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A. It occurs in a third of all patients with panic disorder

B. Atypical antipsychotics should be used a monotherapy for TRP

C. Benzodiazepines can be a safe/effective adjunct to SSRI treatment

D. There are many good studies to inform clinical practice

Some patients with panic disorder have chronic, persistent symptoms. Take the quiz and learn more.

Mini Quiz: Panic Disorder

Panic disorder (PD), a common and impairing anxiety syndrome, is generally readily diagnosable and treatable. Its phenomenology is diverse, including acute fear episodes (spontaneous and cued panics), anticipatory anxiety, and physical sensation sensitivity. PD is also frequently accompanied by agoraphobia and is more likely to affect women.

Concerning the natural history of PD, approximately one-third of patients have a clinical remission with standard interventions (pharmacotherapies and cognitive behavioral therapy [CBT]), without subsequent episodes. In another third, the course of the illness is characterized by recurrent episodes, which remain treatment-sensitive. However, a third go on to have chronic, persistent symptoms-and the majority of these patients have treatment-resistant panic (TRP).

Treatment resistance in PD may be apparent or real. Apparent treatment resistance may be due to a range of clinical factors including unstable psychiatric and medical comorbidities, patient adherence problems, clinician availability (important to PD patients early in treatment), or therapeutic alliance problems, often driven by cognitive and behavioral avoidance. Other treatment-related factors to consider are medication intolerance/pharmacokinetic issues, treatment acceptability, access to care, and treatment costs. However, despite a careful review of the diagnosis and adjustments to the treatment plan, a number of patients will have ongoing, real TRP.

Exactly what constitutes treatment resistance in PD is a topic of debate. However, one clinical definition is continued partial response, or non-response, after 6 months of optimal treatment with at least 2 standard, evidence-based interventions.

A straightforward measurement-based approach can complement this clinical guideline. The Panic Disorder Severity Scale (PDSS), a commonly used outcome in PD clinical trials, is also an excellent scale for general clinical use.

 It is a brief, clinician-rated assessment that consists of 7 items (each rated 0 to 4), which sample different domains of PD symptoms. In clinical trials, a PDSS total score of 4 or lower is often considered a clinical remission, while a clinical response is frequently defined as a 50% reduction from the baseline PDSS total score.

Some experts suggest that patients should not have an individual PDSS item score higher than 1 to qualify for remission status. Thus, by PDSS criteria, TRP patients will have only a partial or limited response to specific interventions and, over the course of treatment, will fail to achieve a remission state.

A chronic, persistent illness course is likely to carry an increased risk of various known complications. These include sequelae such as agoraphobia, major depression, other anxiety disorders, substance abuse, and an increased risk of suicidality. Functional implications include diminished quality of life, under- or unemployment, and social isolation. Moreover, TRP patients might be at higher risk for chronic inflammation and physical health conditions, such as cardiovascular and neurodegenerative diseases.

Potential clinical predictors of TRP are earlier age of illness onset; severity of symptoms; psychiatric comorbidity; high levels of sensation sensitivity; high trait anxiety; chronic, persistent life stressors; and a history of early childhood trauma. The mechanisms responsible for the development of TRP are unclear. However, PD is heritable, and genetic and epigenetic factors have been implicated in its pathophysiology. Genetic variations in key stress and fear-related brain neurotransmitter systems (eg, the 5-HT, norepinephrine, dopamine, GABA, and peptide systems) and their attendant impact on brain fear network activity, and even morphology, are likely to affect treatment sensitivity.

After factors that contribute to apparent resistance have been addressed, the next consideration is a review of the treatment history to ascertain which evidence-based interventions the patient has already received, and to ensure that these have been applied for an adequate period (eg, 8 to 12 weeks) and at an appropriate dose/intensity level.

Evidence-based pharmacotherapies include SSRIs, SNRIs, TCAs, the MAOI phenelzine, and benzodiazepine agonists (eg, clonazepam and alprazolam, which are approved by the FDA for panic). Recommended psychotherapies include CBT (especially individual CBT). Data from a large meta-analysis of anxiety studies suggest that combination treatment (medication plus CBT) is likely to be superior to monotherapy and should now be routinely offered.

 In a large, placebo-controlled, multisite, comparative PD treatment study of CBT (with interoceptive desensitization) plus imipramine versus monotherapies, combination treatment effects were superior at the end of 12 weeks.

 Although the patient has a diagnosis of TRP, the goal of treatment is still to achieve a remission state, as this protects against relapse and lowers the risk of complications.

Genetic testing may be of value if the patient has been intolerant of or resistant to several standard-of-care medication trials. Findings suggest that patients (especially females) with 5-HT transporter promoter gene short (s) alleles, are less likely to respond to SSRI treatment.

 Moreover, patients who are “slow metabolizers” may respond to modest doses of standard agents and require a slower upward titration schedule.

 This next step is a simple one and could be helpful, especially if the patient has other psychiatric comorbidities. However, one controlled trial of next-step treatment in PD patients resistant to an initial SSRI trial did not find additional benefit for core panic symptoms with dose optimization.

 Within-class switching may not be a high-yield intervention. However, switching to an agent with a different pharmacodynamic profile is a reasonable step. For example, one good option is imipramine, often overlooked because of its risk of cardiotoxicity in overdose; yet it is one of the most intensively studied antipanic agents available. MAOIs, also seldom used now, can be surprisingly helpful as well.

Avoid monotherapy with bupropion because this is very activating for the average PD patient. In addition, there are little efficacy data on the benefits of newer antidepressants (eg, vortioxetine, milnacipran) in TRP.

 While clinical guidelines tend to rank benzodiazepines as second- or third-line antipanic agents, this is primarily because of concerns about sedation, physiological dependence, psychological dependence, and the slight risk of benzodiazepine abuse/diversion, especially with longer-term use. In fact, benzodiazepines are similarly effective to antidepressants for panic disorder, and their panicolytic benefit is almost always sustained over the long term.

Adverse effects such as sedation and incoordination are most apparent in the initial weeks of therapy, and this is when the risks for operating heavy machinery and driving are elevated. Thereafter, tolerance to the sedative effects occurs.

Benzodiazepines may have a long-term tolerability edge over the SSRIs, SNRIs, and TCAs, as they do not cause weight gain or sexual dysfunction. Generally, high-potency, shorter half-life benzodiazepines are preferable because of their more predictable pharmacokinetics and simpler metabolism. Regular dosing (vs PRN) is recommended to achieve optimal anxiolysis. In considering the rationale for long-term benzodiazepine administration, review the Dupont criteria clinical probes listed in 

 For additional details on dosing and administration, see 

The concern that benzodiazepines disrupt the effectiveness of evidence-based psychotherapies for panic, such as CBT, has not been confirmed in recent anxiety clinical trials.

). A meta-analysis of controlled studies in resistant anxiety disorders demonstrated limited additional benefits with several augmenting strategies (benzodiazepine, atypical antipsychotic, or pregabalin).

 The second step of the study from Simon and colleagues

 included random assignment to either clonazepam or CBT. These options were similarly effective next-step interventions. Accordingly, coadministration of a benzodiazepine is a reasonable first-choice augmentation option and is safe for longer-term treatment.

If this is not effective or tolerated, coadministration with an atypical antidepressant, such as mirtazapine, is a reasonable second step. A suggested third step in augmentation is addition of an anticonvulsant agent (eg, gabapentin, pregabalin, valproic acid, lamotrigine), as data from meta-analyses provide some support for this practice in anxiety and PD, and even suggest the potential benefit of an EEG in the work-up for TRP patients to improve anticonvulsant outcomes.

Finally, while a positive evidence base for second-generation antipsychotics in PD and TRP is limited, current reports suggest that low-dose coadministration or monotherapy is tolerated in short-term trials.

 Specifically, olanzapine, quetiapine, and risperidone were generally well-tolerated. In one small, 12-week, placebo-controlled trial in patients with SSRI-resistant PD, lower-dose quetiapine ER coadministration, on average, did not provide additional clinical benefit, yet was fairly well tolerated.

Effective psychotherapies for PD include CBT (strongest evidence), panic-focused psychodynamic psychotherapy, and CBT with a mindfulness component, and these are also suitable options for TRP. Where access to therapy is a problem, online CBT programs can be of value and have growing empirical support.

CBT may be augmented with pre-session cognitive enhancement interventions, such as oral administration of the glutamine/NMDA receptor glycine site partial agonist, D-cycloserine. However, results of this strategy in larger-scale trials of anxiety spectrum disorders have been mixed.

 Attention bias modification therapy has shown promise in clinical trials across anxiety disorders and may be useful for some patients.

 Finally, acceptance- and commitment-focused CBT could be of value for the patient with TRP who has been resistant to most other psychotherapeutic approaches.

 Complementary/alternative/integrative interventions for PD, such as moderate exercise, may add additional benefit to the treatment plan. Transcranial magnetic stimulation has demonstrated some promise for difficult-to-treat panic and might become an established care option pending further study. Consultation with a mental health provider who specializes in anxiety should also be considered when treatment has reached an impasse. Area providers can be accessed through the Anxiety and Depression Association of America website: www.adaa.org.

TRP is a common clinical problem that has been understudied and under-recognized compared with other high-prevalence refractory conditions, such as treatment-resistant depression. There has been debate about the criteria for resistance, but failure of optimal treatment (attainment of remission) with 2 evidence-based interventions, over a 6-month period, is a useful clinical definition. One measurement-based approach to TRP recognition involves the use of the PDSS. In general, the goal of clinical treatment of PD is to achieve a remission state (PDSS total score of 4 or lower). TRP should be treated vigorously with this goal in mind, as residual symptoms confer a higher risk of clinical complications.

While few controlled treatment studies inform monotherapy, combination treatment, and augmentation approaches for TRP, clinical guidelines, treatment meta-analyses, and expert opinion offer some guidance. On occasion, special tests such as EEG or genetic testing may be indicated and can contribute to better outcomes. Currently, a range of interventions (pharmacotherapies, psychotherapies, and complementary and neuromodulation interventions) offer hope and help for patients. However, in the future, personalized medicine strategies, involving baseline genotyping and functional neuroimaging, may afford a more predictive approach to TRP care planning.

Dr. Goddard is Professor of Psychiatry, University of California at San Francisco, UCSF Fresno Medical Education & Research Program, Fresno, CA. Dr. Goddard receives royalties from UpToDate for an on-line manuscript publication; he is also the recipient of pilot grant funds from the National Network of Depression Centers (NNDC) for a multisite ketamine trial.

 Batelaan NM, de Graf R, Penninx BW, et al. The 2-year prognosis of panic episodes in the general population. 

 Freire RC, Zugliani MM, Garcia RF, Nardi AE. Treatment-resistant panic disorder: a systematic review. 

 Shear MK, Brown TA. Barlow DH, et al. Multicenter collaborative panic disorder severity scale. 

 Cuijpers P, Sijbrandij M, Koole SL, et al. Adding psychotherapy to antidepressant medication in depression and anxiety disorders: a meta-analysis. 

 Barlow DH, Gorman JM, Shear MK, Woods SW. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: a randomized controlled trial. 

 Perna G, Favaron E, Di Bella D, et al. Antipanic efficacy of paroxetine and polymorphism within the promoter of the serotonin transporter gene. 

 Simon NM, Otto MW, Worthington JJ, et al. Next-step strategies for panic disorder refractory to initial pharmacotherapy: a 3-phase randomized clinical trial. 

 DuPont RL. Panic disorder and addiction: the clinical issues of comorbidity.

 Patterson B, Van Ameringen M. Augmentation strategies for treatment-resistant anxiety disorders: a systematic review and meta-analysis. 

 Starcevic V. The reappraisal of benzodiazepines in the treatment of anxiety and related disorders. 

 Boutros NN, Ghosh S, Khan A, et al. Anticonvulsant medications for panic disorder: a review and synthesis of the evidence. 

 Perna G, Alessandra A, Raffaele B, et al. Is there room for second-generation antipsychotics in the pharmacotherapy of panic disorder? A systematic review based on PRISMA guidelines. 

 Goddard AW, Mahmud W, Medlock C, et al. A controlled trial of quetiapine XR coadministration treatment of SSRI-resistant panic disorder. 

 Andersson G, Cuipers P, Carlbring P, et al. Guided internet-based vs face-to-face cognitive behavior therapy for psychiatric and somatic disorders: a systematic review and meta-analysis. 

 Ori R, Amos R, Bergman H, et al. Augmentation of cognitive and behavioural therapies (CBT) with d-cycloserine for anxiety and related disorders. 

 Hakamata Y, Lissek S, Bar-Haim Y, et al. Attention bias modification treatment: a meta-analysis toward the establishment of novel treatment for anxiety. 

How to help the one-third of patients with panic disorder who have chronic, persistent symptoms?

Treatment-Resistant Panic Disorder

Many readers of my previous blog listing the 

 were shocked that I failed to mention an 11th dangerous mistake-that DSM-5 will harm people who are medically ill by mislabeling their medical problems as mental disorder. They are absolutely right. I apologize for my previous failure to attend to this danger and hope it is not now too late to influence the process.

Adding to the woes of the medically ill could be one of the biggest problems caused by DSM-5. It will do this in two ways: 1) by encouraging a quick jump to the erroneous conclusion that someone's physical symptoms are 'all in the head'; and 2) by mislabeling as mental disorders what are really just the normal emotional reactions that people understandably have in response to a medical illness.

UK health advocate, Suzy Chapman, has closely monitored every step in the development of DSM-5. Her website is the best available resource for finding just about everything you need to know about DSM-5 and ICD-11. Ms Chapman sent me a troubling email that summarizes where DSM-5 has gone wrong and the many harmful consequences that will follow. More details are available at: 'Somatic Symptom Disorder could capture millions more under mental health diagnosis' (

The DSM-5 Somatic Symptom Disorders Work Group is planning to eliminate several little used DSM-IV Somatoform Disorders and replace them instead with an extremely broad new category that is likely to be wildly overused ('Somatic Symptom Disorder'-SSD).

A person will meet the criteria for SSD by reporting just one bodily symptom that is distressing and/or disruptive to daily life and having just one of the following three reactions to it that persist for at least six months: 1) 'disproportionate' thoughts about the seriousness of their symptom(s); or 2) a high level of anxiety about their health; or, 3) devoting excessive time and energy to symptoms or health concerns.

Unless DSM-5 changes these incredibly over inclusive criteria, it will greatly increase the rates of diagnosis of mental disorders in the medically ill-whether they have established diseases (like diabetes, coronary disease or cancer) or have unexplained medical conditions that so far have presented with somatic symptoms of unclear etiology.

The diagnosis of mental disorder will be based solely on the clinician's subjective and fallible judgment that the patient's life has become 'subsumed' with health concerns and preoccupations, or that the response to distressing somatic symptoms is 'excessive' or 'disproportionate,' or that the coping strategies to deal with the symptom are 'maladaptive'.

These are inherently unreliable and untrustworthy judgments that will open the floodgates to the overdiagnosis of mental disorder and promote the missed diagnosis of medical disorder.

The DSM-5 Work Group is taking a flying leap into the unknown. There are no published research data on the likely prevalence rates, clinical characteristics or treatment of 'Somatic Symptom Disorder,' or its validity and safety as a construct. Decisions to code or not to code will hang on the arbitrary and subjective perceptions of DSM end-users who often spend very little time with the patient and lack training in psychiatry.

The DSM-5 field trials produced results that should have scared off the Work Group. One in six cancer and coronary disease patients met the criteria for DSM-5 'Somatic Symptom Disorder.' Do we really want to burden and stigmatize seriously ill people with an additional diagnosis of mental illness, just because they are worried about being sick and are vigilant about their symptoms? Might patients with life threatening diseases become reluctant to report new symptoms that might be early indicators of recurrence, metastasis or secondary disease-for fear of attracting a diagnosis of 'SSD'?

The Work Group is not proposing to classify Chronic Fatigue Syndrome, Irritable Bowel Syndrome, and Fibromyalgia within the DSM-5 'Somatic Symptom Disorders' section, but these patients and others with conditions like chronic Lyme disease, interstitial cystitis, Gulf War illness and chemical injury will now become particularly vulnerable to misdiagnosis with a DSM-5 mental health disorder. In the field trials, more than one in four of the irritable bowel and chronic widespread pain patients who comprised the 'functional somatic' study group were coded for 'Somatic Symptom Disorder.'

To meet requirements for Somatization Disorder (300.81) in DSM-IV, a considerably more rigorous criteria set needed to be fulfilled. There had to be a history of many medically unexplained symptoms before the age of thirty, resulting in treatment sought or psychosocial impairment. The diagnostic threshold was set high-a total of eight or more medically unexplained symptoms from four, specified symptom groups, with at least four pain and two gastrointestinal symptoms.

In DSM-5, the requirement of eight symptoms is dropped to just one. And the requirement of 'medically unexplained' symptoms is replaced by much looser and more subjective 'excessive thoughts, behaviors and feelings' and the clinician's perception of "dysfunctional illness belief' or 'excessive preoccupation' with the bodily symptom.

That, and a duration of at least six months, is all that is required to tick the box for a bolt-on diagnosis of a mental health disorder - Colorectal cancer + SSD; Angina + SSD; Type 2 diabetes + SSD; IBS + SSD.

I would like to put to Dr Dimsdale: what percentage increase in mental health diagnoses across the entire disease spectrum is estimated to result from implementation of his group's ad hoc proposals and has he also considered the increased costs to U.S. health care providers and payers?

Incautious, inept misapplication of these highly subjective and catch-all criteria will likely result in frequent inappropriate psychiatric diagnosis with far-reaching implications for both the health care industry and diverse patient populations. Harms include:

• Missed diagnoses through failure to investigate new or worsening somatic symptoms.

• Patients will be prescribed inappropriate psychotropic drugs with consequent side effects, complications, and costs.

• There may be limits imposed on the types of medical tests and treatments offered for patients misdiagnosed as having a mental disorder.

• Misdiagnosed patients may be disadvantaged in employment, medical and disability reimbursement.

• An additional diagnosis of 'SSD' in a patient's medical history may negatively influence decisions made by agencies involved with social and medical services, disability adaptations, education and workplace accommodations.

• An inaccurate SSD diagnosis will skew the person's view of herself and her illness and perceptions of family and friends.

• In multi-system diseases like Multiple Sclerosis, Behet's syndrome or Systemic lupus, it can take several years before a diagnosis is arrived at. In the meantime, patients with chronic, multiple somatic symptoms who are still waiting for a diagnosis would be vulnerable to misdiagnosis as psychiatrically ill.

• DSM-5 allows for a diagnosis of 'Somatic Symptom Disorder' when a parent is considered 'excessively concerned' about a child's symptoms. Families caring for children with any chronic illness may be placed at risk of wrongful accusation of 'over-involvement' with their child's symptomatology or of encouraging 'sick role behavior.' By what means will a practitioner accurately assess an individual's response to illness within the context of the patient's personal, family and economic circumstances and reliably determine what might be considered 'excessive preoccupation' versus a positive coping strategy for that patient and family?

• The burden of the DSM-5 changes will fall particularly heavily upon women who are more likely to be casually dismissed when presenting with physical symptoms and much more likely to receive inappropriate antidepressants and anti anxiety medications for them.

The Work Group is well aware that patients, families, caregivers and advocacy organizations are strongly opposed to the DSM-5 changes. During the second DSM-5 public review, the 'Somatic Symptom Disorders' proposals attracted more responses than almost any other category.

At the APA's 2012 Annual Meeting, Work Group Chair, Joel Dimsdale, MD, admitted his committee has struggled from the outset with the 'SSD' criteria set. But rather than revising in favor of less inclusive requirements or subjecting the entire section to independent, external scientific review, the Work Group's puzzling response has been to lower the threshold even further from 'at least two from the B type criteria' to 'at least one'-placing even more medical patients at grave risk of attracting an inappropriate mental health diagnosis.

Despite the APA Trustees' signing off on DSM-5, work on specific wording is still not complete. Psychiatric and non psychiatric clinicians, primary care practitioners and specialists, allied health professionals, psychologists, counselors, social workers, medical lawyers and patient advocacy organizations all need to look very hard and quickly at these proposals, consider their safety and the implications of an additional diagnosis of 'SSD,' and weigh in vigorously to the Work Group Chair with a call for urgent revision of this section . . . while there is still time.

Ms Chapman has provided a devastating and compelling critique. It is crucial that DSM-5 tighten its over-inclusive wording to prevent what could otherwise be the wholesale dismissal of real medical symptoms as psychiatric illness-leading to missed diagnoses, incorrect treatment, stigma, and patients understandably feeling greatly misunderstood.

I first became personally and painfully aware of the risks of misdiagnosis of somatic symptoms when, as a new psychiatric resident, I treated a man for depression for two months before discovering that his problems were in fact caused by the brain tumor I had previously missed.

The golden rule: an underlying medical illness or medication side effect has to be ruled out before ever deciding that someone's symptoms are caused by mental disorder. And the underlying medical illness may take time to declare itself. Uncertainty is hard to live with, but much better than jumping to false and risky conclusions.

The boundary between medical and psychiatric illness is inherently difficult to draw, especially since many psychiatric disorders do present with prominent somatic symptoms that are often mistaken for medical illness. Best example-people with panic attacks often get far too many medical tests for the dizziness, shortness of breath, and palpitations that are really just part of the hyperventilation caused by the panic attack. And the emotional distress some people have in reaction to real or feared illness does sometimes get out of all proportion enough to require psychiatric attention.

But there are serious risks attached to over-psychologizing somatic symptoms and mislabeling the normal reactions to being sick-especially when the judgments are based on vague wording that can't possibly lead to reliable diagnosis. DSM-5 as it now stands will add to the suffering of those already burdened with all the cares of having a medical illness.

DSM-5 must emphasize that physical symptoms deserve the respect of a thorough work-up before assuming their cause is psychiatric. And people with defined medical illnesses should not be casually mislabeled as also mentally ill just because they are upset about being sick.

There is a possible solution to the problems we have identified. Somatic Symptom Disorder should be removed from the main body of DSM-5 that is meant to describe the various mental disorders. Instead, unexplained physical symptoms or problematic responses to illness should be covered in the V Code section of the manual that includes Other Conditions That May Be A Focus of Clinical Attention. This would remove the stigma and risks of mislabeling somatic concerns as mental disorders, while still providing clinicians with a code to describe the presentation. Second best solution-tighten the wording of the criteria set to make it less wildly over inclusive. As Ms Chapman points out, time is running out because DSM-5 is being rushed to press half-baked.

Mislabeling Medical Illness As Mental Disorder

The fear of dying during a panic attack is an independent risk factor for subsequent suicide attempts among individuals with depressive disorders, psychiatrists Zimri Yaseen, MD, Igor Galynker, MD, PhD, and colleagues conclude in their recently published prospective study.

 This finding, they assert, may help clinicians assess suicide risk and ultimately prevent suicides.

“Suicide is an epidemic. Rates are rising despite medications. And we are really pitiful at predicting suicide in a specific person,” said Galynker, Professor of Clinical Psychiatry at Albert Einstein College of Medicine in New York and Associate Chairman of Psychiatry at Beth Israel Medical Center.

According to the CDC’s latest published report, there were 38,364 suicides in the US in 2010-an average of 105 each day. Globally, an estimated 1 million suicides occur annually.

“We know a fair amount about who is more likely than average to commit suicide,” said Yaseen, who is with the Department of Psychiatry and Behavioral Sciences at Beth Israel Medical Center. “But we cannot predict the acute event. So we need to better understand the acute state that might trigger suicide. We think that in many cases the acute state might be a panic-like state.”

Even the most planned suicidal act is an urge and an effect of emotional action as opposed to a thought and rational action, Galynker said. When people feel like they are trapped and that no options exist, he said, they start panicking and as a result develop distorted cognitions and impaired judgment, which leads to the suicidal act.

Both ruminative flooding and frantic hopelessness are integral to the positive-feedback model of suicide described in the published article, said Galynker. Individuals are flooded with thoughts they cannot control, usually regarding some negative events in their life about which they feel guilty. The ruminative flooding is coupled with an acute frantic hopelessness, in which not only is there a fatalistic conviction that life cannot improve but also an oppressive sense of entrapment and imminent doom.

The article, Yaseen said, also included an expanded version of the positive-feedback model of suicide that explored an attachment-informed psychiatric understanding of the linkage between panic and depression. The expanded model proposes that panic and depression are connected by a negative view of the self; conditions of psychosocial stress elicit a separation distress response in the form of panic; and negative cognitions about the self result in simultaneous fear of and self-imposition of punishment, which feed the positive-feedback cycle of the panic attack.

A large and growing body of evidence links panic and suicide. “Bolton

 in Canada have done excellent epidemiological work on panic and other anxiety disorders in relation to the risk for suicide,” said Yaseen. “Separately, Hendin

 have done some great studies on the acute suicidal state. In Austria, Deisenhammer

 has been doing really meticulous work on suicide.”

The recent study authored by Yaseen, Galynker, and others builds on the authors’ retrospective study of panic attacks and panic symptoms as they related to lifetime suicidal ideation and attempts. Published in 2011, that study involved 2679 community-dwelling individuals who had experienced major depressive episodes and who were participants in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

The 2011 study found that past-year history of panic attacks was significantly associated with a lifetime history of suicidal ideation, suicide attempts, and suicide attempts among ideators, even after controlling for sociodemographic and comorbid clinical variables.

That study also found that catastrophic cognitions of panic (ie, fears of dying and of losing control or going insane) were more strongly associated with suicide attempt than were dissociation, choking sensations, and chest pain. Catastrophic cognitions may specifically distinguish ideators at higher risk for suicide attempt.

The authors speculated that those catastrophic cognitions activated suicidal ideation and interacted with high limbic activation (the flight-or-fight response) to lead to suicide attempts.

In their recent prospective study, Yaseen and colleagues

 examined the relationship between panic attacks, panic symptoms, and suicidality in individuals who met DSM-IV criteria for past-year major depressive episodes. They looked at NESARC data from 2001-2002 (wave 1) and NESARC data from 2004-2005 (wave 2).

Analyzing data on 2864 participants in the survey’s wave 1 and 2 who had depressive disorders, the authors found that past-year panic attacks in wave 1 significantly increased the odds for subsequent suicide ideation and attempt in the 3-year follow-up interval.

But “not all panic attacks are created equal,” Yaseen cautioned. In multivariate analyses, the researchers found that panic attacks were not a significant predictor but that panic attacks featuring fear of dying were. Among depressed individuals with panic attacks, fear of dying during such an attack increased the odds of a subsequent suicide attempt 7-fold, even after controlling for comorbid psychiatric conditions, pertinent demographic factors, and other panic attack symptoms.

In their article, Yaseen and colleagues noted that more than half of persons suffering from a psychiatric disorder seek medical care in the month before making a suicide attempt.

 Of those, only 5% report thoughts of suicide at the time.

“Identifying characteristic symptoms that are strongly associated with future suicide attempts would have clinical utility,” they wrote.

Yaseen recommends that patients who present to emergency departments with panic symptoms be screened for a mood disorder and suicidality and referred to appropriate psychiatric or psychological help if warranted.

“It is not enough to just reassure them that they were having a panic attack and not a heart attack,” he said. Conversely, “if someone is being treated for major depression or bipolar disorder, even if the patient is not reporting active suicidal ideation, we think it is important for clinicians to ask about panic attacks and pay particular attention to what panic symptoms the patient has, because those symptoms can be a significant warning sign that trouble is brewing.”

Yaseen added that he, Galynker, and others recently authored an open access article about the use in a psychiatric emergency room of a revised version of the Suicide Trigger Scale (STS-3), a 42-item scale designed to measure a panic-like psychopathological state.

 Galynker uses the scale in his clinical practice but also questions patients about their panic symptoms and asks them what the panic feels like. If it is associated with the fear of death, he said, then the patient is “more likely to commit suicide, because death is already in their consciousness.”

Galynker said he considers hospitalizing depressed patients who have made a previous suicide attempt or are experiencing a crisis and are expressing a fear of death.

“On the other hand, if someone has panic attacks and has had depression in the past, but their life is stable at the moment . . . I explain to them that suicidal urges may happen to them,” he said.

He describes what that urge might feel like and asks them to contact him or a psychiatric emergency department if it occurs. He explains that however horrible they feel at the time, the panic attack is going to go away and they are going to be feeling better.

Galynker is excited about the promise of this “new line of research.” In his career, he has seen some 25,000 patients, 7 of whom have killed themselves.

“A patient suicide is a very traumatic event for a psychiatrist. I remember vividly my last directions to these patients. Like nearly every psychiatrist, I questioned whether there was anything I could have identified or done differently,” he said.

Those experiences coupled with a desire to know what happens in a person’s mind before he or she actually commits suicide, he said, propelled him into this research.

 Yaseen ZS, Chartrand H, Mojtabai R, et al. Fear of dying in panic attacks predicts suicide attempt in comorbid depressive illness: prospective evidence from the National Epidemiological Survey on Alcohol and Related Conditions. 

 Bolton JM, Pagura J, Enns MW, et al. A population-based longitudinal study of risk factors for suicide attempts in major depressive disorder. 

 Bolton JM, Cox BJ, Afifi TO, et al. Anxiety disorders and risk for suicide attempts: findings from the Baltimore Epidemiologic Catchment area follow-up study.

Sareen J, Cox BJ, Afifi TO, et al. Anxiety disorders and risk for suicidal ideation and suicide attempts: a population-based longitudinal study of adults. 

 Hendin H, Al Jurdi RK, Houck PR, et al. Evidence for significant improvement in prediction of acute risk for suicidal behavior. 

 Fawcett J. Diagnosis, traits, states, and comorbidity in suicide. In: Dwivedi Y, ed. 

 Deisenhammer EA, Ing CM, Strauss R, et al. The duration of the suicidal process: how much time is left for intervention between consideration and accomplishment of a suicide attempt? 

 Katz C, Yaseen ZS, Mojtabai R, et al. Panic as an independent risk factor for suicide attempt in depressive illness: findings from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). 

 Matthews K, Milne S, Ashcroft GW. Role of doctors in the prevention of suicide: the final consultation. 

 Yaseen ZS, Gilmer E, Modi J, et al. Emergency room validation of the revised Suicide Trigger Scale (STS-3): a measure of a hypothesized suicide trigger state. 

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045157

According to the CDC's latest published report, there were 38,364 suicides in the US in 2010-an average of 105 each day. Globally, an estimated 1 million suicides occur annually.

Panic Attacks and Suicide

Movement and psychiatric disorders are frequently comorbid. When they are, movement abnormalities and psychiatric symptoms often overlap and exacerbate one another. For example, in depressed patients with Parkinson disease (PD), bradykinesia and psychomotor slowing can present similarly and tremor and motor “freezing” can be worsened by anxiety. In some cases, the disorders are thought to share a biological origin (eg, tic disorders). In other cases, the treatment of one condition may evoke the other-for example, treating psychosis with neuroleptics may result in tardive dyskinesia. Clinically, the combined presentation of symptoms often confounds diagnosis and complicates treatment.

The overall prevalence of movement disorders associated with psychiatric disorders is unknown and difficult to estimate because comorbidity occurs across a broad range of conditions and in a wide variety of circumstances. A general estimate, in patients with movement symptoms severe enough to seek neurological treatment, is that 40% of neurology outpatients and 34% of neurology inpatients have psychiatric disorders.

 Comorbidity between movement and psychiatric disorders typically occurs in one or more of the following scenarios:

• Two discrete conditions co-occur (eg, major depression develops in a patient with PD)

• A movement disorder is an adverse effect of treatment (eg, drug-induced parkinsonism)

• The movement disorder is a direct result of the psychiatric condition (eg, conversion disorder)

Movement disorders that have a prominent tremor component can be worsened by pharmacological treatment of psychiatric conditions. For instance, essential tremor and ataxias have an action-type tremor. Action tremor is any tremor that occurs with voluntary activation of muscles and includes postural, kinetic, and intention tremors.

 Many antidepressants, mood stabilizers, and antipsychotics can worsen action-type tremors and should be used cautiously in patients with tremor.

A 39-year-old woman with a history of essential tremor and bipolar disorder is hospitalized for mania. She takes primidone, quetiapine, and bupropion. She has been largely nonadherent with quetiapine, so the decision is made to start lithium, which can be monitored in the blood. After restarting quetiapine, lithium is introduced and increased to a total dose of 900 mg daily on the day before discharge. On the day of discharge, all signs of mania have resolved and her lithium level is 0.7 mEq/L.

Three days after discharge, she presents to the emergency department (ED) with a high-amplitude action tremor that prevents her from eating, drinking, or writing. There has been no change in her essential tremor therapy, and she has been adherent to her medication regimen. What happened?

On the day before her discharge, the lithium dose was increased from 600 mg to 900 mg. Although her blood level was only 0.7 mEq/L on the day of discharge, the half-life of lithium averages 20 to 24 hours. Therefore, her lithium level was still rising and had not yet reached steady-state in her blood by discharge. In the ED, she was found to be within the therapeutic range (0.8 to 1.2 mEq/L) for lithium. However, patients with essential tremor and other disorders with prominent tremor often experience exacerbation of the preexisting tremor, even at therapeutic doses. The tremor returned to baseline after the lithium dose was reduced and the primidone dose was increased.

A 58-year-old woman with a 6-year history of PD has been having 1 to 3 panic attacks daily for the past 3 months. Panic disorder was diagnosed when she was 24 and had been well controlled with sertraline, with fewer than 2 panic attacks per year. Her medical history is significant for gastroesophageal reflux disorder and osteoporosis. Her medications include carbidopa/levodopa 25/100 mg, 2 tablets 4 times daily and 1 tablet at bedtime, calcium and vitamin D supplements, and sertraline 100 mg daily. She has had no medication changes in the past year.

The panic attack episodes last for 30 to 60 minutes; typically come on gradually over the course of 15 to 20 minutes; and include sweating, flushing, palpitations, increased tremor, difficulty in drawing a full breath, intense anxiety, and a fear that “something bad is happing.” Episodes seem to occur most often in the late morning, mid-afternoon, and just after dinner. She finds that she cannot concentrate or function well during these episodes and, as a result, has been refusing activities outside of the house between 10am and 7pm.

Medical examination and relevant laboratory studies revealed no acute health issues. Her blood pressure is 130/80 mm Hg while sitting and 119/76 mm Hg while standing; pulse is 65 beats per minute while sitting and 68 while standing. Several treatment trials, including increased dosages of sertraline, a cross-taper first to escitalopram then to duloxetine, and the addition of clonazepam up to 1 mg bid, have been unsuccessful.

Anxiety occurs with wearing-off in up to 88% of patients with PD.

 Wearing-off is the predictable emergence of motor or nonmotor PD symptoms before the next scheduled antiparkinsonian medication dose.

 Wearing-off develops in up to 80% of PD patients within 5 to 10 years of starting levodopa therapy. Therefore, the most likely cause of the daily panic attacks, in the absence of medication changes or medical issues, is the progression of the disease causing wearing-off of the previously adequate antiparkinsonian therapy.

What new information does this article provide?

â  Phenomenological descriptions and case vignettes help the reader better understand the differential diagnosis of movement disorders when they co-occur in patients with psychiatric conditions.

What are the implications for psychiatric practice?

â  The goal of this article is to improve recognition of comorbid psychiatric and movement disorders and to help the reader formulate a management strategy using a multidisciplinary approach.

This vignette illustrates some of the challenges in assessing and treating psychiatric disorders that are comorbid with a movement disorder. In this case, the nonmotor symptoms of PD associated with wearing-off include anxiety, return of tremor, and other autonomic symptoms that closely mimic the symptoms of a classic psychiatric panic attack. Distinguishing features include the gradual onset of symptoms and cyclical occurrence toward the end of each carbidopa/levodopa dosing interval.

Patients and doctors often fail to recognize the relationship between the timing of PD medications and anxiety episodes. Several issues can confound detection, including variability in patient adherence to a strict medication schedule and wearing-off episodes that may be better tolerated and therefore unreported during a particular interval because of reduced activity or napping. To improve detection, have the patient or caregiver keep a journal of the anxiety symptoms in relation to the time of actual antiparkinsonian medication administration. Clinicians can use scales such as the Wearing-off Questionnaire, which has been designed to help identify nonmotor symptoms of wearing-off in PD and distinguish them from other disorders.

When movement and psychiatric disorders present concurrently, multidisciplinary cooperation between the neurologist and psychiatrist is essential. Neurological and psychiatric symptoms often overlap and exacerbate one another. When this happens, optimal treatment response cannot be achieved unless both conditions are recognized and addressed. In this case, while antidepressants and benzodiazepines may help reduce wearing-off related anxiety, they usually do not produce significant or long-lasting relief.

Definitive treatment of wearing-off related anxiety is best achieved through adjustment of antiparkinsonian therapy. Common strategies to prevent or decrease wearing-off are to decrease the interval between levodopa doses (eg, from every 4 hours to every 3 hours); add a catechol 

-methyltransferase inhibitor; start adjunctive therapy with a dopamine agonist; or use a monoamine oxidase B inhibitor. Cognitive-behavioral therapy (CBT) is also effective for anxiety and should be used in conjunction with these strategies.

Movement disorders with associated dementia syndromes

. Cognitive impairment and dementia occur in a wide range of movement disorders. The time of onset, quality, and prominence of cognitive symptoms vary between movement disorders, which may complicate recognition. In Lewy body dementia for instance, cognitive impairment affects cortical and subcortical processes and is often the first and most clinically apparent symptom. However, in Huntington disease, the course of decline is more insidious because factual information and overall intelligence quotient scores remain stable until relatively late in the disease, despite significant executive dysfunction and procedural learning deficits.

Psychiatrists who treat patients with movement disorders should remain vigilant for cognitive changes, such as executive dysfunction in essential tremor and primary dystonia; frontal-subcortical dementia syndromes in progressive supranuclear palsy, corticobasal syndrome, and multisystem atrophy; and sporadic and progressive cognitive impairment in multiple sclerosis and certain cerebellar ataxias. Consider formal neuropsychological testing to establish a cognitive baseline and to detect more subtle cognitive impairments.

Movement disorders as a consequence of psychiatric treatment

. In ancient Greek, akathisia means “not to sit.” Patients with this condition present with complaints of inner tension, restlessness, anxiety, and the urge to move. Observable motor features are complex, semi-purposeful, and repetitive (eg, foot shuffling or tapping, pacing, shifting of weight, rocking).

Psychopharmacological agents that induce this movement disorder include typical and atypical antipsychotics, antidepressants, dopamine blocking antiemetics, reserpine, Î±-methyldopa, lithium, calcium channel blockers, and tetrabenazine. Onset is variable but is often associated with dose escalations. Treatment includes lowering or stopping associated medication or switching to an antipsychotic with lower risk of extrapyramidal symptoms (EPS). In addition, iron levels need to be checked. In order of best evidence, the following agents are safer, with a smaller risk of inducing akathisia: -blockers, benzodiazepines, anticholinergics, clonidine, amantadine. Mirtazapine and serotonin antagonists (cyproheptadine, mianserin) may also be safer to use.

. This movement disorder most often affects the orofacial and lingual musculature (eg, lip smacking, chewing, protrusion, curling or twisting of the tongue, puckering, bulging of the cheeks). Choreoathetoid movements of the fingers, hands, and upper and lower extremities are also common. Dyskinesias increase with emotional arousal or distraction, and diminish with sleep, relaxation, or volitional effort.

Associated with prolonged exposure to antipsychotic medications, the onset of tardive dyskinesia is typically after longer than 3 months of exposure. Reducing or stopping the current antipsychotic or switching to a lower-potency antipsychotic may temporarily worsen tardive dyskinesia, but will ultimately help in most cases. Treatment with anticholinergic medications or tetrabenazine may also be indicated.

. This disorder presents as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures, such as blepharospasm, forced jaw opening, grimacing, laryngospasm, oculogyric crisis, spasmodic torticollis, and tongue protrusion or twisting. In 95% of cases, dystonia appears within 5 days of starting or increasing a dose of antipsychotic medication. First-line treatment includes anticholinergics (oral or intramuscular) or antihistamines; benzodiazepines can be used as second-line treatment. If the patient is unresponsive, check for hypocalcemia.

. This is a life-threatening syndrome characterized by autonomic and mental status changes, fever, and severe muscular rigidity. The first symptom to emerge in 82% of patients is change in mental status. Supporting, but nonspecific, laboratory findings include elevated serum creatine kinase level, leukocytosis, elevated liver function tests, hypocalcemia, hypomagnesemia, hyperkalemia, and metabolic acidosis.

More than half of cases (66%) occur within the first 1 to 2 weeks after initiation of antipsychotic medications. Higher doses and rapid dose escalation are risk factors. Treatment includes removal of the causative agent and supportive care (intravenous fluids, metabolites). Some patients will need to be admitted to an ICU. Benzodiazepines can be used for agitation, and electroconvulsive therapy is an option. Controversial treatments include dantrolene, bromocriptine, and amantadine.

. This syndrome mimics PD, with symptoms of bradykinesia, rest or postural tremor, and rigidity. Onset is subacute and bilateral, with early presence of postural tremor and concurrent oral-buccal dyskinesias, which are usually not responsive to levodopa. Antipsychotics, lithium, antiemetics (prochlorperazine, metoclopromide), calcium channel blockers, reserpine, Î±-methyldopa, tetrabenazine, and some antidepressants are responsible for the disorder.

Lowering the dosage of or stopping the responsible medication or switching to an antipsychotic with lower EPS liability will usually remit symptoms within days or weeks; in the elderly, it may take longer-sometimes several months. Up to 15% of cases may persist.

. From the Swedish slang for “block-head,” punding was first described in amphetamine addicts. Patients with this movement disorder present with complex stereotyped behavior, with repetitive examining, handling, or manipulation of objects usually without clear purpose. Stimulants and dopamine agonists are the responsible agents, and treatment consists of lowering the dosage of or stopping the medication.

. This adverse drug reaction stems from an excess of serotonin. It presents as a triad of autonomic hyperactivity, mental status change, and neuromuscular symptoms. Akathisia, clonus, diaphoresis, hyperreflexia, muscular rigidity, and tremor may also be seen. Antidepressants, valproate, fentanyl, tramadol, metoclopramide, sumatriptan, lithium, and MAOIs are responsible for this disorder. Up to 60% of patients present within 6 hours of initiation of medication, a dosage change, or an overdose. Treatment involves stopping the medication and providing supportive care to control autonomic instability and hyperthermia. Serotonin 2A antagonists may also be used.

. Postural tremor is most common and usually presents bilaterally as unintentional, rhythmic, muscle movement involving oscillations of one or more parts of the body. Responsible agents include antidepressants, antipsychotics, lamotrigine, lithium, and valproic acid; treatment consists of lowering the dosage of or stopping the associated medication.

Movement disorder as the result of a psychiatric condition

Psychogenic movement disorders are “disorders that cannot be attributed to any known structural or neurochemical disease but result from an underlying psychiatric illness or malingering.”

 Patients who have these problems often meet diagnostic criteria for a somatoform disorder; conversion disorder is the most common. Symptoms include a variety of abnormal movements, and gait is often affected. The disorders can present as entire movement disorder syndromes (eg, psychogenic parkinsonism).

Psychogenic movement disorders are thought to account for up to 9% of all neurological diagnoses and represent 2% to 3% of cases seen in movement disorder specialty practices.

 Women are more often affected than men, and the typical age at onset is between 37 and 50 years. Organic neurological disorders are present in 10% to 15% of patients and often have overlapping symptoms, making it difficult to distinguish between the two conditions. The 

 lists clinical features that are characteristic of psychogenic movement disorders. Ancillary tests that can help clarify the diagnosis in some cases are electromyography; evoked potentials; and functional imaging, such as dopamine transporter imaging.

Untreated psychogenic movement disorders become chronic in 65% to 95% of patients and produce significant disability and increased health care costs.

 The first goal of treatment is accurate diagnosis to prevent iatrogenic harm by avoiding unnecessary invasive tests or medications.

A therapeutic approach outlined by Williams and colleagues

 asserts that gaining the patient’s acceptance of the psychogenic origin of the diagnosis is fundamental to treatment success. They recommend a multidisciplinary diagnostic debriefing that involves the neurologist, psychiatrist, and patient, delivered in a way that is sensitive to the patient’s conception of the disease. Although no single treatment approach has yet been shown to be superior to others, a limited number of clinical trials have found antidepressants, psychotherapy (particularly CBT, which has a positive treatment effect in up to 71% of patients), and referrals to occupational and physical therapy to be helpful.

Multidisciplinary treatment for patients with comorbid movement and psychiatric disorders should be established as soon as comorbidity is identified. The team typically includes a psychiatrist/therapist, neurologist, and physical and occupational therapists. Formal neuro-psychological testing and speech/language pathology are often helpful when cognitive impairment, dysphagia, and speech problems are present. Communication is the most important aspect of the team-based approach. Good communication ensures that overlapping treatments do not unnecessarily exacerbate comorbid symptoms and helps clarify the overall goal of treatment, which should be to improve the quality of life and functioning of the patient rather than to serve as a checklist for alleviating individual symptoms.

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 Witjas T, Kaphan E, Azulay JP, et al. Nonmotor fluctuations in Parkinson’s disease: frequent and disabling. 

 Stacy M, Bowron A, Guttman M, et al. Identification of motor and nonmotor wearing-off in Parkinson’s disease: comparison of a patient questionnaire versus a clinician assessment. 

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The goal of this article is to improve recognition of comorbid psychiatric and movement disorders and to help the reader formulate a management strategy using a multidisciplinary approach.

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