Contemporary psychoanalysts know that behavior is a form of communication.

Treatment Resistance and Patient Authority: The Austen Riggs Reader,

edited by Dr Eric Plakun, describes the work being done at the Austen Riggs Center, a psychodynamic institution in Stockbridge, Mass. Specializing in work with treatment-resistant, usually highly comorbid, and often high-risk patients, the Center’s intensive multimodal psychoanalytic treatment program considers the most passive, disturbed, or disturbing behavior of treatment-resistant patients as cause for hope rather than pessimism.

Treatment resistance, defined as a failure to respond to customary psychiatric treatment, is now considered a fairly common occurrence that can involve substantial suffering and disability. Almost all mental health professionals have had contact with complicated, severe cases that tax resources and discourage clinicians. Given the magnitude of the problem of treatment resistance, the impact on patients and those who care about them, and the consumption of health care resources, the subject of this book is very important indeed.

To explain the practicalities of treatment resistance, the authors of each chapter describe contemporary psychoanalytic work and transmit the attitude required for this work. Furthermore, they keep in mind an audience that may be accustomed to approaching difficult clinical problems with a very different state of mind.

Aptly titled a “reader,” the book seems designed for the ongoing development and use of certain basic skills. Like the best of “readers,” it contains elements for the ambitious student. “The Third,” for example, which is discussed throughout the book, is a term currently at the cutting edge of psychoanalytic theory. Therefore, its inclusion may be a drawback for the inexperienced or less ambitious scholar.

The text is well organized with take-home messages set apart in boxes. The phenomenon of treatment resistance is reviewed, as are data that support the positive results obtained at the Riggs Center. A variety of issues are addressed, including negative transference; the transmission of trauma; psychodynamic psychopharmacology; and working with suicidality, family resistance, and psychotic disorders.

We are urged to look beyond the phenomenon of “acting out” toward the notion of “enactment,” which implies clinician participation in the unfolding treatment-resistant behavior. From this point of view, treatment pivots around the empowering concept of authority-the patient as author of an engaged relational narrative previous-ly carried in action (and inaction) rather than in words.

The book is worth reading by all mental health professionals. Of particular interest is the chapter “What is psychodynamic psychopharmacology? An approach to pharmacological treatment resistance,” by Drs Mintz and Belnap. The 2 main subjects in this chapter are deserving of book-length treatment. These are “resistance 

medications” (including the nocebo effect) and “resistance 

 medications,” wherein use of medications and the medical model contribute psychologically to treatment resistance.

Another notable chapter is “System pressures, ethics, and autonomy,” by Marilyn Charles, PhD. Dr Charles emphasizes that for treatment-resistant patients, “the standard of care is a floor, not a ceiling.” She describes how various types of fear on the part of the clinician often create a tendency toward oversimplified thinking in the treatment of these patients.

The only shortcoming of this excellent book is its minimal discussion of the issues involved in applying its understandings to less intensive clinical settings. The reader feels this as an aching need. One is left with the disquieting implication that much of current treatment with some patients, because it is “deaf” to the communication in their behavior, may actually further entrench treatment resistance.

Articles

Contemporary psychoanalysts know that behavior is a form of communication. This book describes the work being done at the Austen Riggs Center, a psychodynamic institution in Stockbridge, Mass.

Treatment Resistance and Patient Authority: The Austen Riggs Reader

Social media can be intimidating to those who provide mental health care. Why? Privacy and liability concerns are probably the first things that come to mind. However, careful and creative use of social media Web sites, such as Twitter, Facebook, and LinkedIn, can enhance your professional profile, promote high standards of patient care, and facilitate collaboration among colleagues.

Social media encompasses a wide range of Internet-based activities, including blogs, microblogs, wikis-and social networks. Blogs can help educate patients and caregivers about mental health topics, such as recently approved treatments, and typically provide such content on a regular basis. Blogs reach a wide audience and provide easy links to other sources of information (eg, the FDA).

For psychiatrists, being aware of topics that generate interest on social media sites not only fuels ideas for your own “tweets” or blog posts but also helps you anticipate concerns raised by your patients.

Note, however, that this sort of social media activity does not 

Many social media sites are designed to facilitate conversations among users, thereby creating an interactive social network. This may be very useful, since you can share information with and respond to posts received from others on the site (eg, about medication efficacy studies). Social networking sites that provide secure and private access (such as the APA page on LinkedIn) can also promote professional collaboration.

Because a psychiatrist must not do anything to compromise a patient’s right to confidential communication, social networking that involves patients does not have much utility in clinical practice. Many patients invite their psychiatrist or other behavioral health provider to join a social network (eg, a Facebook “friend” request). If the clinician accepts the invitation, communication with the patient is by definition not confidential and could easily impede treatment.

Setting up an account for your practice on social media Web sites such as Facebook and Twitter is very easy. One caveat is to keep your practice account separate from any personal accounts you may have on the same sites. Also, many social media sites encourage or require you to sign up with “business” accounts. Such accounts often have more controls over which features your business wants to present on the social network. For example, Facebook allows you to turn off the ability for other Facebook users to write on your “wall” (the most publicly viewable part of any Facebook page).

With your newly created social media account, you can begin to follow other behavioral health professionals or start to write about mental health topics yourself. As your network increases in number and in breadth of discipline, you will find new material in new places-other clinicians, journal newsfeeds, and items from the popular press.

Social media and networking offers an amazing amount of information to patients and quickly spreads treatment resources to behavioral health care providers.

A strong social media presence also helps generate referrals. Often potential patients will use search tools built into the social networks or traditional search engines (eg, Google and Bing) to learn more about a condition or health care provider. What they find may lead them to your Web site . . . and into your office.

Networking with colleagues on sites such as LinkedIn may also generate direct referrals from those colleagues.

For more and more of us, social media is the primary way we use the Internet-and this trend has been growing for years. According to the Pew Research Center, for example, “As of February 2012, one-third (34%) of Internet users aged 65 and older use social networking sites such as Facebook, and 18% do so on a typical day.”

 According to Wikipedia, “If Facebook were a country, it would be the world’s third largest in terms of population, larger even than the USA.”

 And like any other technology, the more we use it, the more dependent on it we become.

Having even a basic idea of the potential-as well as of the perils-of social media is therefore not only important to good practice, but it may be essential to good practice.

 Zickuhr K, Madden M. Older adults and internet use. PewInternet. June 6, 2012. 

http://pewinternet.org/Reports/2012/Older-adults-and-internet-use.aspx

http://en.wikipedia.org/wiki/Social_media#cite_note-19

Having even a basic idea of the potential--as well as of the perils--of social media is therefore not only important to good practice, but it may be essential to good practice.

Social Media: A Key Component to the Psychiatrist's Practice

Psychiatric disorders are heterogeneous and of multifactorial origin.

 The illness course is often chronic and associated with high rates of nonrecovery, episode recurrence, interepisodic dysfunction, and morbidity as well as premature mortality.

It is therefore not surprising that MDD, bipolar disorder, and schizophrenia are among the primary leading causes of disability and economic burden worldwide. One major contributor to the economic burden associated with these conditions is the limited capability of available treatment options to effectively modify the disease process, fully restore function, halt illness progression, and treat cognitive deficits.

Since the original description of lithium’s efficacy for mania in 1948, followed by chlorpromazine and iproniazid shortly thereafter, no substantial pharmacological advances have been made in the field of psychiatry. Although advances in safety, tolerability, and simplicity of use have been made, the long-term outcomes for most patients with MDD, bipolar disorder, or schizophrenia remain largely the same as they did several decades ago, ie, many of these patients do not achieve symptomatic, syndromal, and functional recovery with conventional pharmacotherapy. This underscores the need for restructuring the current disease model.

The prevailing theory for the past 50 years has been that affective and psychotic disorders are subserved by disturbances in monoamines. Yet, despite intensified research efforts, monoamines have not proved to be reliable biomarkers of psychiatric disorders and no disease-modifying agents have been discovered on the basis of this model. A more comprehensive disease model that encompasses other physiological systems may accelerate progress toward novel treatment development.

Results from preclinical and clinical translational research indicate that disturbances in inflammation may play a role in the pathophysiology of psychiatric disorders, including MDD, bipolar disorder, and schizophrenia. Hence, it could be hypothesized that inflammatory mediators may constitute novel targets for drug development.

Cytokines are pleiotropic and often redundant soluble proteins that regulate survival, differentiation, proliferation, and effector functions of tissues and cells. While these proteins are well-known mediators of innate and adaptive immunity, more recently they have been implicated in a variety of other systems. For example, inflammatory cytokines have been shown to interact with neurotransmitter metabolism, neuroendocrine function, and neural as well as glial plasticity. Peripherally and centrally derived inflammatory cytokines exert a bidirectional influence across the blood-brain barrier or via peripheral afferent nerve fibers (ie, vagus nerve).

The increased incidence of inflammatory diseases in individuals with psychiatric disorders (eg, cardiovascular disease, obesity, autoimmune diseases) provides conjectural evidence that inflammatory mediators may be involved in the pathophysiology of these conditions. The obverse association is also reported, wherein in individuals with rheumatic diseases, the incidence of subsequent psychiatric disorders is higher.

In a population-based study that evaluated the entire Swedish population, the standardized incidence ratio of subsequent psychiatric disorders was highest for individuals with systemic lupus erythematosus followed by ankylosing spondylitis and rheumatoid arthritis.

 Further analysis revealed a higher incidence of subsequent affective, psychotic, and personality disorders, as well as dementia and delirium, although the risk of psychotic disorders was significant only in women with rheumatoid arthritis and systemic lupus erythematosus.

Other population-based studies, however, have reported a lower incidence of schizophrenia in individuals with rheumatoid arthritis.

Higher rates of depression are also evident with various other medical conditions, including obesity and cardiovascular disease.

 The bidirectional co-occurrence of psychiatric and autoimmune or inflammatory diseases suggests the involvement of common networks central to the pathophysiology of these conditions.


Triggers of inflammation in psychiatric disorders

The hypothesis that inflammatory cytokines play a role in the pathophysiology of psychiatric disorders stems from the observation that sickness behavior is characterized by signs and symptoms that are common to major depression. Sickness behavior is a nonspecific reaction to inflammation that is mediated by proinflammatory cytokines (eg, interleukin (IL)-1, IL-6, tumor necrosis factor Î± [TNF-Î±], and interferon-Î³ [IFN-Î³]) and is characterized by decreased appetite, amotivation, cognitive impairment, and neurovegetative symptoms.

During the past 2 decades, numerous studies have documented abnormal inflammatory cytokine concentrations in patients with MDD, bipolar disorder, or schizophrenia.

 Most replicated and common to all 3 conditions are elevated concentrations of circulating TNF-Î±, IL-6, and IL-1Î². Preliminary evidence also documents abnormalities in concentrations of proinflammatory cytokines in the cerebrospinal fluid of patients with MDD, bipolar disorder, or schizophrenia.

 It has been hypothesized that inflammation in mood disorders may arise from an imbalance between proinflammatory and anti-inflammatory cytokines. This is supported by evidence of increased proinflammatory to anti-inflammatory cytokine ratios in these populations.

There is a pressing need for studies of inflammatory markers in children and adolescents at risk for or in the early stages of a psychiatric disorder. At this point, it is not known if inflammatory cytokine abnormalities are a cause or consequence of the illness. Preliminary evidence suggests that manic but not depressive symptom severity in adolescents with bipolar disorder is significantly associated with high-sensitivity C-reactive protein (CRP) levels, an acute phase reactant that is elevated in response to inflammation, but not with IL-6 levels.

 A preliminary proinflammatory gene expression signature has been reported in offspring of individuals with bipolar disorder, and elevated messenger RNA (mRNA) levels as well as protein expression levels of IL-1Î², IL-6, and TNF-Î± have been reported in the prefrontal cortex of adolescent suicide victims.

 Longitudinal studies in children at genetic risk for major psychiatric disorders may aid identification of biomarkers that allow for earlier detection of candidates for prophylactic treatment.

Although the triggers of inflammation in psychiatric disorders are unknown, they are likely multifactorial in origin and encompass environmental and genetic factors (

). For example, maternal infections as well as maternal stress have been reported to pose a risk for the onset of schizophrenia later in life.

 Early childhood stress has also been shown to trigger an inflammatory response and may render individuals more vulnerable to psychiatric disorders.

Among female adolescents at high risk for depression, transition to depression was associated with increases in CRP and IL-6 levels; the magnitude of these changes was greater among females with multiple types of childhood adversity.

 Lower socioeconomic status in early childhood (1 to 2 years of age) has also been associated with elevated circulating IL-6 levels in adulthood.

 Environmental factors during the prenatal period or early childhood may activate the inflammatory response, which in combination with a genetic susceptibility or epigenetic modification, may increase the risk of psychiatric disorders.

Inflammation is highly interconnected with oxidative stress and results in a widespread influence on protein expression and cell survival. Oxidative stress exerts effects on DNA methylation patterns and produces unique epigenetic profiles that may increase vulnerability to psychiatric disorders. For example, decreased IL-6 CpG methylation is associated with elevated serum IL-6 and CRP levels in individuals with lifetime depression.

 Moreover, inflammation and oxidative stress are associated with increased apoptosis and decreased neural and glial plasticity.

 Abnormalities in these processes have also been reported in persons with MDD, bipolar disorder, and schizophrenia.

Anti-inflammatory agents have been shown to mitigate psychiatric symptoms. For example, adjunctive celecoxib has been shown to exert antidepressant effects in MDD and bipolar disorder as well as ameliorate symptoms of schizophrenia.

 Minocycline, a tetracycline antibiotic with anti-inflammatory properties, has also been shown to mitigate negative symptoms and improve cognitive function in patients with schizophrenia.

 Moreover, evidence from animal studies and a pilot open-label clinical trial in patients who had MDD with psychotic symptoms suggests that minocycline exerts antidepressant effects.

 TNF antagonists may also have antidepressant effects, as suggested by improvements in secondary measures of depression and quality of life in individuals with inflammatory disorders.

Conventional antidepressants, mood stabilizers, and antipsychotics, in varying capacities, down-regulate proinflammatory cytokine mRNA and protein levels. Moreover, for patients who are candidates for IFN-Î± therapy, antidepressant pretreatment has been shown to reduce the risk of cytokine-induced depression.

 Interestingly, preliminary preclinical evidence suggests that SSRIs and antipsychotics suppress inflammatory cytokine production and inhibit disease progression in an animal model of rheumatoid arthritis.

A plethora of studies support the hypothesis that inflammation plays a role in the pathophysiology of major psychiatric disorders. A unique inflammatory signature capable of distinguishing between each condition, however, remains to be elucidated. Although differences between the psychiatric disorders have been reported, no consistent disorder-specific profiles have emerged from these efforts. The heterogeneous presentation of each psychiatric disorder and the pleiotropic nature of inflammatory cytokines support the hypothesis that a combination of biomarkers along with genetic and environmental risk factors may prove to be a more reliable predictor of disease.

Considering that not all individuals will manifest inflammatory abnormalities, identifying subtypes of mood disorders (perhaps informed by biomarkers) may help identify a subgroup of individuals with mood disorders wherein inflammatory disturbances are a critical component of the pathoetiology and/or treatment. With technological advancement, it is now possible to conduct microarrays and evaluate over 1000 analytes simultaneously. Preliminary studies using this method have begun to delineate common and distinct biological processes in MDD, bipolar disorder, and schizophrenia, bringing us one step closer to a more comprehensive model of disease and pharmacological revolution.

Acknowledgment-The authors would like to thank Marena Manierka for her invaluable input and comments during the writing of this article.

 Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. 

 Raison CL, Borisov AS, Majer M, et al. Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. 

 Sundquist K, Li X, Hemminki K, Sundquist J. Subsequent risk of hospitalization for neuropsychiatric disorders in patients with rheumatic diseases: a nationwide study from Sweden. 

 Chen SJ, Chao YL, Chen CY, et al. Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study. 

 Eaton WW, Byrne M, Ewald H, et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. 

 Dean B. Understanding the role of inflammatory-related pathways in the pathophysiology and treatment of psychiatric disorders: evidence from human peripheral studies and CNS studies. 

 Miller BJ, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. 

 Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. 

 Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. 

 Garver DL, Tamas RL, Holcomb JA. Elevated interleukin-6 in the cerebrospinal fluid of a previously delineated schizophrenia subtype. 

 Levine J, Barak Y, Chengappa KN, et al. Cerebrospinal cytokine levels in patients with acute depression. 

 SÃ¶derlund J, Olsson SK, Samuelsson M, et al. Elevation of cerebrospinal fluid interleukin-1Ã in bipolar disorder. 

 Kim YK, Jung HG, Myint AM, et al. Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. 

 Dhabhar FS, Burke HM, Epel ES, et al. Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression. 

 Kim YK, Myint AM, Lee BH, et al. Th1, Th2 and Th3 cytokine alteration in schizophrenia. 

Prog Neuropsychopharmacol Biol Psychiatry

 Goldstein BI, Collinger KA, Lotrich F, et al. Preliminary findings regarding proinflammatory markers and brain-derived neurotrophic factor among adolescents with bipolar spectrum disorders. 

 Padmos RC, Hillegers MH, Knijff EM, et al. A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. 

 Pandey GN, Rizavi HS, Ren X, et al. Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. 

 Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. 

 van Os J, Selten JP. Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands. 

 Miller GE, Cole SW. Clustering of depression and inflammation in adolescents previously exposed to childhood adversity. 

 Carroll JE, Cohen S, Marsland AL. Early childhood socioeconomic status is associated with circulating interleukin-6 among mid-life adults. 

 Uddin M, Koenen KC, Aiello AE, et al. Epigenetic and inflammatory marker profiles associated with depression in a community-based epidemiologic sample. 

 Lucassen PJ, Meerlo P, Naylor AS, et al. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: implications for depression and antidepressant action. 

 Leonard B, Maes M. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. 

A plethora of studies support the hypothesis that inflammation plays a role in the pathophysiology of major psychiatric disorders.

Are Psychiatric Disorders Inflammatory-Based Conditions?

When the patient comes, I say: “I know it is not easy to start talking about oneself to a stranger, but what can you tell me that would be helpful for me to understand you?” I see how they begin and I notice the content, but I also pay attention to the defense mechanisms, the avoidances, to what they don’t want to talk about. I let them know that it is important to say everything that occurs to them. “Free association” is really our basic tool . . . it yields insights that the patient does not censor.

So after I come to some conclusion, I say: “From what you tell me, I understand the following . . .” Then, I judge their capacity for insight. With some people, you can go deeper faster; with others, it is extremely delicate. You learn whether you have to watch your words very carefully, depending on how suspicious, disturbed, or trustful the patient is.

So you gradually create within yourself an image of the person and then you communicate out of your image. As you get to know the patient, the image becomes more articulate. In all of this, I am not focused on change. I am trying to understand what the patient is about and allowing him or her to develop the goal of his or her own changing.

I also use metaphors. Let’s say a patient is upset that he is not making any progress, then I might tell the following story. “Two men meet in Tel Aviv, and their conversation goes like this: ‘I haven’t seen you in a while!’ ‘Of course not, I was in South Africa.’ ‘What were you doing there?’ ‘I was on a safari.’ ‘The whole year?’ ‘Yes, the whole year. I was hunting lions.’ ‘How many lions did you get?’ ‘How many did I get? None!’” When it comes to lions, none is quite a bit!

I tell this vignette when a patient complains. It conveys the idea that some goals are difficult to attain. Like Alice in Wonderland, it takes all the running you can do, just to stay in the same place. That would be a similar idea.

I have been an analyst for 50 years, and if there is anything that I still find astonishing, it is that 

 patient has something new to communicate. Some have so much new to say that it’s bewildering.

It is as if an analyst is not only living his own life but also the lives of countless other people. So I think I am making a bargain with death. I am cheating. I am living more than one life.

Being a Therapist features intimate portraits of psychotherapists in their own work spaces. An excerpt of his interview with Dr Martin S.

Intimate Portrait: Martin S. Bergmann, PhD

As with many psychiatric drugs, the discovery of irreversible MAOIs was serendipitous. While being used as an antitubercular agent in the 1950s, iproniazid-a derivative of the hydrazine compound isocarboxazid-was observed to have significant antidepressant properties. Almost at the same time as the discovery of TCAs such as amitriptyline and imipramine (which were also discovered by chance), MAOIs began to be widely used as the first effective antidepressants.

In 1957, Nathan Kline, MD, one of the pioneers of psychopharmacology, published the first report on the neuropsychiatric experiences with iproniazid, referring to it as a “psychic energizer.”

 Within a year of the original report by Kline, more than 400,000 patients with depression had received iproniazid. This development led to the discovery of other, more potent MAOIs and more effective antidepressants, including phenelzine, isocarboxazid, and the nonhydrazine derivative tranylcypromine.

The vast majority of MAOI prescriptions were for tranylcypromine and phenelzine, which largely remain the MAOIs of choice today. Thus, MAOIs became the first class of antidepressants that became widely used in the early 1960s. In the 1960s and 1970s, combination drugs that included antidepressants and neuroleptic agents became popular. One such example was Parstelin, a combination of tranylcypromine and trifluoperazine.

The success of MAOIs in the late 1950s and early 1960s suddenly changed when iproniazid was removed from the US market because of concerns regarding hepatotoxicity. MAOIs were quickly replaced by the TCAs in the 1960s. Lpez-Muoz and Alamo

 suggest that the withdrawal of these drugs because of hepatotoxicity and jaundice may have been an overreaction. They also highlight the dramatic effect that an “antidepressant” drug had on the general attitude toward depression.

The fact that a medication that altered brain monoamines could treat a psychiatric illness such as depression suggested that the mechanism of action may be a chemical imbalance and not a predominantly psychological reaction. Even though ECT had been known to have a potent antidepressant effect, it was not until a pharmacological antidepressant was discovered that the fundamental concept of a neurobiological cause for depression was crystallized.

The enzyme monoamine oxidase exists as 2 subtypes, MAO-A and MAO-B. MAO-A metabolizes serotonin and norepinephrine (NE), the monoamines most closely linked to depression. MAO-B preferentially metabolizes dopamine and trace amines, including phenethylamine. Tyramine is metabolized by both MAO-A and MAO-B. Inhibition of MAO-B is not effective as an antidepressant because there is no direct effect on either serotonin or NE metabolism. Brain MAO-A must be inhibited for an antidepressant effect to occur. The ratio of MAO-A to MAO-B varies throughout the body. In the human brain, the ratio of MAO-A to MAO-B is 25% to 75%, whereas in the liver, the ratio is 50% to 50%. The ratio is 80% to 20% in the intestine, and in the peripheral adrenergic neurons, the ratio is 90% to 10%.

MAOIs act by inhibiting the activity of MAO and preventing the breakdown of monoamine neurotransmitters (serotonin and NE), thereby increasing their availability. Inhibition may be reversible or irreversible. When an MAOI covalently binds to the enzyme, it is irreversibly inhibited and the enzyme is permanently deactivated.

 Enzyme activity cannot be restored until the body replaces the enzyme through new enzyme synthesis. Restoration of full activity can take up to 2 weeks. Tranylcypromine and phenelzine, the most commonly prescribed MAOIs, are nonselective, irreversible inhibitors of isoforms MAO-A and MAO-B. Tranylcypromine was originally developed as an amphetamine analogue and thus also has some amphetamine-like effects.

The pharmacokinetics of both drugs are very different. Caddy and colleagues

 observed that phenelzine has a half-life of 2 hours. Weber-Grandke and colleagues

 observed that tranylcypromine exists as both a + enantiomer, with a half-life of 0.75 hours, and a − enantiomer, with a half-life of 1.5 hours. Nevertheless, since activity occurs through irreversible inhibition of MAO, the pharmacokinetics of the concentration of these drugs appears to have little relationship to effect. MAO inhibition will persist long after the drug has been eliminated from the body.

Shortly after the introduction of MAOIs into clinical practice in the early 1960s, the very serious adverse effect of hypertensive crisis was observed. The hypertensive crisis was initially described as a “cheese effect.”

 It is now known that this effect is caused by and proportional to the amount of tyramine ingested. Tyramine is a potent releaser of NE. When MAO activity is normal, the NE released by oral tyramine can be metabolized,including metabolism by MAO-A in the gut wall. However, when MAO is inhibited, the amount of NE released can elevate blood pressure. The average person can ingest about 400 mg of tyramine before excessive stimulation of adrenergic receptors occurs and blood pressure rises.

Because MAOIs inhibit MAO-A and MAO-B, if an MAOI such as tranylcypromine or phenelzine is administered before tyramine ingestion, tyramine sensitivity is dramatically increased. Ingesting foods high in tyramine can cause a pressor response in a patient with MAO-A and MAO-B inhibition, which is an increase in systolic blood pressure of 30 mm Hg or more. Tyramine that escapes into the systemic circulation is delivered to noradrenergic sympathetic neurons, where it causes the release of NE. Since MAO-A is inhibited, NE release results in a rise in blood pressure. In patients who have received either tranylcypromine or phenelzine, the amount of tyramine that can safely be ingested is likely less than 8 mg.

The tyramine-cheese reaction, hypertensive crises, and MAOI diets

The amino acid tyrosine (from the Greek word for cheese, tyros) was isolated from cheese as early as 1846. By 1911, it was known that tyramine (derived from tyrosine) had the potential to increase blood pressure. However, it was a series of case reports in the 1960s that described hypertensive crises associated with MAOIs that brought the MAOI-cheese relationship to the forefront and contributed to the rapid decline in MAOI use at a time of increasing medicolegal sensitivity.

This also led to the development of detailed dietary restrictions that were not always evidence-based. An international survey conducted in the early 1980s found that as many as 70 restricted food items had appeared on various MAOI diets.

 went on to conduct a series of systematic and carefully conducted tyramine analyses that in conjunction with a literature review of case reports led to a dramatically simpler MAOI diet (

). This diet attempts to find a balance between patient safety and compliance-only a few food items are restricted, such as aged cheeses and meats, draft beer, concentrated yeast extract (marmite), sauerkraut, and soy sauces.

The use of MAOIs has declined since the 1960s. Health care data from 1997 through 2007 were used in a population-based observational cohort study to determine prescribing trends and safety profiles of MAOIs in older adults.

 Only 348 new continuous users of irreversible MAOIs were identified over the 10-year period. The yearly incidence rate of MAOI prescriptions (new users for whom no MAOIs had been prescribed in the previous year) decreased from 3.1 per 100,000 in 1997 to 1.4 per 100,000 in 2006, while prevalence (among individuals in Ontario for whom MAOIs were prescribed) decreased from 400 in 1997 to 216 in 2006. During 2002, antidepressants as a whole were being prescribed at an increasing rate (10,900 per 100,000 of older adults). In stark contrast, during the same year, prescriptions for MAOIs were down to 21.3 per 100,000. In other words, only 1 of 500 prescriptions for antidepressants for older adults was for an MAOI. As expected, MAOIs were being used primarily for those older adults who had a high rate of prior use of other antidepressants and ECT.

While the use of MAOIs as first-line treatment has declined dramatically, these agents have remained in the clinical armamentarium for refractory depression and atypical depression. Winbiscus and colleagues

 reviewed the evidence for the use of MAOIs in atypical depression. This subtype of depression is defined by mood reactivity and 2 of the following symptoms: weight gain or hyperphagia, increased sleep, subjective feeling of leaden paralysis, and a personality trait of rejection hypersensitivity. It has been estimated that 30% of patients with unipolar depression may meet criteria for atypical depression.

The largest study of atypical depression was undertaken by Quitkin and colleagues.

 Phenelzine was shown to be superior to the TCA amitriptyline for atypical depression in more than 400 patients. Using a meta-analysis, Henkel and associates 

 found a mean effect size of 0.45 in favor of MAOIs over placebo and a more modest effect size of 0.27 in favor of MAOIs over TCAs, similar to the results of Quitkin and colleagues.

The widely cited STAR*D (Sequenced Treatment Alternatives to Relieve Depression) naturalistic study conducted in the US provided for a sequence of therapeutic options depending on response. The primary outcome measure in this study was remission, defined as a score of less than 7 on the Hamilton Depression Rating Scale. The secondary outcome was response defined by a 50% reduction on the Quick Inventory of Depressive Symptomatology (QUIDS).

Of the 4 levels of treatment in the study, level 4 included a switch to the MAOI tranylcypromine or to a combination of 2 antidepressants, mirtazapine and venlafaxine. Response and remission rates were found to be nonsignificantly greater in the antidepressant combination group than in the tranylcypromine group. The remission rate for the combined antidepressants was 14%, while it was only 7% for tranylcypromine. The response rate for the combination of antidepressants was 24% compared with only 12% for tranylcypromine. There were significantly fewer trial dropouts in the antidepressant combination group than in the tranylcypromine group. In the 21 patients with atypical depression, there was no significant difference in response rates between the two groups. The mean dose for tranylcypromine was 36.9 mg and the mean dose for the antidepressant combination was 210.3/95.2 mg. All in all, this was a disappointing outcome for MAOIs.

 highlights the fact that of the patients randomized to the tranylcypromine group, 41% had entered the study because of previous medication intolerance in other STAR*D trials, while only 22% of patients who were randomized to the combination antidepressant group had a similar medication intolerance. This could very well account for the increased dropout rate for tranylcypromine and the relatively poor response.

Professor Phillip Cowan, a prominent psychopharmacologist from the University of Oxford, reports his personal favorable experience with the use of tranylcypromine. Although the wait is well worth it, he notes the practical problem of using an MAOI in refractory depression-the need for a prolonged washout period to avoid possible serotonin syndrome. The wait is 2 weeks when switching from an SSRI and 5 weeks when switching from fluoxetine. This interim period requires close follow-up with symptomatic management only.


Sunnybrook Health Sciences Centre dietary restrictions for patients taking MAOIs

Two recent articles report on recommendations for an algorithm-guided treatment for depression, similar to that in the STAR*D trial. Spijker and Nolen

 compared a Dutch algorithm for the treatment of depression with 4 other guidelines, including those from the Texas Medication Algorithm Project (TMAP), the Canadian Network for Mood and Anxiety Treatments (CANMAT), the Royal Australian and New Zealand College of Psychiatrists (RANZCP), and the STAR*D study.

The RANZCP guideline does not mention MAOIs at all. However, the Dutch algorithm recommends tranylcypromine as a step-4 treatment and as a step-2 treatment for atypical depression. TMAP and CANMAT guidelines recommend MAOIs as an option in step 3.

A German study used a 10-step algorithm that involves antidepressant monotherapy, lithium augmentation, combined lithium and MAOI therapy, and finally ECT.

 Steps 7 and 8 of the algorithm comprise MAOI combined with lithium. In this single-center prospective study, algorithm-guided therapy was demonstrated to produce significantly better outcomes and less frequent medication changes than treatment as usual.

This algorithm uses lithium augmentation followed by lithium monotherapy. If this is unsuccessful, the next step includes the use of an MAOI (tranylcypromine) at 20 mg/d in combination with lithium. If that fails, then 40 mg/d of tranylcypromine combined with lithium is used. The researchers suggest that a better response may have been achieved with a higher dosage of tranylcypromine than the maximum 40 mg/d recommended in this algorithm. This is similar to the concerns for the STAR*D trial in which a mean dose of 36.9 mg of tranylcypromine was used.

 reflects the personal opinion of another experienced and well-respected psychopharmacologist. Because of limited numbers of patients available for clinical trials, guidance is often dependent on the personal experience of opinion leaders. In his experience, many patients with treatment-resistant depression may reach remission when given a course of MAOI treatment. Fawcett considers a full course of treatment to be at least 6 weeks at the maximum tolerated dose. He also comments on the relative safety of MAOIs. In over 40 years, he had only 1 case of hypertension with headache induced by diet, which was managed in the office with thioridazine.

Fawcett highlights the nature of treatment-refractory depression and the misery to which it condemns its victims. While acknowledging some increased risk, he feels that there is still a good chance of “resurrecting a life devastated by depression or even saving a life.” He discusses 7 patients from his personal practice with recalcitrant depression who were treated with MAOIs-6 of the patients had symptom remission. Three of the 6 patients were given additional augmentation with stimulants. Fawcett provides sage advice: “Before initiating an MAOI, I ask myself, ‘if this patient is unlucky enough to have a serious adverse reaction as a result of the MAOI, can I honestly say that the MAOI was fully indicated?’” In retrospect, he found the answer to be a resounding “yes.”

Opinion leaders and several international consensus guidelines include MAOIs in the armamentarium of treatment-refractory depression and atypical depression. As such, we feel-like Fawcett-that the current low rate of MAOI prescriptions is not consistent with current recommendations. The safety profile of MAOIs seems to have improved significantly, based on a population-based cohort study of older adults; there were no episodes specific for a hypertensive crisis or serotonin syndrome identified in that study.

Given the likelihood that insufficient numbers of patients will be available for a randomized controlled trial of MAOIs in refractory depression or atypical depression, we must still rely on consensus guidelines and expert opinion. The proportion of patients who may potentially benefit from MAOIs is substantial. The atypical depression subtype of mood disorder may represent 15% to 29% of all patients with MDD.

Findings from STAR*D suggest that a third of patients with MDD meet criteria for stage 2 treatment-refractory depression. Potentially, MAOIs could be used in a much larger proportion of patients with mood disorder than is currently the case. Revised dietary recommendations in combination with psychoeducation regarding the need to avoid concomitant exposure to serotonergic and sympathomimetic agents should provide a reasonable balance of risk and benefit in the use of irreversible MAOIs. Because they are not promoted by any major pharmaceutical company and because of their checkered history, we are at risk for seeing this class of drugs with the potential to benefit a significant subset of patients with mood disorder relegated to obscurity.

Editor’s Note: Our Category 1 CME articles are on a brief hiatus. In the meantime, we invite you to test yourself: read the article, take the posttest on the next page, and then check the answer key on the last page of this article for the correct answers.

 Which of the following was the first MAOI-referred to as a “psychic energizer”?

A. Tranylcypromine
B. Iproniazid
C. Phenelzine
D. Selegiline

 Once ECT was shown to be effective for treating depression, the neurobiological cause for depression was crystallized.

A. True
B. False

As a metabolizer of serotonin and norepinephrine, which of the following is most clearly linked to depression?

A. MAO-A
B. MAO-B

 Which of the following is true of an irreversible MAOI?

A. The binding of the MAOI to the enzyme is temporary
B. It inhibits the activity of monoamine oxidase
C. Depending on the MAOI, the half-life of the drug plays an important role in efficacy

When MAO is inhibited, tyramine will release ________________; excessive amounts will consequently raise blood pressure.

A. Dopamine
B. Serotonin
C. Epinephrine
D. Norepinephrine

 Which of the following is safe on a low-tyramine diet?

A. Red wine
B. Beer on tap
C. Salami
D. Sauerkraut

 MAOIs have remained in the armamentarium as a first-line treatment for which of the following?

A. Unipolar depression
B. Atypical depression
C. Bipolar depression

 Patients with refractory depression treated with tranylcypromine should start the restricted diet 1 day before taking the medication and continue the diet for 2 weeks after stopping the medication.

A. True
B. False

Answer key to the Mine Your Mind posttest:

 B; It inhibits the activity of monoamine oxidase



 LÃ³pezMuÃ±oz F, Alamo C. Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. 

 Patkar AA, Pae CU, Masand PS. Transdermal selegiline: the new generation of monoamine oxidase inhibitors. 

 Schatzberg AF. Safety and tolerability of antidepressants: weighing the impact on treatment decisions. 

 Caddy B, Stead AH, Johnstone EC. The urinary excretion of phenelzine. 

 Weber-Grandke H, Hahn G, Mutschler E, et al. The pharmacokinetics of tranylcypromine enantiomers in healthy subjects after oral administration of racemic drug and the single enantiomers. 

 Blackwell B. Hypertensive crisis due to monoamine-oxidase inhibitors. 

 Bieck PR, Antonin KH. Oral tyramine pressor test and the safety of monoamine oxidase inhibitor drugs: comparison of brofaromine and tranylcypromine in healthy subjects. 

 Blackwell B, Mabbitt LA. Tyramine in cheese related to hypertensive crises after monoamine-oxidase inhibition. 

 Sullivan EA, Shulman KI. Diet and monoamine oxidase inhibitors: a re-examination. 

 Shulman KI, Walker SE, MacKenzie S, Knowles S. Dietary restriction, tyramine, and the use of monoamine oxidase inhibitors. 

 Shulman KI, Fischer HD, Herrmann N, et al. Current prescription patterns and safety profile of irreversible monoamine oxidase inhibitors: a population-based cohort study of older adults. 

 Winbiscus M, Kostenko O, Malone D. MAO inhibitors: risks, benefits, and lore. 

 Asnis GM, McGinn LK, Sanderson WC. Atypical depression: clinical aspects and noradrenergic function. 

 Quitkin FM, Stewart JW, McGrath PJ, et al. Columbia atypical depression. A subgroup of depressives with better response to MAOI than to tricyclic antidepressants or placebo. 

 Henkel V, Mergl R, Algaier AK, et al. Treatment of depression with atypical features: a meta-analytic approach. 

 Wingo AP, Ghaemi SN. STAR*D level IV methodology. 

 Spijker J, Nolen WA. An algorithm for the pharmacological treatment of depression. 

 Bauer M, Pfennig A, Linden M, et al. Efficacy of an algorithm-guided treatment compared with treatment as usual: a randomized, controlled study of inpatients with depression. 

 Fawcett J. Why aren’t MAOIs used more often? 

 Thase ME. Recognition and diagnosis of atypical depression. 

Given the likelihood that insufficient numbers of patients will be available for a randomized controlled trial of MAOIs in refractory depression or atypical depression, we must still rely on consensus guidelines and expert opinion.

Irreversible Monoamine Oxidase Inhibitors Revisited

Nearly 50 years ago, psychiatric diagnosis was described as the “soft underbelly” of psychiatry because of poor inter-rater agreement.

 Historically, psychiatric diagnoses were interpretive and somewhat subjective. Relative to medicine as a whole, psychiatry has few laboratory markers or imaging data to confirm a preliminary diagnosis. However, subsequent iterations of DSM have aspired to more accurate, reliable diagnoses. Despite this, the inter-rater reliability of psychiatric diagnosis remains a challenge as American psychiatry prepares to welcome DSM-5.

Inter-rater (or intercoder) reliability is a measure of how often 2 or more people arrive at the same diagnosis given an identical set of data. While diagnostic criteria help establish reliable diagnoses, the methods of gathering and interpreting patient data have a tremendous effect on how likely it is that 2 examiners will come to the same diagnostic conclusion for a given patient. Here we review inter-rater reliability research, identify factors that threaten diagnostic reliability, and offer examples of assessment strategies that may provide increased diagnostic reliability in general clinical settings.

Reliability of psychiatric diagnoses today

In diagnostic assessment, perfect inter-rater reliability would occur when psychiatric practitioners could always arrive at the same diagnosis for a given patient. When evaluating and interpreting inter-rater reliability, the measurement statistic used is kappa; the higher the kappa ranking, the stronger the degree of agreement is between raters. Indeed, no field of medicine is able to achieve perfect agreement-there are degrees of variance among diagnosticians in other specialties.

We are not saying that psychiatric diagnoses wholly lack objectivity, nor do we dismiss the “art” of psychiatry. Dependent on the skill of the rater and category of disorder, the inter-rater reliability of psychiatric diagnoses can be quite high and comparable to the kappas obtained for several diagnoses in other medical specialties. For example, Ruskin and colleagues

 demonstrated a kappa of 0.83 for 4 common psychiatric diagnoses. However, lacking some of the more objective measures enjoyed by other specialties, psychiatry faces additional challenges with inter-rater reliability.

Similar to goals of other fields of medicine, a central goal of psychiatric nosology is diagnostic reliability and consistency. Despite this goal, however, diagnostic reliability for some psychiatric disorders remains low. For example, studies have revealed a strong discordance among the diagnoses of psychotic disorders. McGorry and colleagues

documented 66% to 76% inter-rater reliability for this class of disorders and a corresponding discordance of 24% to 34%. Likewise, Maj and colleagues

 demonstrated a low kappa of 0.22 for the diagnosis of schizoaffective disorder.

Despite the ongoing revision of diagnostic criteria with each subsequent iteration of DSM, clinicians report concerns that diagnostic reliability generally remains poor. In a small-survey study in 2007, Aboraya 

DSM-5 presents psychiatry with a potential “reset button” for diagnostic reliability.

Psychiatric Times Vol 29 No 10

Treatment Resistance and Patient Authority: The Austen Riggs Reader

Social Media: A Key Component to the Psychiatrist's Practice

Are Psychiatric Disorders Inflammatory-Based Conditions?

Intimate Portrait: Martin S. Bergmann, PhD

Irreversible Monoamine Oxidase Inhibitors Revisited

Inter-Rater Reliability in Psychiatric Diagnosis

POINT: The Case for Gun Control

COUNTERPOINT: Gun Control and the Second Amendment

Sharp-Shinned Hawk

Violence in the Media: What Effects on Behavior?

Eating Disorders in Males

Neuropsychiatric Differences Between Boys and Girls With ADHD