Melatonin is ubiquitous. It is present in nearly all life forms, including plants and animals, and even single cell organisms. Evolutionarily, it dates back billions of years serving essential cellular processes with its antioxidant and free radical scavenging functions, and more recently as a 

 in the regulation of circadian rhythms and the sleep-wake cycle.

 As humans, we benefit from our endogenous melatonin in support of our complex cellular activity and in helping to orchestrate wide-ranging physiological processes influenced by our circadian system.

 We are not conscious of most melatonin actions, but certainly experience its effects on sleep and waking.

It is useful to think of our endogenous melatonin in 2 ways: 1) reactions occurring intracellularly that do not necessarily involve specific melatonin receptors and 2) the more familiar circadian role associated with regular changes in circulating melatonin and effects on melatonin receptors. Although present in a variety of tissues, circulating melatonin is predominantly produced in the pineal gland under the control of the master 

 transcription-translation loops in the hypothalamic suprachiasmatic nucleus (SCN), which is entrained by exposure to the light-dark cycle.

Normally, plasma melatonin levels are very low during the daytime and gradually rise in the evening as bedtime approaches, typically about 2 hours before a person’s natural sleep onset time; however, the actual clock time of the melatonin rise can vary considerably among individuals. Melatonin production also can be suppressed by light exposure, so this can be a factor affecting the circulating levels and sleep patterns. Usually melatonin plateaus at a relatively high level throughout the night and then declines by morning. When the pineal gland produces melatonin, it is immediately released into the bloodstream and cerebrospinal fluid. This pattern of markedly elevated melatonin levels during the nighttime has led to its description as the “hormone of darkness.” Note that the production of melatonin is primarily under circadian control: while bright light during the nighttime time will suppress it, darkness during the daytime will not turn it on.

The circulating melatonin levels provide the body’s physiology with a clock and a calendar. Changing melatonin concentrations reinforce circadian activity in nearly all tissues and the changing duration of nighttime melatonin secretion reflects the time of year, especially important for seasonally breeding species.3 As humans, our ability to fall asleep at our typical bedtime and the robustness of our circadian cycle are both reinforced by melatonin interacting with the MT1 and MT2 receptors that are highly concentrated in the SCN. The normally coordinated functioning of homeostatic and circadian processes promotes our nighttime sleep of about 8 hours and our daytime-evening wakefulness of about 16 hours.

From late afternoon into the evening, the SCN-driven circadian system produces arousal that counters the homeostatic sleepiness that has accumulated since the morning awakening, thus allowing sustained functioning into the evening. Typically, we are the most alert in the early evening than any other time of the day or night. With approaching bedtime, the rising melatonin agonist activity at the SCN melatonin receptors decreases the stimulation, leaving the homeostatic sleepiness unopposed, thus facilitating bedtime sleep onset. It is notable that the melatonin action is not sedation, but rather a reduction in the evening circadian arousal.

In everyday life, we think of melatonin as a widely available, fairly benign, and maybe helpful sleep aid product. In the United States, it is categorized as a dietary supplement, although in some countries it requires a prescription. Unlike official over-the-counter (OTC) products, which are highly regulated (composition, manufacturing, indications, labeling, and marketing), dietary supplements have little oversight. Studies analyzing consumer melatonin products have shown varying amounts of the compounds, as well as the presence of other unlabeled and sometimes surprising ingredients.

Does exogenous melatonin taken as a dietary supplement enhance sleep? Is it safe?

There is a reasonable argument that taking evening melatonin might augment the natural process of reducing circadian arousal to help people fall asleep more quickly. In general, meta-analyses and systematic reviews of evening melatonin doses compared with placebo show statistically significant improvements in sleep onset that are of questionable clinical 

 Studies have shown little or no benefit for sleep maintenance or total sleep time. The best evidence is for people having a circadian rhythm phase delay (“night owls”), blind individuals with the non-24-hour sleep-wake rhythm disorder, and some children with neurodevelopmental disorders.

 However, much of the research with melatonin has been with few subjects, mixed clinical populations, and for short durations, all limiting the quality of the evidence.

Clinical trial assessments of melatonin safety share the same study limitations, so high-quality data are not available. The more common adverse event reports include daytime drowsiness and nightmares, though the rates are low. Generally, melatonin is well tolerated in these placebo comparison studies with typical consumer product doses.

A darker side of both endogenous and exogenous melatonin has been emerging in recent years with investigations of circadian rhythms and 

, specifically examining glucose tolerance, insulin release and sensitivity, weight gain, and the timing of food intake.

 The circadian regulation of metabolism is just right for people who are active, get plenty of light exposure, and have their meals during the daytime, and who are in the dark sleeping during the nighttime. In our society, many people eat at irregular times, including late in the evening and during the night, when our circadian system expects us to be fasting. An evening meal will result in higher glucose and insulin levels compared with the identical meal eaten early in the day. Over time these elevated evening glucose and insulin levels increase the risk for obesity and type 2 diabetes mellitus. The timing of food intake in relation to our evening melatonin rise appears to be an important factor.

 studied the sleep-wake patterns of healthy young adults over a 30-day period that included 1 week of monitoring the timing and content of all food they ate, and also an overnight laboratory assessment of their melatonin patterns and body composition. They found a significant relationship between the timing of food consumption relative to melatonin onset and the percentage of body fat and body mass index, controlling for the actual clock time, caloric amount, activity or exercise level, and sleep duration. Eating food later in the day had a detrimental effect.

These findings are consistent with studies demonstrating the weight loss and metabolic benefits of time restricted eating routines where people consume their meals on a relatively early schedule and fast through the evening and nighttime. Avoiding evening eating close to and following our melatonin rise appears to have advantageous metabolic effects.

If we should avoid eating and digesting food close to our evening endogenous melatonin rise, what are the implications for using exogenous melatonin as a sleep aid? There is evidence that taking melatonin also leads to impairment in glucose tolerance. Rubio-Sastre and colleagues

 studied 21 healthy women, giving them either melatonin 5 mg or a placebo in the morning and evening on different days. An oral glucose tolerance test monitoring glucose and insulin levels for 3 hours began 15 minutes after each dose. Finding that the melatonin use was associated with elevated glucose levels at both time points, they concluded that the optimum timing for melatonin doses should be at least 2 hours after the last meal.

Perhaps the best plan for melatonin to help with sleep is to give our own circadian rhythm and melatonin release a chance to do the job.

 Maintaining regular sleep-wake hours, plenty of daytime activity and light exposure, and early meal timing should aid in stabilizing the circadian cycle. Avoiding bright light in the evening for a few hours prior to bedtime should limit the suppression of melatonin, especially if using reddish low color-temperature lighting, now readily available with LED products. Using electronic screens (eg, phones, tablets, laptops) held close to the face should be limited as bedtime approaches—even when using those devices with blue spectrum-blocking apps or filters. These good sleep habits that facilitate earlier and higher melatonin release may be the solution to achieve an earlier sleep onset.

If one is inclined to take a dose of melatonin to enhance sleep, it probably will help the most when taken prior to bedtime, but ideally well after the last meal.

 Even very low doses result in blood levels hundreds to thousands of time higher than the normal endogenous circulating amount. Low doses should be as effective as high doses, since the primary action of melatonin is not sedation. The ultimate benefit in helping people fall asleep more quickly may take several days or weeks as melatonin advances and stabilizes the circadian system.

The bright side of this “hormone of darkness” is the extraordinary roles it serves in stabilizing our cellular and circadian functioning. If we manage to live our lives closer to our natural circadian physiology, we can avoid melatonin’s potential metabolic darkness.

is associate professor in the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD. He spoke at PsychCongress 2020 in a presentation titled Melatonin: What, Why, and Why Not? The author reports he is a consultant with Eisai Inc and Abbott Laboratories.

Melatonin synthesis and function: Evolutionary history in animals and plants

2. Claustrat B, Leston J. Melatonin: Physiological effects in humans. 

3. Arendt J. Melatonin: Countering chaotic time cues. 

4. Erland LA, Saxena PK. Melatonin natural health products and supplements: Presence of serotonin and significant variability of melatonin content. 

5. Buscemi N, Vandermeer B, Hooton N, et al. 

The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis

6. Buscemi N, Vandermeer B, Hooton N, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: Meta-analysis. 

7. Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: A meta-analysis. 

8. Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. 

9. Garaulet M, Qian J, Florez JC, et al. 

Melatonin effects on glucose metabolism: Time to unlock the controversy

10. Stenvers DJ, Scheer, FAJL, Schrauwen P, et al. Circadian clocks and insulin resistance. 

11. McHill AW, Phillips AJ, Czeisler CA, et al. 

Later circadian timing of food intake is associated with increased body fat

12. Rubio-Sastre P, Scheer FA, Gomez-Abellan P, Madrid JA, Garaulet M. Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. 

Articles

Psych Congress

Our own melatonin plays an important role in regulating our sleep-wake cycle. Recent evidence raises questions about whether we should be taking extra doses to try to improve our sleep. 

Melatonin: The Dark Side of the Hormone

Every clinician who works with individuals who have dementia-what we now refer to as major neurocognitive disorders-encounters states of agitation that can worsen function, pose safety concerns, and increase caregiver stress. It can be both confusing and frustrating to understand and manage these behaviors, but there are several approaches that can make all the difference.

 by the International Psychogeriatric Association as involving excessive motor activity or verbal or physical aggression that causes emotional distress and excess disability for the affected person, and impairs relationships, social functioning, and activities of daily living.

 These behaviors are commonly part of a larger 

 of behavioral and psychological symptoms that are associated with all major forms of dementia, including mania, depression, anxiety, apathy, and psychosis.

Agitation has many medical, medication-related, psychiatric, psychological, and environmental causes-but underlying all of them is a damaged and vulnerable brain that is less able to properly regulate affect and respond to challenges in an organized manner. Specifically, agitation has been associated with damage to key brain nuclei that 

A thorough medical and psychiatric evaluation as well as a review of the circumstances before, during, and after periods of agitation may reveal both enduring causes, such as an underlying depression or the use of a stimulating medication, and transient triggers such as boredom, hunger, or a noxious stimulus in the environment. The DICE algorithm developed by 

 is an excellent tool for clinicians as it guides them to describe the behaviors in detail, investigate potential causes, create a team approach to implement various treatments, and then to evaluate the relative success of the interventions.

Management of agitation involve three basic approaches. The first is to identify and address potential causes. The second is to implement behavioral approaches, ranging from increased therapeutic activities (eg, art or music therapy), to redirecting and refocusing the person to more positive activities, especially ones that meet the basic function of the agitation in the first place. The third approach involves the use of psychotropic medications that are targeted towards underlying factors such as anxiety or psychosis, or primarily aimed at reducing agitation by calming brain activity. Benzodiazepines and trazodone are often used emergently but can cause sedation and increase the risk of falling. Antidepressants are being studied since their modulation of serotonergic activity is aimed at reducing impulsivity and aggression. Anticonvulsants have been used to inhibit brain activity causing agitation, but with limited scientific support.

Antipsychotic medications have been widely studied, and while there is a fair amount of 

 suggesting modest benefit for agitation, there are also significant safety concerns, including the black box warnings for an increased risk of death.

 With any pharmacologic approach, the goal is to use the least amount of medication for the shortest time possible. Finally, clinicians need to be aware of the many regulations concerning the use of psychotropic medications in long-term care settings, including guidelines from the Omnibus Budget Reconciliation Act (OBRA) of 1987 guidelines, American Geriatrics Society Beers Criteria, and definitions of unnecessary drug use.

The best outcome will always stem from a systematic approach that seeks to understand and address the underlying causes and triggers of agitation, and then implements and evaluates both behavioral and pharmacologic approaches, with a clear eye on safety.

This article was originally posted on 10/8/19 and has since been updated.

Dr Agronin is a geriatric psychiatrist and currently serves as the Senior Vice President for Behavioral Health and the Chief Medical office at MIND Institute at Miami Jewish Health in Miami, FL. He is the author of 

The Dementia Caregiver: A Guide to Caring for Someone with Alzheimer’s Disease and Other Neurocognitive Disorders

. Dr Agronin was a speaker at the 2019 Psych Congress in San Diego, CA, he presented “Behavioral and Pharmacologic Approaches to Agitation and Dementia Associated with Major Neurocognitive Disorders.”

The author reports no disclosures concerning the subject matter of this article.

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Agitation in Cognitive Disorders. International Psychogeriatric Association provisional consensus clinical and research definition

2. Lyketsos CG, Carrillo MC, Ryan JM, et al. 

Neuropsychiatric symptoms in Alzheimer's disease

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The relationship between psychiatric symptoms and regional cortical metabolism in Alzheimer's disease

Central serotonergic hyperresponsivity in late-onset Alzheimer's disease

5. Kales HC, Gitlin LN, Lyketsos CG; Detroit Expert Panel on Assessment and Management of Neuropsychiatric Symptoms of Dementia. 

Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel

6. Tampi RR, Tampi DJ, Balachandran S, Srinivasan S. 

Antipsychotic use in dementia: a systematic review of benefits and risks from meta-analyses

Agitation can worsen function, pose safety concerns, and increase caregiver stress. It can be both confusing and frustrating to understand and manage these behaviors, but there are several approaches that can make all the difference.

Understanding and Managing Agitation Associated with Dementia

Age is the greatest risk factor for memory loss and dementia, defined as a cognitive decline that interferes with independent functioning. By age 45, the objective memory performance of average individuals is lower than it was during their twenties, but for most, these mental slips are minimal and do not progress.

For those with a family history of Alzheimer disease (AD), these agerelated memory complaints cause considerable anxiety: patients worry that their normal aging symptoms are the initial indication of a progressive cognitive impairment that they have observed in their relatives.

AD is the most common cause of dementia. It has a gradual onset and progression and leads to abnormal protein deposits-amyloid plaques and tau tangles-that accumulate in the brain regions that control thinking and memory. However, many other conditions can cause dementia, such as depression, adverse effects of medications, thyroid imbalances, and other medical illnesses. Treating these underlying medical conditions may cure a reversible dementia or lead to partial symptom improvement.

Other irreversible neurodegenerative diseases that cause dementia include Lewy body disease, vascular dementia, and frontotemporal degeneration. Even if there is no cure for the underlying cause of a dementia, treatments are available that stabilize symptoms and help people remain healthier longer.

A clinical assessment of cognitive issues includes a search for risk factors, such as smoking history, lack of sleep, prior head trauma, or history of untreated high blood pressure or high cholesterol. A detailed inventory of the patient’s medications is essential. Many prescription and over-thecounter drugs for allergies (diphenhydramine) or sleep (eg, Sominex, which also contains diphenhydramine) can impair cognition. Sedating medicines, narcotic agents, histamine H2-receptor antagonists (eg, famotidine, cimetidine) for gastrointestinal problems, cardiac medications such as digoxin and beta-blockers, corticosteroids, NSAIDs (eg, naproxen, ibuprofen), and antibiotics are all among the list of medicines that may contribute to symptoms.

A mental status assessment will help determine the patient’s degree of cognitive impairment, as well as the presence of depression or anxiety that can worsen memory. A brief evaluation of cognitive abilities will determine degree of cognitive impairment, and neuropsychological cognitive testing may be ordered to detail these deficits through neuropsychological testing.

A physical and neurological examination and screening blood tests for thyroid, metabolic, and other possible abnormalities are recommended to uncover medical causes of confusion. To ensure that a tumor, stroke, or other brain abnormality is not present, a computed tomography (CT) or magnetic resonance imaging (MRI) scan is performed.

For patients with a diagnosis of Alzheimer dementia, symptomatic medications temporarily stabilize symptoms but do not cure the disease. These medicines help patients remain at a higher functional level longer than if they did not take the medicine and may benefit patients with other forms of dementia such as Lewy body disease and vascular dementia.

Patients are often started on a cholinergic medicine, such as donepezil or a rivastigmine patch (if patients have adverse effects from the former). Cholinergic medicines are thought to exert their effects by increasing availability of acetylcholine, which is important for normal cognitive functioning.

Once the patient is stabilized on one of these cholinergic drugs, the clinician often adds a second symptomatic medication, the 

-methyl-D- aspartate (NMDA) receptor antagonist memantine. We know that combining a cholinergic drug with memantine leads to a better outcome than using either type of medication alone. In addition to helping with cognitive symptoms of dementia, these symptomatic medicines have been shown to delay the emergence of agitation and other behavioral symptoms associated with dementia.

It is important for clinicians to manage patient and family expectations about medication benefits. One strategy is to explain that if the patient tolerates the drug, then that patient will do significantly better than without the medication after a year, but some patients do experience temporary improvement. However, if there is an expectation of definite improvement and it does not emerge, patients and family members may become discouraged and prematurely discontinue the medicine.

It is also helpful to inform patients and families that symptoms eventually progress. However, remaining on the medicine when that occurs will lead to a slower rate of cognitive decline than discontinuing the medication.

Recent research has shown that a healthy lifestyle can protect brain health as people age. A healthy brain lifestyle includes regular physical activity, balanced nutrition, stress management, and mental stimulation.

Healthy lifestyle programs that seem most effective include three elements: educating patients about the association between daily habits and brain health; setting reasonable goals that are not too daunting; and providing feedback of initial success to motivate participants.

Many families express interest in volunteering for research protocols involving new dementia interventions. Usually patients can remain on their symptomatic treatments while participating in research.

A variety of interventions are currently being tested, including new medications, vaccines, supplements, antibody blood infusions, nasal insulin spray (diabetes increases dementia risk), and focused ultrasound waves targeting the brain’s hippocampal memory center in attempts to activate these neural circuits. Most of the clinical trials are testing disease-modifying treatments, which would lead to an enduring change in the clinical progression of AD by interfering with the underlying pathophysiological mechanisms of the disease.

Dr Small is Parlow-Solomon Professor on Aging, Professor of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA; Director of the UCLA Longevity Center; and Director, Geriatric Psychiatry Division at Semel Institute for Neuroscience and Human Behavior, Los Angeles. 

Dr Small spoke at the 2019 Psych Congress in San Diego, CA, in a presentation titled “Age-related cognitive decline: clinical applications of new research.”

This article was originally published on 10/7/19 and has since been updated.

The author reports that he is Consultant/Advisor: Acadia, Actavis/Allergan, Avanir, Forum, Genentech, GlaxoSmithKline, Herbalife, Handok, Otsuka, RB Health, Roche, Theravalues Speakers Bureau: Acadia, Actavis/Allergan, Avanir, Forum, Herbalife, Handok, Otsuka, RB Health, Theravalues, Board Member: CereMark; and Stockholder: CereMark.

Patients with a family history of Alzheimer disease worry that normal aging symptoms are the initial indication of a progressive cognitive impairment that they have observed in their relatives. A variety of interventions are discussed.

Management of Age-Related Cognitive Decline

A colleague approached me and said that she was referring a patient to the partial hospital program who had borderpolar. Having not previously heard this term, clarification was sought, and it was explained that the patient had both borderline personality disorder and bipolar disorder. My colleague further explained that this term is frequently used in the psychiatrist chat room she visits as a shorthand for patients with both disorders who are severely ill and have high levels of psychosocial morbidity. A Pubmed search on the term borderpolar did not turn up any citations.

Both bipolar disorder and borderline personality disorder (BPD) are significant public health problems. Both disorders are associated with impaired functioning, high utilization of psychiatric services, high rates of substance use disorders, and suicidality. Despite the psychosocial morbidity and risk for premature mortality, both disorders are frequently underdiagnosed. As a result, calls for improved recognition have been voiced for both disorders.

For years there has been debate as to how to conceptualize the relationship between BPD and bipolar disorder. Some experts have suggested that BPD is part of the bipolar spectrum. Review articles have summarized the evidence supporting and opposing the bipolar spectrum hypothesis, with most of the recent reviews concluding that BPD and bipolar disorder are valid and distinct diagnostic entities. And since each disorder suggests different treatment emphases-a focus on pharmacotherapy with possible adjunctive psychotherapy for patients with bipolar disorder versus a focus on psychotherapy with possible adjunctive medication for patients with BPD-making the differential diagnosis is that much more important. Meanwhile, many authors and clinicians have described the diagnostic uncertainty and the challenges in determining if a patient has bipolar disorder or BPD.

The most frequently researched aspect of the relationship between BPD and bipolar disorder has been the frequency of their co-occurrence. Several reviews report an estimated 20% overlap in diagnostic frequency.

 That is, approximately 20% of patients with bipolar disorder have comorbid BPD and approximately 20% of patients with BPD have bipolar disorder. Thus, while only a minority, there is a meaningful number of patients with a comorbid diagnosis.

Meanwhile, reviews and commentaries have focused on identifying clinical characteristics that distinguish the two disorders to help with differential diagnosis. This approach implies that the diagnosis is an either/or decision. Framing the discussion as a dichotomous choice underplays the fact that one-fifth of patients have both disorders. The almost exclusive focus on differential diagnosis might discourage clinicians from making both diagnoses when appropriate and can result in overlooking an important comorbidity in patients with the greatest need.

 reviewed the literature on the clinical impact of one disorder on the other. Overall, they found that there have been far more studies that compared patients who have bipolar disorder with and without BPD than there have been of patients with BPD who do and do not have bipolar disorder. The researchers also noticed that amongst patients with bipolar disorder, those with comorbid BPD reported more mood episodes, an earlier age of onset of bipolar disorder, greater suicidality, greater hostility, and a higher prevalence of substance abuse. Of note, they found little research that examined treatment response, psychosocial functioning, time unemployed, disability payments, or prospectively observed longitudinal course.

It has been my clinical experience that patients with both bipolar disorder and BPD (hereafter referred to as 

) are a group at elevated risk for suicide and marked impairment; they also are high utilizers of the most costly levels of care. My colleagues and I recently examined this issue in the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project. We compared psychiatric outpatients with borderpolar to patients with BPD without bipolar disorder and patients with bipolar disorder without BPD. We hypothesized that the borderpolar patients would exhibit significantly more psychosocial morbidity than patients with only one of these disorders.

The Rhode Island MIDAS project represents an integration of research methodology into a community-based outpatient practice affiliated with an academic medical center.

 Psychiatric outpatients presenting for treatment were evaluated with semi-structured interviews. We compared the demographic, family history, and clinical characteristics of three nonoverlapping groups of patients: borderpolar (n = 59), BPD without bipolar disorder (n = 330), and bipolar disorder without BPD (n = 128).

The results showed that significantly more patients with borderpolar had diagnoses of three or more Axis I disorders than patients with bipolar disorder. Borderpolar patients also reported significantly more PTSD, obsessive-compulsive disorder (OCD), substance use disorder, and somatoform disorder compared with the patients with bipolar disorder. Similarly, patients with borderpolar reported significantly more OCD than patients with BPD.

In terms of risk factors, the MIDAS study found that borderpolar patients had the most psychopathology in their first-degree relatives. Compared with patients with bipolar disorder, the morbid risk for depression, bipolar disorder, PTSD, specific phobia, drug and alcohol use disorders was significantly higher in the borderpolar patients. Compared with patients with BPD, borderpolar patients had significantly higher morbid risks for bipolar disorder, PTSD, and drug and alcohol use disorder.

Furthermore, psychosocial morbidity was greatest in the borderpolar patients. Compared with bipolar disorder patients, the borderpolar patients reported more episodes of depression, more anger, suicidal ideation, history of suicide attempts, childhood trauma, chronic and persistent unemployment, impaired social functioning, and psychiatric hospitalizations. These patients were also more likely to receive disability payments and they exhibited significantly more psychosocial morbidity than the patients with BPD. The borderpolar patients reported more episodes of depression, childhood trauma, chronic and persistent unemployment, history of suicide attempts, and psychiatric hospitalizations.

The results from the MIDAS project indicate that patients with both bipolar disorder and BPD are more severely ill than patients with only one of these disorders. While clinicians might seek diagnostic parsimony and diagnose only one disorder, it is important that they not overlook the potential presence of the other disorder.

During the past decade, significant effort has been put forth to improve the recognition of bipolar disorder in depressed patients. Several screening scales for bipolar disorder have been developed, and they have been extensively researched. Similarly, peer reviewed journals have published review articles and commentaries about the importance of recognizing bipolar disorder in patients presenting for treatment of depression. Much less has been written about the importance of improving the recognition of BPD. Just as it is important for clinicians to include questions to screen for a history of manic or hypomanic episodes in their evaluation of depressed patients, it is important to screen for the presence of BPD in patients with mood disorders.

To date, practically no research has examined potential treatments for patients with both diagnoses. There are only a small number of open-label trials of medication, one controlled medication trial, and no controlled psychotherapy trials of patients with both disorders.

While the literature has clearly demonstrated that bipolar disorder and BPD are distinct disorders, the importance of diagnosing both disorders when comorbid has gotten lost in the dialogue. It is our hope that by giving this group of severely ill patients a unique name-borderpolar-the recognition of this comorbidity will increase. And, as such, there will be increased efforts to identify the most effective treatment approaches.

The ongoing debate as to whether BPD belongs on the bipolar spectrum, which has generated a robust empirical data base establishing that these are distinct diagnostic entities, has sidetracked researchers and clinicians from recognizing the importance of diagnosing both disorders when both are present. Patients with comorbid bipolar disorder and BPD (ie, borderpolar) represent a group with severe psychosocial morbidity who are often unemployed, suicidal, and utilize more costly forms of health care services. Efforts to identify effective approaches towards treating these patients have been minimal and are needed.

This article was originally published on 10/4/19 and has since been updated.

Dr Zimmerman is Professor of Psychiatry and Human Behavior at The Warren Alpert Medical School of Brown University and Director, Partial Hospital Program and Adult Outpatient Psychiatry at Lifespan. He presented “Borderpolar: Diagnosis and Treatment of Patients With Bipolar Disorder and Borderline Personality Disorder”at the 2019 Psych Congress in San Diego, CA.

1. Dunner DL. Clinical consequences of under-recognized bipolar spectrum disorder. 

2. Zimmerman M. Borderline personality disorder: a disorder in search of advocacy. 

3. Zimmerman M, Morgan TA. The relationship between borderline personality disorder and bipolar disorder. 

4. Frias A, Baltasar I, Birmaher B. Comorbidity between bipolar disorder and borderline personality disorder: Prevalence, explanatory theories, and clinical impact. 

5. Zimmerman M. Integrating the assessment methods of researchers in routine clinical practice: The Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project. First M, Ed. 

Standardized Evaluation in Clinical Practice

. Washington, DC: American Psychiatric Publishing, Inc; 2003: 29-74.

6. Zimmerman M, Balling C, Dalrymple K, et al. Screening for borderline personality disorder in psychiatric outpatients with major depressive disorder and bipolar disorder. 

7. Frankenburg FR, Zanarini MC. Divalproex sodium treatment of women with borderline personality disorder and bipolar II disorder: a double-blind placebo-controlled pilot study. 

The most frequently researched aspect of the relationship between BPD and bipolar disorder has been the frequency of their co-occurrence. Several reviews have estimated a 20% overlap in diagnostic frequency.

Borderpolar: Patients with Borderline Personality Disorder and Bipolar Disorder

From addressing borderline personality disorder to preventing drug-drug interactions and more, Psych Congress faculty shared useful diagnostic and treatment information. The featured speakers, which included 

’ Editorial Board members Phillip Resnick, MD, and Thomas Kosten, MD, discussed hot issues in psychiatry during the four-day conference.

Several sessions addressed the complexities of treating patients as well as new potential treatment options. For instance, Marlene Freeman, MD, Director of Clinical Services in the Perinatal and Reproductive Psychiatry Program at Massachusetts General Hospital, shared tips and insights for treating women of reproductive potential. One important point she impressed on attendees is balancing the risk of psychopharmacological agents with the risk associated with an untreated mental disorder. For instance, untreated antenatal depression is associated with the risk of low birth weight, prematurity, small gestational age, and neonatal behavioral differences (eg, irritability and decreased activity). Yet recent findings indicate the absolute risk of selective serotonin reuptake inhibitor exposure in pregnancy is small. Similarly, case-control studies have shown inconsistent data regarding teratogenic risk of SSRIs. Thus, for moderate-to-severe depression, Freeman suggested clinicians discuss the risks and benefits of antidepressants with mothers and, when warranted, use the lowest effective dose. She also emphasized that non-medication alternatives, such as psychotherapy, should be maximized.

On the opposite side of the spectrum, Rick Doblin, PhD, founder and executive director of the 

Multidisciplinary Association for Psychedelic Studies

 (MAPS), shared insights in using methylenedioxy-methamphetamine (MDMA) to treat posttraumatic Stress Disorder. Although MDMA has received a bad rap as an illicit party drug (eg, Molly, Ecstacy), Dobin explained its pharmacology could be utilized in patients who do not respond fully to psychotherapy alone. According to Doblin, MDMA increases the release of serotonin, norepinephrine, and dopamine and it enhances the release of oxytocin, prolactin, vasopressin, and cortisol. Brain bioimaging studies have shown that the positive effects of MDMA can counter the negative neurological effects of PTSD.

MAPS concluded its Phase 2 trial of MDMA-assisted psychotherapy with positive results. They found that 56% of patients no longer met criteria for PTSD following the treatment, compared with 23% in the placebo group. Plus, the number grew over time for the MDMA group, with 68% no longer meeting criteria at 12-month follow-up. Building on this success, MAPS has initiated Phase 3 studies, with the hope of obtaining FDA approval for the treatment at the conclusion of these studies.

On the attention-deficit/hyperactivity disorder front, Timothy Wilens, MD, Chief of the Division of Child and Adolescent Psychiatry and Associate Professor of Psychiatry at 

 in Boston, discussed newer medications and those in development to treat children and adolescents. New formulations have come out in recent years that allow easier treatment, including dissolving and chewable pills.

Now, the focus is on new pharmacological approaches to treating ADHD. Wilens noted a few drugs that are recently approved or in the later stages of study. For instance, dasotraline, which is a novel dual-acting dopamine and norepinephrine reuptake inhibitor, is in the registration phase with the FDA. Centanafadine, a triamine reuptake inhibitor that works with dopamine, serotonin, and norepinephrine, is in Phase 3 trials. Molindrone (SPN-810) is being studied to address impulsive aggressive behavior associated with ADHD; it is in Phase 3 trials. Another norepinephrine reuptake inhibitor, known as SPN-812, is in Phase 3 randomized control trials for ADHD in adolescents. Wilens also reported that the norepinephrine reuptake inhibitor 

, which was previously approved by the FDA for the treatment of obesity, had positive results in Phase 2 studies.

of their sessions with readers. The diverse faculty and topics underscore the wide variety of issues facing psychiatrists and their patients. As always, 

 strives to keep our valued readers up-to-date with practical clinical information and guidance to help your practices and patients. In doing so, we welcome your feedback!

If you would like to learn more about these and other topics from 

, or have suggestions for future meeting or topic coverage, please let us know via email 

From addressing borderline personality disorder to preventing drug-drug interactions and more, Psych Congress faculty shared useful diagnostic and treatment information.

Presenters at Psych Congress Share Clinical Tips, New Research

Patients on opioids for chronic pain management develop common complications that respond best to discontinuation and consideration of alternative pharmacotherapies, often in combination with behavioral interventions. A presentation at the October 2019 Psych Congress in San Diego covered these chronic opioid complications in detail. This overview addresses two medications for analgesia of chronic benign pain, both of which have substance abuse risks themselves-cannabinoids and 

are associated with complications in terms of their use, potential for abuse, and administration. Without concurrent opioids, cannabinoids’ efficacy as an analgesic is poor; and 10% of people who use tetrahydrocannabinol (THC) become addicted to it.

In addition, the cannabinoids, particularly cannabidiol (CBD), can potentiate the efficacy to, and reduce tolerance to, opioids. This brief overview focuses on CBD, because data and legal regulation have been rapidly progressing for its potential role in chronic pain management both within psychiatric and primary care settings. Furthermore, all 50 states have laws legalizing CBD with varying degrees of restrictions, and many people obtain CBD online without a medical cannabis license or physician prescription.

Although we do not know the most effective therapeutic dose of CBD for pain, some preliminary estimates are available, such as the 5mg/kg twice-daily dose of Epidiolex for treating two rare seizure disorders.

 Moreover, we can compare analgesic effects using the number of patients needed to treat (NNT) for a clinically significant therapeutic effect. Tricyclic antidepressants and opioids have the lowest NNT for treating neuropathic pain (2.6 and 2.1, respectively).

 This NNT means that for every single patient showing a therapeutic response to each of these agents, we need to treat 2.6 patients and 2.1 patients for tricyclics and opioids, respectively. Perhaps more simply, one of every two patients treated with opioids will have satisfactory analgesia from chronic neuropathic pain. In comparison, an oral CBD spray was found to have an NNT of 5.0, which is comparable to many routine agents used in treating neuropathic pain, including SSRIs (NNT=5.0) and gabapentin (NNT=6.4).

It is also important to look at the negative aspects of treatment. A meta-analysis of 18 double-blind, randomized controlled trials on CBD efficacy analyzed the harms associated with CBD. They found that the number needed to harm (NNH) with CBD, which ideally would be high, was instead relatively low. For CBD, the NNH ranged from 5 to 8 patients, while other analgesics have NNH values above 20.

Specific adverse events contributing to the poor value for NNH included impaired motor function (NNH=5), altered perception (NNH=7), and altered cognitive function (NNH=8). Thus, assessing the efficacy of CBD must be balanced against the potential for harm in the management of neuropathic pain.

The CBD oral solution Epidiolex is available in the US for management of refractory epilepsy, but it has been used off label for chronic pain conditions.

 GW pharmaceuticals also produce nabiximols, which is a marijuana extract currently approved in the UK to treat neuropathic pain, pain due to spasticity, overactive bladder, and other symptoms associated with multiple sclerosis. GW Pharmaceuticals is currently planning Phase 3 trials for nabiximols in the US.

 Thus, these medications are likely to become available in FDA-approved formulations at doses that have potential analgesic efficacy in the not too distant future.

The role of ketamine for chronic pain is more complex, including the setting for delivery. However, ketamine use for chronic pain could be adopted within the specialized psychiatry settings that the new REMS (Risk Evaluation and Mitigation Strategies) programs are mandating for esketamine to treat depression.

Ketamine might best be considered among the antidepressants that have consistently shown efficacy for chronic pain in conditions such as peripheral neuropathy, diabetic neuropathy, phantom limb pain, and patients with depression and pain.

 The relative efficacy of antidepressants based on NNT follows the efficacy of opioids, which has an NNT of 2.1, as previously noted. In comparison, the NNT for similar opioid alternatives are as follows: 3.6 for tricyclic antidepressants; 6.4 for serotonin- norepinephrine reuptake blockers; 7.2 for gabapentin; and 7.7 for pregabalin. However, the onset of full efficacy for opioids is rapid (and usually only a few minutes after oral ingestion), while these other medications typically take six to eight weeks for full efficacy as analgesics.

In contrast to the slow onset for these antidepressant and related agents, ketamine for chronic pain has shown surprisingly quick and long-lasting results. Ketamine has obvious acute analgesic efficacy, and sustained infusions of ketamine over one to 100 hours have produced sustained analgesia for months after these single treatments.

 Specifically, one study found substantially reduced chronic neuropathic pain after 30 minutes of ketamine infusion at 0.5 mg/kg, but this relief only lasted several hours in some patients. A second set of studies using 100-hour infusions of ketamine at 20 to 30 mg/hour or 4-hour daily infusions for 10 days relieved pain for three months, but relief started declining by four to six weeks after the acute treatments. Overall, these ketamine studies showed large effect sizes in the first week following treatment (1.2; 

<.001), but by week four, the effect sizes dropped to 0.4 (although they remained statistically significant at 

=.04). Unfortunately, these reports are five to 10 years old, and there are not more recent reports. Similarly, there are no studies using the newly available intranasal formulation of esketamine, which would make the administration easier than the previous intravenous studies.

These ketamine studies have some important caveats:

• There was no improvement in functionality with analgesia from ketamine.

• Cognition and memory impairment may be persistent with longer duration or more frequent administration; and no long-term data exist.

• Ketamine has negative inotropic effects on the heart and can produce elevated liver functions with repeated dosing.

• Less serious side effects include drowsiness and dizziness during repeated treatment (about one-quarter of patients reported these symptoms).

• Dissociation and abuse are potential psychiatric complications from even a single administration of ketamine.

Chronic pain continues to be a hot button issue, and psychiatrists need to be aware of non-opioid options, especially for their patients with substance use histories. Both ketamine and CBD are on the horizon as new treatments for chronic pain. Since both have risks for inducing substance use disorders, their use needs to be considered cautiously.

Dr Kosten is Professor at the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Staff Psychiatrist at Michael E. DeBakey VA Medical Center, Houston.

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This overview addresses two medications for analgesia of chronic benign pain, both of which have substance abuse risks themselves.

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