work on dopamine but not in the same way, not to the same extent, and not on the same receptors. Now, as a clinician I have a lot of choices. I can start with a mood stabilizer: lithium, as in the case of this young man. Or I could start with an atypical antipsychotic. Usually, what you’ll see is that patients don’t know. Thus, it is up to us, but we develop algorithms depending on where we’ve trained and how we’ve trained and the populations that we treat: very sick or not very sick.

Where do we go from here? Based on the metabolic profile of the patient, their family history, their medical history, and what I’m seeing right now, I would have to pick an agent that hopefully catches the symptomatology and controls it. First, we want it to be monotherapy. It’s always better to do monotherapy instead of 2 or 3 agents. People don’t like it when you give them 3 or 4 prescriptions because they feel that they’re broken; they feel that they’re really sick. Sometimes we need that, but ideally, monotherapy is what your patient will stay with. We’re thinking a little about dopamine, glutamate, and serotonin here, and it’s beyond the scope of this talk to talk about all the receptors. But with dopamine agonism, the older agents used to focus on the detour receptors. The newer agents would lean toward D3 receptor agonism, and instead of having full agonism or full antagonism, now we have partial agonism and partial receptor agonism, which is extremely precious because it gives you more nuanced effects. Some of the newer atypical ones will have partial agonism, and that’s helpful. Also, in this type of treatment, we really value the effect on serotonin receptors, and when the atypical and the second-generation antipsychotics first came out, it was a really big deal that they worked on 5HD2 and conversely on 5HD2C. 2A and 2C are the 2 serotonin receptors that are opposing in action, but activation of 5HD2C as in the case of olanzapine could trigger some of the weight gain.

Why do we care about serotonin? We care about serotonin because it modulates dopamine release. Dopamine is a big agent in bipolar disorder. It’s a neurotransmitter that causes a lot of these symptoms, and modulating dopamine is one of our goals. We do it via serotonin and glutamate, but because there are so many other receptor subtypes involved when we pick an agent, we want that agent to cover a wide variety of profiles. We want that profile to cover some dopamine, some serotonin. We would like to have some histaminergic agent to help with sleep but not too much, and we definitely don’t want a muscarinic agent because this is when you get your anticholinergic adverse effects.

One of the considerations we have not talked about, but it would change how you approach things, is age. You want to make sure the person knows that this is potentially a lifelong treatment and that if they are female and of childbearing age, this will change. They would have to use contraception, and if they get pregnant, then it could affect them. The treatment could affect the pregnancy, and bipolar I disorder could also affect the pregnancy, and the pregnancy in turn could affect the bipolar I symptomatology. Thus, with women, you want to caution them that the postpartum period would be a very high-risk period for depression, etc.

My approach to the treatment of patients who have failed multiple therapies is to make sure that I’m maximizing the use of psychosocial treatments, especially psychotherapy, and then to deviate from monotherapy to maybe adding other agents.

My first step would be to add psychotherapy. I would want to make sure that the patient really understands what’s going on and is maximizing the use of their own psychological resources. Then, I would go beyond monotherapy, and I would consider adding a second or perhaps a third agent. In the case of this young man, we have lamotrigine and quetiapine. I would consider 2 agents and then maybe consider an adjunct. Maybe this person needs a little bit of help for anxiety or for sleep, so I would like to combine psychosocial treatment with psychotherapy and then change agents. I would also talk to the patient about how realistic it is when we talk about mood control and adverse effects, and this is where the tough conversation of benefit outweighs risk comes in. If they have a 5-lb weight gain, could that be acceptable? If they tell me a 20-lb weight gain I would say, “No, that’s really too much.” But if it’s a small weight gain or if it’s an adverse effect that’s mild, could we then accept it if the medication gives us benefit? That conversation has to be very customized and very tailored to the patient’s presentation and it relies on your rapport with the patient. If you have a good rapport with the patient, usually you end up with a much better outcome when treating those conditions. There are other things we have not talked about; ECT, which is electroconvulsive therapy for mania, is there when somebody is really ill. There is hospitalization, but we’re assuming for the purposes of this case that this is outpatient.

Nidal Moukaddam, MD, PhD, provides insight on the evolving treatment landscape for bipolar disorder and optimizing therapies for disease management.

Treatment Selection for Bipolar Disorder

 The art of psychiatry is making sure to look at the patient holistically and having a comprehensive history that then links to treatment, because you don’t want to ignore important things such as their medical history, metabolic profile, constraints on their job, and family history. Let me go into some of these. If you think that the treatment that they would benefit from is a pill that’s given 3 times a day, but their work does not allow them to do that, then you would not want to proceed because the patient would not be adherent. Similarly, financial considerations are very important. If I think a particular pill would be fantastic for the patient, but they cannot afford it for more than a month, then it would not be sustainable.

These would be your first considerations: Can they afford it, will it mesh with their schedule, and does it fit well with their medical profile? We have not talked about this patient’s medical history but somebody who has obesity, diabetes, or other conditions could not potentially take an agent that causes weight gain. Because even though the agent could be beneficial for psychiatric symptoms, the weight gain would be unacceptable and make the other conditions worse. Those are huge considerations: the metabolic profile and medical history. As mentioned in the case, this patient developed hyperthyroidism, so that’s one of the things we consider with lithium, especially long-term treatment.

The one other thing you discuss with the patient, which is really important, is that bipolar disorder doesn’t typically go away. You will have to be on medications for an extended period of time, perhaps for the rest of your life, so we really want to find a medication regimen that is comfortable for you. When I say treatment, treatment is not only medications. We have to consider whether there’s any therapy that could work. Psychotherapeutic modalities are extremely effective for certain things, especially for rhythm therapy and making sure people know how to manage their sleep and energy and how to catch symptoms before they start. Psychoeducation is your first step. You can do that in office, but therapy is often missed or underused, and I think that would be important for anybody making a treatment plan.

Dr Moukaddam shares factors to consider when approaching the treatment of bipolar disorder.

Approaching the Treatment of Bipolar Disorder

 Today, we’re going to talk about a new case. A 30-year-old man has taken short-term disability leave from work due to the progression of a depressive episode. He received a diagnosis of bipolar I disorder about 10 years ago. He had his first episode of mania at the age of 20 and 2 subsequent episodes of mania between the ages of 21 and 29. He was treated with lithium, which was highly effective, but he experienced excessive thirst and developed hyperthyroidism. His lithium level at the time was in the therapeutic range of 0.8 mEq/L. He was switched to valproate; however, valproate lacked the efficacy of lithium and caused adverse effects of sedation and weight gain. During his third manic episode, he started on olanzapine but experienced excessive weight gain. He was then cross-titrated to quetiapine, which improved his manic symptoms. However, weight gain again became an adverse effect, and he also complained of sedation. The patient reported sleeplessness and made unnecessary online purchases when unable to sleep, but the quetiapine sleepiness was unacceptable. Despite these adverse effects, he continued taking] quetiapine until he decompensated into his third depressive episode. The quetiapine was then augmented with lamotrigine, which was titrated up to 300 mg per day but demonstrated no efficacy. At the time of presentation, the patient was adhering to the medications. He did not have a substance use disorder, which was confirmed by a negative toxicology screen. His TSH [thyroid-stimulating hormone] level was in the middle of the normal range, and he had no suicidal ideations or psychotic symptoms.

I think the most important thing to do when somebody comes to you, even if they tell you they have a diagnosis, is to confirm the diagnosis. You want to start by making up your own mind, and sometimes the patient is not a good source of information. But in the case of bipolar disorder without psychosis, you expect the patient to be able to give you a solid history. Typically, the part of the history that’s hardest to nail down is mania. When people experience mania, they have excessive energy and excessive activation that creates the need for sleep, and sometimes they like it. They feel that this is the way it should be, so they don’t point it out as pathological. Now, the 

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

] criteria tell us that mania that leads to hospitalization or some negative consequence like incarceration is problematic no matter what the duration is. Assuming the patient did not end up in the hospital or in prison, we want to verify the story of mania. In the current case presentation, I can see many of my colleagues saying, “Hey, you’re not giving us enough symptoms of mania. He’s a bit sleepless. He makes frivolous purchases. That’s bipolar disorder but not bipolar I; maybe it’s bipolar II.”

Thus, my first step would be to explain that this patient had at least a week without sleep. During that week, he was spacing, had pressured speech, and was talking fast to the point that others around him commented about it. He became more impulsive, and buying things was the tip of the iceberg. He also became more sexual to the point where it got him in trouble in his relationships, he spent more money than he had planned, etc. These examples of impulsivity often nail down the diagnosis of bipolar disorder. Of course, these symptoms change with the time that we live in. For example, before unlimited plans on cell phones, you would have been taught to ask: “Do you get a very high bill on your phone when you’re manic?” Because patients with mania talk a lot, and the bills would be higher when they call across state lines or internationally. First, I would recommend verifying the diagnosis. My impression of the patient is that this is somebody with a set diagnosis of bipolar I. Three manic episodes is a lot. He has impairment because of it, and it’s affected his job. Thus, my first step is confirming the diagnosis. My second would be a lot of psychoeducation; make sure that the patient understands what he’s up against and why he needs treatment.

Nidal Moukaddam, MD, PhD, presents the case of a 30-year-old male diagnosed with bipolar 1 disorder and shares her initial impressions on diagnosis.

Patient Case: 30-Year-Old Male With Bipolar Disorder

(In honor of Women’s History Month, we invited our contributors to write about the women who inspire them.—Ed.)

“Generosity is giving more than you can, and pride is taking less than you need.”

The setting: a city in the midst of a civil war. Let’s not dwell too much on the details—it could be anywhere, and war is terrible in any form. The year does not matter, either. In this chapter of this nameless war, the electric grid has been hit and running water is erratic. The city is plunged in silence earlier than usual, deprived of its busy, noisy social varnish, and the flickering of lanterns, candles, or the stray cell phone that has not lost power yet are the only lights.

However, this civil war has lasted enough that people have acclimated. It has been months—years—with intermittent exacerbations. They have nonperishable foods stored. They have their preferred news channel and political analyses to plan their day and calibrate the risks they take. They strive for a desperate sense of normalcy between fighting interludes.

The woman I will tell you about was lucky enough to live in a section of the city that still had power—during this chapter of the war, at least. She was determined to help others in her own discrete way. She never bragged about it—never even thought of herself as helping—and yet her actions are seared in my memory.

One day, she comes home with a couple of shirts. “I need to iron them; this is for Joe.” Joe, who could really be anyone, just like this story could be anywhere affected by strife, was an elderly gentleman who was very embarrassed that he could not iron his shirts, look presentable, or take care of his grooming the way he wanted. He had stopped leaving the house completely. Joe was, in fact, an esteemed writer who just happened to live in a section of the city without water or power.

His wife, an artist made famous by her delicate carved compositions, had shared in a private conversation how embarrassed he was, and how she felt bad that she could not solve this problem for him. He did not wear T-shirts, they had nowhere else to go, and they could not leave the city—they just had to wait. He would never ask for help—he was just isolating instead. To the mind of the 7-year-old I was back then, this was baffling. Why didn’t he wear T-shirts? You did not need to iron T-shirts. I did ask that question, with the gusto, and perhaps cruelty, of a child.

So, the shirt turns out to have a hole in its sleeve—a large enough tear that it could not have gone unnoticed to its owner. It also had a patch, closely matching in color, which would blend in when ironed. I recall the conversation that ensued about the patch, and the fact that people may need help, but not ask for it. And when they do ask, they may be simply glossing over heaps of deeper issues. The patch was neatly ironed into the shirt that day, and no one spoke of it ever again. Joe and his wife’s financial misery was not mentioned, and their pride and respect were preserved. My 7-year-old eyes did not get it that day, and I never asked whether financial assistance—food, cash, anything—went back with the shirt. But decades later, this event still lives in my memory as one of the most inspirational, subtle, and understated ways I have witnessed anyone give help.

Small moments count and make our lives what they are. Small moments like the one shared above are what gives medicine—especially psychiatry—its depth, joy, and purpose. When patients come to us, we cloak their sadness, misery, or fear in hope and respect. We treat the human being they strive to be, with their priorities and their dreams. We look at the ironed, polished shirt—not at the hole that has been patched. And my mother, who taught this lesson without saying a word, will forever be the most inspiring person in my life, for what is life without dignity and respect?

 is an associate professor in the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, as well as the Ben Taub Adult Outpatient Services director and the medical director of the Stabilization, Treatment & Rehabilitation (STAR) Program for Psychosis, also at Baylor College of Medicine. She also serves on the 

Is there a woman who inspires you? Write to us at 

Articles

A subtle, yet inspirational lesson of helping others with dignity and respect.

A Hole in a Sleeve

Tales From the Clinic: The Art of Psychiatry

 in a young man who otherwise presents as the perfect patient who is treatment adherent. Individuals with anxiety suffer pervasive impairment in everyday life, and treatment is often not fully effective. Somatic and physical comorbidities typically complicate clinical anxiety presentation, but there are exciting conceptual and treatment considerations in this field worth highlighting, including novel concepts such as gut microbiome influence on anxiety disorders, high body awareness, and somatosensory amplification dimensions.

“Mr West,” aged 30 years, is a well-groomed, soft-spoken man who presents to the clinic for anxiety. He gives you access to extensive medical records spanning the past 8 years, during which time he has received treatment for generalized anxiety. He complains of intense anxiety, fatigue, and hopelessness on a daily basis. According to the patient, his symptoms are comparable with a “living hell on earth.” Mr West had a history of illicit drug use—stimulant use—for a brief period in his early 20s but has not relapsed since. He describes a rich cultural background with life in different countries (accompanying his family as they moved), as well as medications and illicit substance use that are unfamiliar to you, prompting some frantic internet searching. At one point, he mentions fenethylline, which he felt had helped him “fight being tired,” but says he has not used it in about 7 years.

Roberto D. Sanchez, DO; Benjamin Li, MD; Nidal Moukaddam, MD, PhD

To tackle anxiety symptoms, he has been on a plethora of medications, all of which had adverse effects (AEs) and were discontinued. He has been fully adherent to all treatment recommendations, has never missed any of his appointments, and produces multiple negative urine drug screens. He is diligent in attending all of his psychotherapy sessions as well. Despite his symptoms, he maintains a job, pays his bills with no issues, and dedicates a lot of attention to his ailing mother. However, you note upon history-taking that he has no close friends and has not had romantic involvements, which he attributes to his symptoms: “I’m just not OK, doc, I tell you.” The patient is followed for 6 years.

The first year is spent establishing rapport and getting to know the patient. Monthly visits follow the same pattern: The patient profusely describes beliefs of having “something wrong” that is not properly diagnosed. He asks for brain imaging and cortisol levels, and he brings literature showing sustained brain damage from substance use. Attempts at reassurance often fall flat and are of limited effectiveness, but, as he is a model patient otherwise, you keep trying. Attempts at cognitive behavioral therapy produce limited positive effects, and the patient frequently comments, “This is too simple for me.”

You believe, based on his description, that he has irritable bowel syndrome (IBS), but he has not received specialized care. He reports that the fatigue and anxiety correlate with his gastrointestinal (GI) symptoms. He does slightly better when he is able to wake up between 9 and 10 AM; when he has to awaken earlier (ie, for work), he experiences loose bowels, burping, indigestion, and nausea.

At the end of year 1, Mr West tells you he has to seek “more care. I have to get answers—something is wrong with me.” He moves to another country in the hopes of more thorough treatment. He returns in 2 years, and you are surprised to see his name appear on your clinic roster.

Out of the blue, Mr West returns, bringing with him a panoply of medical test results, all of which are negative, as expected. He continues to report that he feels he has a terrible missed diagnosis, but he is less forceful in that statement and more amenable to reassurance. He continues to report daily GI symptoms and fatigue that severely limit his social interactions. Mr West mentions 2 medications that have been somewhat helpful, both of which you had to Google: Motival (fluphenazine and nortriptyline) and Deanxit (melitracen and flupentixol). He continues to take fluoxetine, as he has done for years.

In year 5, Mr West agrees to go to a GI specialty clinic. As a result, he changes his diet drastically, with partial anxiety improvement. However, he continues to complain of daily tinnitus. He continues to use medications not available in the United States. As you look for alternatives available here, you start him on lisdexamfetamine, which he feels is helpful with fatigue. At most sessions, however, he still reports his life is hell.

Generalized anxiety disorder (GAD) is characterized by exaggerated tension, worrying, and nervousness about daily life events. GAD is often a lifelong disease, causing significant impairment.

 The prevalence of anxiety disorders in the United States is approximately 10% in adults

 Symptoms include restlessness, irritability, and fatigue, with overthinking and consideration of worst-case scenarios predominating cognitive schemas of GAD patients. Patients with anxiety frequently have GI symptoms (about 18% of individuals).

 Individuals with IBS are twice as likely to have physical fatigue, GI-specific anxiety, perceived stress, pain catastrophizing, and trait anxiety.

 More severe mental symptoms and distress are associated with IBS severity, and vice versa.

Past Year Prevalence of Generalized Anxiety Disorder Among US Adults (2001-2003)

Past Year Severity of Generalized Anxiety Disorder Among US Adults (2001-2003)

Computational modeling confirms what clinicians already know: Evidence suggests that individuals with psychiatric illness such as depression and anxiety misread and misinterpret visceral information compared with healthy controls.

 As a result, a patient with anxiety may feel a benign physical symptom very acutely and interpret the symptom in a catastrophizing way, instead of dismissing it as normal. A relevant concept is body awareness.

 Somatic internal perceptions—which are often preconscious—involve interoception and proprioception, and these neurological paths can be altered or damaged by disease processes. Those sensations arrive to consciousness and are interpreted by the individual, with an assigned explanation for the sensation in question. Thus, when dealing with patients who have anxiety and comorbid somatic symptomatology, the clinician may be faced with somatosensory amplification and potential exaggerated or maladaptive interpretation of bodily symptoms. This is a budding research field, with further definitions and clarification of terminology needed.

Patients with anxiety disorders have a tendency to avoid making changes to their medications, as trying new things and making alterations to their routine makes them apprehensive. This may make them more likely to report AEs after trying new treatment options, which could explain why this patient had low symptomatic tolerance to many of the attempted alternate treatments. It is important to give patients with anxiety disorders ample time to adapt to changes in their treatment regimens. Forcing change, or switching too rapidly, may be counterproductive and could create apprehension, possibly worsening anxiety and creating a barrier to adherence. Slow dosing and upward titration are essential to avoid AEs and a mental aversive reaction to treatment.

It is sometimes difficult to unravel all aspects of a clinical case within a few visits. Intrinsic personality aspects can underlie much of the behaviors we label as anxiety; this includes neuroticism.

 For example, the patient’s mother had possible paranoid traits, chronically thinking that the neighbors made noise to bother her. Therefore, paranoia in this patient may be part of the family’s disposition, further explaining response to agents containing low-dose antipsychotics. Anxiety and depression tend to be highly comorbid, so it should be a priority to screen for and treat both as part of the treatment plan.

For anxiety disorders, guidelines usually recommend a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor as first-line treatment,

 with augmenting agents such as the azapirones (like buspirone) and antihistamines (like hydroxyzine). Only 1 antipsychotic—trifluoperazine—is approved by the US Food and Drug Administration for use in treating anxiety, although off-label use of multiple antipsychotic agents is very prevalent in clinical practice.

 GABAergic agents are also profusely used with some success. Serotonergic mechanisms are important, given the presence of serotonin receptors throughout the gut and the known dysregulation of serotonergic afferent neural signals in functional GI disorders.

In terms of dosing, clinicians anecdotally note that some patients with anxiety seem to require multiple doses of medications, even for those agents that can be dosed once daily. This is another clinical correlate of anxiety that may be unrelated to treatment, but more linked to patient satisfaction, as systematic reviews show that most classes of psychotropics can be dosed once daily without a decrease in efficacy.

In this case, the patient did well on Deanxit and Motival, each of which combines an antipsychotic medication and an antidepressant medication. A positive response to Deanxit and sertraline vs sertraline alone has been shown in patients with chronic somatic diseases, so this could explain the success of the regimen in this patient.

 Mr West continued to be stressed about having to ask people to get his medication when they travel and wanted a substitute. He achieved the best results with chlorpromazine, which is chemically similar to the flupentixol in Deanxit.

Psychotherapeutic interventions are crucial in anxiety disorders in general, not just GAD. Symptomatic improvements of more than 50% can be achieved with cognitive-behavioral therapies, meta-cognitive therapy, mindfulness-based cognitive therapy, and acceptance and commitment therapy.

Lastly, lifestyle factors such as exercise (eg, running) are underemphasized and underused modalities of treatment that have shown to be helpful in decreasing depression and anxiety,

 and they should be strongly encouraged. Diet modification, whether the patient has GI symptoms or not, is also relevant, as multiple studies now highlight the role of gut microbiome in depression/anxiety disorders.

 is a volunteer research fellow in the Department of Psychiatry at the American University of Beirut. 

 is an associate professor in the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, as well as the Ben Taub Adult Outpatient Services director and the medical director of the Stabilization, Treatment & Rehabilitation (STAR) Program for Psychosis, also at Baylor College of Medicine. She also serves on the 

Symptoms of depression, anxiety, and post-traumatic stress disorder and their relationship to health-related behaviors in over 12,000 US military personnel: bi-directional associations

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Why are psychotherapeutic interventions crucial in the treatment of GAD and anxiety disorders in general?