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All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to explore historical and current diagnostic approaches toward patients who present in mixed affective states.

1. Explore historical and current diagnostic approaches toward patients who present in mixed affective states.

2. Examine how current DSM nosology defines the proper method of assessing a mixed-episode patient and which diagnostic labels to give them based on their presenting symptomatology.

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.

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This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource®, LLC, and Psychiatric Times™. Physicians’ Education Resource®, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

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Depression has been well known to the medical community for multiple millennia. Through the ages, the understanding of depression and other affective disorders has undergone multiple revisions based on an evolving foundation of knowledge from contributing scientists and physicians (

). In 400 BCE, Hippocrates first used the terms 

 as a means of describing mental illness. Later, in the year 30 AD, Celsus, who was a physician in Rome, noticed that there was a relationship between depression and black bile, thus describing the term 

. As the understanding of mood disorders broadened over the centuries, clinicians began to notice the tendency for patients to fluctuate between mood states. In 1854, French psychiatrist Jean-Pierre Falret created the term 

 to signify the alternating moods of depression and mania.

 By 1889, the physician Emil Kraepelin described what he called a manic-depressive illness, using very similar criteria that are used today to diagnose 

. Kraepelin also noticed a differentiating factor between manic-depressive and psychotic illnesses, noting that the former did not have a deteriorating course.

 Nevertheless, the definition of manic-depressive illness did not account for patients presenting with both depressive and manic symptoms simultaneously within a similar time frame.

Although many diagnostic schemas have been created to define various mood states over the years, the intermixed presentation of depressed and manic symptoms has remained one presentation that has been difficult to define.

 was a term used by Kraepelin, which he defined as containing all affective states; nevertheless, other psychiatrists (even at the time) were skeptical of such definitions.

 Kraepelin stated later in his career that he believed that mixed episodes were the most common type of mood episodes.

 were just as important as the polarity when diagnosing manic-depressive illness.

 That is to say, repeated mood episodes of any polarity were diagnosed as manic-depressive illness as long as there were some mixed characteristics. This hints at the importance of detecting not only the content but also the frequency of mood episodes when diagnosing patients.

Even in the contemporary era, it has been suggested that the difference between diagnosing bipolar disorder versus major depressive disorder should not be limited by the presence or absence of a history of manic or hypomanic episodes.

 In cases where it is not possible to determine a patient’s history of 

 or hypomania, strategies have been researched to diagnose bipolar disorder from the characteristics of a patient’s depressive episodes, which—compared with patients with only major depression—have more atypical features such as leaden paralysis, hypersomnia, or (and) hyperphagia.

 Having broader, more dynamic diagnostic tools would increase clinicians’ ability to diagnose and treat patients’ affective conditions, even in circumstances where the presentation may not be as clear.

We performed a literature search on PubMed, an electronic database for the scientific literature on May 10, 2020, using the search phrase “depression with mixed features.” Articles were restricted to publication dates between 1973 and 2020. No restrictions were placed on language or article type. Articles were selected for inclusion based on the relevance of their titles and abstracts to the topic of mixed affective states. Information from review articles, retrospective studies, and clinical trials was ultimately included. The studies’ reference lists were also surveyed to discover additional pertinent articles. The cumulative history of mixed affective states was analyzed, and information from several of Kraepelin’s publications was included, along with information from Kaplan and Saddock’s 

 in the historical context. Several versions of the DSM were included as references.

Since the topic of manic-depressive illness was popularized by Kraepelin, there has been debate regarding the proper diagnostic segmentation of affective states. Eventually, in the early 20th century, 2 polar archetypes including 

 and bipolar disorder were clinically defined and accepted.

 Nevertheless, many noticed that some affective states appeared to remain intermediate between depression and mania.

) first formally acknowledged this state as a third major affective syndrome and labeled it as a mixed episode, which simultaneously met the diagnostic criteria for both major depressive and manic episodes nearly every day for at least a week.

), it was decided to include a less stringent mixed feature specifier, instead of an entirely separate diagnosis, to modify and describe individual manic and depressive episodes to account for subthreshold affective symptoms when assessing patients on either end of the mood spectrum.

 Exploring DSM-5’s mixed features designation further, it is apparent that symptoms, including distractibility, irritability, and psychomotor agitation, as criteria were left out completely.

 Nevertheless, many clinicians have argued that use of the mixed features specified in depression is compelling enough to alter diagnostic and treatment strategies because a patient may be at risk for having underlying bipolar disorder.

By eliminating the more rigid mood disorders section in the previous edition and placing bipolar and depressive disorders in separate chapters with their own unique modifiers, the 

 seems to be attempting to transition from a categorical approach to a more multidimensional one when diagnosing mood disorders.

 However, it must be stated that the aforementioned symptoms of distractibility, irritability, and psychomotor agitation were left out of the mixed features specifier criteria in the DSM-5.

 Nevertheless, the aforementioned overlapping features that have been omitted in the mixed features specifier symptom list of the DSM-5 do occur often during mood episodes. One study found that among patients diagnosed with an active major depressive episode, irritable mood was present in 32.6%, distractibility was present in 24.4%, and psychomotor agitation was present in 16.1%.

 Ultimately, the exclusion of these overlapping symptoms may serve to limit the practitioner from using the mixed features specifier, which may be detrimental to the patient, as many see the mixed affective state as a unique and commonly occurring syndrome in its own regard, with unique prognostic and therapeutic properties.

The DSM-5 workgroup decided to exclude these 3 overlapping symptoms—distractibility, irritability, and agitation (DIP)—because they lack the specificity to differentiate between depression and mania.

 Emerging evidence suggests, however, that having mixed episodes represents a unique syndrome with its own novel mechanism of pathogenesis.

 As a result, certain researchers have suggested a return to a Kraepelinian approach by reintegrating DIP symptoms into the mixed features classification system in a more inclusive manner.

 Others have gone so far as to say that mixed affective states need their own diagnostic category instead of a specifier due to the spectrum of state models proposed by Kraepelin in the 19th century.

 It seems the exclusion of DIP symptoms from the diagnosis of mixed features per DSM-5 will likely serve to alter the methods clinicians use to diagnose the condition and change the direction of future research.

 However, there have always been many interpretations and subcategorizations of mixed affective states based on the type and strength of the patient’s presenting symptoms.

Specialized diagnostic methodologies exist in the literature to better dissect and interpret mixed affective traits, such as segmenting the mixed episode into either a mixed depressive state or a mixed manic state on the basis of psychomotor activity and energy levels and treating accordingly.

 Nevertheless, an idea on which many researchers can agree is that the DSM-5 designation of mixed features is inadequate because it does not include the DIP symptoms in its criteria.

 Although the DSM-5 definition of the mixed episode is broader than the DSM-IV definition, it fails to include a sufficient number of symptoms altogether.

 This leaves a large number of cases undiagnosed and patients untreated as a result of the DSM-5’s lack of diagnostic openness and clarity.

Evidently, the DSM-5 chose to exclude these aforementioned core DIP symptoms from the mixed features specified for pragmatic purposes and to avoid the overdiagnosis of mixed symptoms.

 However, recent studies may prove this to be an important oversight (

). For instance, a recent study found that many patients presented with distractibility (59.2%), irritability (57.3%), and psychomotor agitation (36.5%) in mixed depression, whereas only 18% and 6.6% presented with euphoria and grandiosity, respectively.

 Furthermore, other studies have shown that psychomotor agitation was the symptom observed most frequently in patients with both bipolar disorder (59.8%) and 

 (48.8%) who presented in a major depressive episode.

 Because of this, clinicians and researchers have created more inclusive ways to define mixed episodes that do include symptoms such as psychomotor agitation and irritability.

Another major criticism that has been made against the new DSM-5 mixed features specifier is that the manic or hypomanic symptoms required during a major depressive episode were the least common symptoms that actually arise in depressive mixed states.

 This notion was further reinforced by other researchers and clinicians who criticized the DSM-5 for including uncommon symptoms such as euphoria and grandiosity as mixed feature criteria in major depressive episodes.

 Mixed depression does not respond to traditional 

, and these drugs may in fact worsen the clinical picture by further agitating them or causing mania.

It has been shown that patients with mixed depression compared to typical depression have a higher rate of 

, greater use of mood stabilizers and antipsychotics, and higher overall treatment cost.

 Fortunately, the clinical significance of patients who display mixed affective features is slowly being recognized, and future larger-scale studies are being conducted to investigate these patients and how to effectively treat them.

Patients who have underlying bipolar disorder and experience major depressive episodes with mixed features have higher rates of substance and alcohol use compared to those without mixed features.

 Additionally, patients with depression and bipolar disorder with mixed episodes were found to be more likely to have cardiovascular disease compared to patients who did not display mixed mood episodes, hinting at a distinctive pathologic origin of this condition.

 Patients who experience bipolar depression with concurrent manic or hypomanic symptoms are also found to report a younger age of illness onset, more severe illness course, higher percentage of rapid cycling course, more frequent hospitalizations, longer time to achieve remission, and concurrent psychotic features compared to patients who do not experience mixed features.

Thus, a more nuanced diagnostic approach is needed for patients who typically present with mixed episodes. Researchers have proposed alternate methods of assessing affective states in general, such as the ACE model, which considers 3 domains: activity, cognition, and emotion (thus, the name).

 One proposed model of assessing mood states compared the use of the DSM-5 model of assessing mixed depression to a research-based diagnostic criteria (RBDC) model that included DIP symptoms and found that mixed depression was detected in 29.1% of patients using an RBDC model and only 7.5% of patients using the DSM-5 criteria model.

In contrast, many have argued that the DSM-5 system of assessing mixed states actually facilitates the inclusion of subthreshold symptoms of opposite polarity and is overall less restrictive than previous versions of the DSM.

 This could help encourage diagnosis of mixed states on behalf of clinicians, thus possibly preventing the excessive prescription of antidepressant medications, which has been postulated to induce a type of hypomania in primarily depressive patients, referred to as bipolar III disorder.

Although there is room for improvement, at least the new DSM-5 classification system has helped to identify more patients suffering from mixed states compared with previous nosology because of broadening the DSM-IV-TR criteria.

 For example, in one study, patients previously diagnosed with bipolar disorder were examined when they were having a manic or hypomanic episode, and mixed features were detected in 20.4% during the episode using the DSM-5 criteria; however, using the DSM-IV-TR criteria, only 12.9% of the patients had a mixed episode, showing what appears to be a lower degree of sensitivity toward mixed affective states.

 Another study found an approximately 3-fold-greater risk for a patient with bipolar disorder to be diagnosed as having mixed symptoms using DSM-5 criteria compared with using DSM-IV-TR criteria, concluding that additional patients identified with mixed features could have been underdiagnosed without the DSM-5 change.

 There continues to be debate regarding the effectiveness of the current DSM system in capturing mixed affective symptoms.

Conclusions, Limitations, and Implications

Although there is some disagreement regarding how to diagnostically define a mixed affective state, it is evident that understanding their pathogenesis, epidemiology, and treatment is becoming increasingly important. A recent study of 36,309 US adults found that 10.4% experienced DSM-5–defined major depression in the past 12 months, and 20.6% of adults experienced DSM-5–defined major depression at least once in their lifetime.

 Interestingly, the mixed features specifier criterion was met in 15.5% of the major depressive cases, showing that close to 1 in 5 patients experiencing 

 may also be experiencing mixed symptoms.

This increasing incidence of mixed affective presentations highlights the importance of recognizing mixed features of depression and mania early in the course of illness in order to tailor a specialized treatment plan. Although “mixed features” is only a specifier and not a diagnosis per DSM-5, novel drugs such as lurasidone (Latuda) or cariprazine (Vraylar) are already being suggested for the treatment of patients who specifically display DSM-5–defined mixed features, hinting at a growing trend toward proper identification of this subset of patients.

There are a few limitations of this analysis. For instance, only PubMed was used to search for articles relevant to the topic. Similarly, the study only used the search phrase “depression with mixed features.” “Mania with mixed features” was not used as a search term because “depression with mixed features” yielded a sufficient number of articles with information on mixed affective states of either polarity. Moreover, the amount of information available on patients who experience mixed affective states is relatively small compared to that on manic and depressed patients, which can create a publication bias. Ironically, the reason for limited data for patients with mixed episodes could be due in part to the dichotomous views that mental health professionals have toward mood states.

Moving forward, clinicians should keep a watchful eye on this subtype of depression and mania. Having a more clearly delineated understanding of the mood spectrum would certainly carry beneficial implications for patients with mixed episodes by improving treatment modalities, diagnostic methods, and, ultimately, clinical outcomes. More research is needed to better understand the root of mixed states pathology so that better treatment solutions can be offered to this patient population.

 is a psychiatric resident at Unity Health White County Medical Center in Searcy, Arkansas.

is director of research at Unity Health White County Medical Center in Searcy, Arkansas, and a GME Research Consultant at Kansas City University. She is also an assistant professor of preventive medicine and public health, and director of the Preventive Medicine Research Center at the New York Institute of Technology College of Osteopathic Medicine.

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In this CME article, examine how current DSM nosology defines the proper method of assessing a mixed-episode patient and which diagnostic labels to give them based on their presenting symptomatology.

Exploring Diagnostic Strategies in the Assessment of Mixed Affective States

H. Steven Moffic, MD, in this very special episode of the weekly Psychiatry & Society series, interviews a patient, Nancy Dale Alterman. By sharing her story about how ECT treatment improved her life, she hopes to help others and end stigma. 

is an award-winning psychiatrist who has specialized in the cultural and ethical aspects of psychiatry. A prolific writer and speaker, he received the one-time designation of Hero of Public Psychiatry from the Assembly of the American Psychiatric Association in 2002. He is an advocate for mental health issues relate to climate instability, burnout, Islamophobia, and anti-Semitism for a better world. He serves on the Editorial Board of

is a patient who has lived in Denver her whole life. She is an artist and is also very involved in nonprofits focusing on the mental health community, and various causes, including animal welfare.

ECT played an important role in this patient's journey to recovery.

Heroic Journey to Recovery: A Patient's Story

“Charlie” is an 18-year-old Caucasian male with recently diagnosed bipolar disorder. He has no significant family psychiatric history. His early growth and development was typical, although he was a colicky baby. In early elementary school, he was demanding and outspoken, with increased energy. At age 10, his parents noticed some mood changes and that he was overly sensitive. Charlie had worsening mood lability at age 13, with periods of irritability and depression. At times, he was active and bossy on the playground—other times, he preferred to isolate inside and read during recess. He had some intermittent sleep difficulties and periodic anger outbursts at home. He also occasionally reported some unusual experiences. At age 16, his symptoms dramatically worsened, and he was hospitalized for a first episode of mania.

There is a recent increased effort to identify at-risk subjects for major psychiatric disorders, including 

 and bipolar disorder, and to predict individuals with prodromal symptoms who will progress to full-threshold disorder.

 First-episode mania (FEM) has been less frequently studied than first-episode psychosis (FEP). Furthermore, studies of FEP do not typically distinguish between affective and non-affective FEP,

 Risk/vulnerability markers include a family history of mood disorders and 

 for bipolar disorder, perinatal complications, worse premorbid adjustment, and increased 

 aimed to identify symptomatic and temporal differences between the prodromal phases of FEM and FEP with onset in young adulthood or adulthood, as well as differences in risk factors and vulnerability markers. The authors performed a retrospective cross-sectional analysis, as part of a larger 2-year study in Spain. Diagnosis was confirmed using a semi-structured interview according to DSM-5 criteria. Inclusion criteria were outpatients aged 18 to 45 and a FEM or FEP in the past 4 years. They excluded subjects with intellectual disability, severe medical conditions (eg, HIV or cancer), alcohol or other substance dependence, or 

Data on clinical features at illness onset, current clinical symptoms and treatments, and medical histories were collected. Data on prodromal symptoms (within 3 years of onset) were obtained retrospectively from patients (and caregivers), including using the semistructured Bipolar Prodrome Symptom Scale-Retrospective. Data on risk factors, including family history of psychiatric disorders, life stressors, childhood trauma, delayed language or psychomotor development, nocturnal enuresis, and difficulties in writing and reading were assessed. Clinical information on mental health services during youth (including diagnoses and medications) were also obtained. Logistic regression models were used to investigate prodromal symptoms as predictors of FEM and FEP. Differences in the duration of prodromal symptoms in FEM and FEP were assessed using Student’s t-test.

The study sample included 108 subjects (n=72 with FEM and n=36 with FEP). There were no sociodemographic differences between subject groups, except worse psychosocial functioning in patients with FEP. Subjects with FEM had a significantly shorter duration of untreated psychosis. There were no significant differences in the number of total prodromal symptoms between FEM and FEP. Social isolation was significantly associated with the prodromal stage of FEP, and increased energy or goal-directed activity with the prodromal stage of FEM. FEP was associated with a longer and more gradual onset and slower deterioration than FEM. The depression symptom “physically slowed down” was most associated with a gradual onset pattern, whereas “increased energy” was most associated with more rapid onset. There were higher rates of obstetric complications and reading/writing difficulties in FEP than FEM. Impaired premorbid adjustment was characteristic of FEP; otherwise, there were no differences in vulnerability factors.

The authors concluded that different clinical symptoms were associated with the prodromal phases of FEP and FEM; FEP was associated with a longer prodrome; reading/writing difficulties differentiated FEP and FEM; and impaired premorbid adjustment was more characteristic of FEP. The main study strength was the use of comprehensive and exhaustive assessments. Study limitations included the relatively small sample size (particularly for FEP) and the potential for recall bias with retrospective assessments.

The psychosis and mania prodromes, coupled with risk and vulnerability markers, may contribute to identification of individuals at increased risk of conversion to fulminant disorders. Together, this information may help identify targeted early treatment strategies based on individual characteristics.

is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

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3. Barajas A, Pelaez T, González O, et al. 

Predictive capacity of prodromal symptoms in first-episode psychosis of recent onset.

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Prodromal phase: differences in prodromal symptoms, risk factors and markers of vulnerability in first episode mania versus first episode psychosis with onset in late adolescence or adulthood.

Predicting mania versus psychosis: Researchers performed a retrospective study of prodromal symptoms, risk factors, and vulnerability markers in first-episode mania and psychosis.

Prodromal Mania and Psychosis

Last month we taught you how evening light can worsen mood. Today we teach you how to fix that. 

, "the voice of psychiatry." With thoughtful insights into the world of mental health, this podcast provides timely clinical commentary and practical cutting-edge pearls for you and your practice. We hope you enjoy.

I’m Chris Aiken, the Mood Disorders Section Editor for 

, and I’m Kellie Newsome, a psychiatric NP and the cohost of the 

: Evening light worsens sleep and mood, and 

 we unraveled the biology behind that association. To recap, evening light – particularly the blue wavelength suppresses melatonin, worsening 2 systems that are already fragile in people with mood disorders: sleep and circadian rhythms. In animal studies it even altered the core architecture of the brain – shrinking the dendritic spines that 

But you don’t have to go into the woods and live deliberately to fix this problem. Today, we’ll teach you how to use blue light filters to stabilize the circadian rhythms that regulate mood and sleep, and how to use them in 

: There are 2 well-known photoreceptors in the eye. The rods see black and white, and the cones add color vision. But in the 1990s a new photoreceptor was discovered – melanopsin – which only responds to the blue wavelength of light. This photoreceptor doesn’t help us see, but it does regulate our circadian rhythm. In the past, this system worked well because we didn’t have much blue light in the evening. There were candles, starlight, fireplaces – all yellow light.

: Except once a month when the blue moon was full. And it’s no coincidence the word lunatic arose in the middle ages as a term for mental illness. It was believed that some people went into temporary bouts of insanity that followed the lunar cycle – the moon. Seven hundred years later, 

 linking the full moon to worsening of psychiatric disorders continue to roll in.

: And in today’s world, every night is a full moon, because cell phones, plasma TVs, and energy efficient bulbs emit a lot of blue light. But technology has also come to the rescue in the form of blue light filtering glasses. These are amber colored glasses, and when you wear them they filter out close to 100% of blue light. They’ve gained popularity among sports figures and celebrities, because wearing them at night improves sleep – which then raises cognitive and athletic performance. But most models out there do not filter enough blue light to make a meaningful difference in psychiatric disorders. We recommend the glasses that were used in the clinical research – and there are 2 types. Some studies have used Uvex glasses, eg Uvex Skyper S1933X and Uvex Ultra-spec 2000, which are $10 to 15 dollars on Amazon.

Any pair on that site will work, and these are much better quality for a higher price, around $50.

: I keep a pair of these glasses at my desk for patients to try on. They’re usually surprised to see the world looks quite pleasant through them. They don’t make things dark, but give the world a relaxing, yellow hue. Some patients find them so soothing that I have to warn patients not to wear them during the day, because doing so will flip their circadian rhythm in the wrong direction. When you wear them, your brain will think it’s in pitch darkness, and we only want that effect at night.

: Wearing them has real biological effects. When you put them on, your melatonin starts to rise, the same as it does in a 

 Sometimes patients ask if they can just take melatonin instead, but that doesn’t have the same effect. In a recent randomized controlled trial, taking artificial melatonin did nothing to stabilize mood in bipolar disorder.

 So it’s not enough to have melatonin drizzled on the brain. There are other biological effects involved in pumping out the brain’s indigenous melatonin that are necessary here.

How to regulate circadian rhythms and regulate mood using dark therapy. 

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Exploring Diagnostic Strategies in the Assessment of Mixed Affective States

Heroic Journey to Recovery: A Patient's Story

Prodromal Mania and Psychosis

Blue Light Blockers: A Behavior Therapy for Mania

Four Myths About Lamotrigine

Can This Cancer Treatment Cause Manic Episodes?

Co-Occurring Mania and ADHD in Youths

Natural Products Used to Treat Depressed Mood as Monotherapies and Adjuvants to Antidepressants

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