Phebe Tucker, MD

Nonsuicidal self-injury to the genitalia, or genital self-mutilation (GSM), is an uncommon form of self-harming behavior seen primarily, but not exclusively, in male patients with psychosis or schizophrenia spectrum disorders. As with any nonsuicidal self-injurious behavior, the severity of GSM 

 Since GSM was first described in the medical literature in 1901, infrequent case reports have been published in both psychiatric and urologic literature. The majority of these cases have been examples of patients exhibiting a single episode of GSM often involving amputation of all or part of the penis and testicles.

In this report, we present a complex and unusual case of repetitive GSM and explore the differential diagnoses and psychodynamic and psychosocial underpinnings, describing the patient’s unfolding presentation while exploring and expanding upon the limited existing literature on the subject.

A 26-year-old man presented to an outpatient mental health clinic with complaints of persistent depressed mood and emotional outbursts. During the interview, “Mr Carr” incidentally disclosed a 13-year history of repetitive, superficial cutting of the ventral aspect of his penis. Adding to the intrigue of this case, he initially denied any history of overt psychotic symptoms.

Mr Carr reported persistent depressed mood, anxiety, outbursts of anger, and increasing social isolation. He recently began taking courses to be trained as an information technology technician and soon after had a physical altercation with a classmate whom he believed was talking about him behind his back. This altercation led him to seek help at the clinic.

Mr Carr described a lifelong history of untreated depression with an aborted suicide attempt at the age of 12 (in which he held a knife to his wrist) and 1 hospitalization at the age of 24 due to suicidal ideation. As an inpatient, he was given an unknown medication, which he discontinued shortly after discharge. Around the time of this hospitalization, he began to feel self-conscious around his friends and family.

Mr Carr used to enjoy traveling and meeting new people but is now a loner without lasting friendships. He wanted to work as an information technology technician so that he could work in an isolated environment away from others. His interactions with family, classmates, and strangers on the internet have become more negative, which he attributes to his increasingly pessimistic world view. He endorsed low self-esteem and troublesome interpersonal sensitivity and felt that others are critical of him but admitted that he may be projecting his own feelings about himself onto those around him. He expressed a desire to improve his life and his social skills so that his interactions with others are more positive.

During the interview, Mr Carr was thoughtful, articulate, and had partial insight into his problems. He was attentive and polite to clinicians, and his thought processes were linear, logical, and goal directed. He was fully oriented with depressed affect. He scored 15 on the Patient Health Questionnaire-9 (PHQ-9), which indicated moderately severe depression. He denied current suicidal ideation.

When asked about nonsuicidal self-injury, he reported that since age 13, he has been cutting layers of skin from the ventral side of his penis about 2 to 3 times a year. He did not endorse erotic sensations or emotional relief as motivating these acts. Mr Carr stated all his sexual partners were female and that the cutting of his genitalia did not interfere with his sex life. He has not had any long-term romantic relationships.

Upon questioning, he denied any history of physical or 

. However, he later stated, “My whole life has felt like emotional abuse.” Mr Carr said his family makes him feel inadequate, and they wanted him to be circumcised. He said he was raised Catholic and was of Hispanic and Northern European ancestry. He did not know why he was not circumcised as an infant. An aunt recently asked him, “Why don’t you just have it done and be over with it?” He believes circumcision is not natural; he became visibly upset talking about the subject and declined to answer further questions regarding the cutting of his penis.

Mr Carr did not have a history of mania, 

, or visual hallucinations, and as far as he knows, there was no family history of psychiatric illness. He reported infrequent alcohol and cigarette use and daily marijuana use as self-treatment for his depression and anxiety. He used cocaine and psilocybin each on 1 occasion several years ago; he denied use of other drugs.

Mr Carr was agreeable to medication treatment and was started on 25-mg hydroxyzine and 30-mg duloxetine with instructions to increase the duloxetine dose to 60 mg after 7 days. He was also assigned to meet with a licensed clinical social worker for counseling.

Four days later, Mr Carr called a crisis hotline and reported that he was hearing voices. His psychiatrist was made aware of this call and phoned him to follow up. Mr Carr said he was unsure whether the voices were his neighbors “talking about him” or if the voices were internal. Two weeks later, he called his psychiatrist requesting a higher dose of hydroxyzine to treat his anxiety. When discussing what he was anxious about, he described an earlier event during which he was running errands when he became concerned that the strangers around him did not like him and were calling him names. He also stated that his hotel room was burglarized the night before, and he believed someone was “trying to intimidate [him].” Shortly after these incidents of increasing paranoia, Mr Carr accused his psychiatrist of not caring about him, moved out of state, and was lost to follow-up.

Although it is clear GSM behaviors occur within a spectrum of severity, a limitation of most literature reviews is that few have differentiated between low-intensity and more life-threatening GSM behaviors. The most recent systematic review of the available literature explored this issue directly but also called into question previous reports of the percentage of patients who are psychotic at the time of self-harm.

 sought to compare the psychiatric diagnoses behind 173 cases of GSM and to differentiate between mutilation-only and more extreme cases such as amputation of the penis, castration, or combined amputation and castration. Their review of the literature classified just 12.1% of GSM incidents as mutilation-only cases, whereas 35.8% involved penile amputation, 32.4% were cases of self-castration, and 19.7% were combined amputation/castration cases (

Psychiatric diagnoses were identified in 157 of the 173 cases examined (

). Common psychiatric disorders included schizophrenia spectrum as the most common (49%), followed by substance use (18.5%), personality (15.9%), and gender dysphoric (15.3%). These figures are in stark contrast to other reviews that placed the percentage of schizophrenia spectrum disorders higher, from 77% to 87%.

Veeder and Leo’s analysis found that patients who had a diagnosis of schizophrenia spectrum disorders were more likely to amputate their penises (with or without accompanying castration) than patients with other diagnoses and that castration only was more likely in patients with gender dysphoria. In the cases of mutilation only, 23.8% of patients had a diagnosis of schizophrenia spectrum disorders, 19% had a diagnosis of substance use disorder, 19% had a diagnosis of personality disorder, 9.5% had a diagnosis of depression, 9.5% had a diagnosis of gender dysphoria, and for 14.3%, a diagnosis was unknown or not reported.

Because he was lost to follow-up, many questions regarding Mr Carr’s GSM cannot be answered, and so a wide diagnostic net must be cast to explore the underlying diagnoses that may explain his behavior.

Given Mr Carr’s unfolding psychotic symptoms with auditory hallucinations and persecutory delusions after his visit, and considering the previously mentioned data, it seems most likely that he was experiencing the onset of a schizophrenia spectrum disorder.

 If (conservatively) 49% of patients exhibiting any form of GSM and 23.8% with mutilation-only GSM end up with a diagnosis of a schizophrenia spectrum disorder, then the cutting of his penis may have been Mr Carr’s first presenting sign, preceding the major criteria for any schizophrenia spectrum disorder by many years. Moreover, Mr Carr described himself as a loner, consistent with personality characteristics often noted in patients before the onset of psychosis.

There is at least 1 case in the literature in which a man castrated himself years before the onset of overt psychosis. At the time of the autocastration, this man received a diagnosis of schizotypal personality disorder due to odd beliefs or magical thinking and social withdrawal. Three years later, the patient presented with overt paranoia, disorganized thought, and the diagnosis was schizophrenia.

In addition to schizophreniform disorder, schizophrenia, and schizoaffective disorder, medication-induced psychotic disorder should also be 

in the differential diagnosis because Mr Carr’s psychotic symptoms appeared days after the initiating duloxetine.

 found that mood disorders were not a common diagnosis in the setting of GSM: only 8.9% of cases of any form of GSM and 9.5% of mutilation-only GSM involved patients meeting criteria for major depressive disorder (MDD).

 Mr Carr reported a long history of depression and met MDD criteria at the time of his presentation to the clinic. Therefore, MDD with psychotic features should be included in the differential diagnosis.

There is also the possibility that Mr Carr has been suffering with bipolar disorder for many years. He described a time before his hospitalization in which he hitchhiked, traveled through many states, slept on the couches of strangers, and pursued sexual relationships with women he had only just met. Without more information, it is difficult to determine whether this was simply age-appropriate youthful adventurous behavior or hypomanic episodes. The fact that Mr Carr experienced psychosis after starting duloxetine further supports the inclusion of bipolar disorder with psychotic features in the differential diagnosis.

In light of his almost-daily marijuana use, substance use disorder should be considered. Substance use disorders were reported in 19% of individuals with mutilation-only GSM.

 Mr Carr denied any cognitive or other impairment from his marijuana use, but one cannot rule out that marijuana or other possible additives may have exacerbated his paranoia or triggered the auditory hallucinations. Dual diagnosis is not uncommon in patients with psychotic disorders. No urine drug screen was performed to confirm that marijuana was the only substance in his system. Mr Carr stated that he began cutting himself before he began using marijuana, suggesting that marijuana use did not explain his GSM.

When considering a personality disorder (diagnosed in 19% of mutilation-only cases) as an underlying diagnosis, Mr Carr did exhibit some cluster A personality traits such as suspicion of others as found in paranoid or schizotypal personality disorders and a preference for solitary activities as seen in schizoid personality disorder.

 He also had some symptoms of borderline personality disorder with self-mutilating behavior (although not suicidal) and described intense anger and paranoid ideation, which may have been stress related and evolved into psychosis. However, he did not meet DSM-5) criteria for any one disorder. Moreover, these personality traits merge with Mr Carr’s psychotic and mood symptoms.

Of the 4 diagnoses, Veeder and Leo found most commonly in mutilation-only cases, gender dysphoria is the least likely to explain Mr Carr’s case, as he did not describe any dissatisfaction with his gender.

It is very difficult to find examples of patients who have practiced GSM 

. A report from 2002 found only 13 cases of repetitive GSM in the literature. The authors reported that 8 of the 13 cases (61.5%) involved male patients with gender dysphoria and in only 5 of the cases (38.5%) was the patient psychotic at the time. Of these 13 total cases, 46.2% began with low-intensity, nonpermanent forms of mutilation and progressed to more severe acts.

 Although it is a small sample size, this report highlights the importance of asking these patients about gender dysphoria and determining whether their self-harming behavior has evolved in severity over time.

DSM-5 cites nonsuicidal self-injury as a condition warranting further research. While Mr Carr’s behavior does not entirely fit within the proposed criteria for this disorder, it is worth noting here. DSM-5 characterizes 

 as repetitive, shallow but painful injuries to the body surface that commonly produce feelings of relief. Many individuals who practice this behavior report feelings of tension and craving for the mutilation followed by reduced tension and anxiety after the act. Whether Mr Carr felt this pattern of craving followed by relief, we do not know, but it is clear he did not intend to kill himself by GSM.

Case reports on GSM are not only scarce, they are also inconsistent in their documentation of the psychosocial factors underlying these acts. In the case of Mr Carr, one wonders what role the pressure from his family to undergo circumcision played in his GSM or whether his feelings of having been emotionally abused contributed to self-punishing behavior.

Several psychodynamic theories have been proposed regarding GSM. Some have posited that it could be related to Freudian castration anxiety. Thompson and colleagues

 described 2 cases of GSM by 2 young men who had recently lost their fathers, suggesting that an unresolved oedipal complex may have contributed to the GSM. The authors proposed that guilt about an attachment to their mother, ambivalence toward the father, and intense grief might have led to self-punishment by carrying out castration fears.

Findings from another case study of 3 patients suggest that GSM could be related to castration anxiety and unresolved oedipal situations.

 A case study of 2 patients with schizophrenia who carried out a different and extreme form of self-mutilation, self-enucleation, suggested that castration fears and failure to resolve oedipal conflicts, severe guilt, and self-punishment all contributed to these desperate acts.

 Mr Carr did not share specific details about his relationship with his parents other than general feelings of emotional abuse to support unresolved oedipal issues as influencing him.

Other risk factors identified in the literature include feelings of guilt surrounding a sexual conflict, as well as experiences of separation, a recent failure, and a history of self-mutilation (genital and nongenital).

 Unfortunately, the case of Mr Carr, like cases before it, lacks many important details that could contribute to our understanding of this unusual behavior. Questions such as whether he felt guilty about a past sexual encounter or if he was punishing himself for disappointing his family may never be answered. Consistent with the diagnostic complexity of Mr Carr, for 14.3% of mutilation-only GSM cases, a diagnosis was unknown or not reported.

GSM is an infrequent form of nonsuicidal self-injury that occurs within a spectrum of severity. It is very likely that less severe forms of GSM may be both underreported and unpublished. These factors combined with the immense shift in scientific understanding of human sexuality since the first cases were reported has contributed to the clinical mystery of GSM. When facing a case of GSM, clinicians should explore the motivations underlying the self-injury and consider a wide variety of psychiatric diagnoses. Medical treatment should be tailored to the patient’s presentation and underlying diagnosis, and the patient should be closely monitored for recurrence and escalation.

 is a medical student, University of Oklahoma Health Sciences Center, Oklahoma City, OK. 

is Vice Chair of Education, Ungerman Endowed Chair of Psychiatry, Department of Psychiatry and Behavioral Sciences, University of Oklahoma Health Sciences Center. The authors report no conflicts of interest concerning the subject matter of this article.

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Articles

This form of nonsuicidal self-injury occurs within a spectrum of severity, and it is very likely that cases are both underreported and unpublished.

Genital Self-Mutilation: A Cutting Conundrum

Slideshows

Patients with difficult conditions such as delusional parasitosis tend to resist the notion that a psychiatric problem underlies their symptoms.

5 Techniques to Help Your Patient Accept a Difficult Psychiatric Diagnosis

The recent suicides of two teenaged survivors of the 2018 school shooting at Marjory Stoneman Douglas High School in Parkland, Florida and the father of a child killed in the 2012 Sandy Hook Elementary School shooting raise the question of the interplay and impact of survivor guilt, post-traumatic stress disorder, and traumatic bereavement among survivors and victims’ loved ones after such traumatic events. Alarmingly, these three suicides occurred within a 10-day period. The mother of one shooting survivor who died by suicide shared publicly her daughter’s PTSD and survivor guilt. The father of the young Columbine victim had struggled with prolonged grief over 6 years after his daughter’s death, according to his wife. In addition, suicides have also occurred in the wake of the Columbine and Virginia Tech school shootings.

DSM-5 and its predecessors clarify diagnostic criteria for PTSD, but do not specifically name survivor guilt as an outcome of PTSD or traumatic exposure. PTSD’s criterion D (negative alterations in cognitions and mood associated with trauma) includes persistent distorted cognitions such as blaming oneself or others and persistent negative emotional state such as guilt or shame. Risk for suicidal ideation and attempts in PTSD is clearly discussed in the text, as well as the risk for comorbid depression. DSM-5 differs from previous DSMs, which excluded depression diagnosis for symptoms lasting less than two months after a loved one’s death. Thus, at the clinician’s judgment, major depression can now be diagnosed in the presence of bereavement.

Survivor guilt occurs when individuals believe they have done something wrong in surviving a traumatic event in which others have perished. It has been described among Holocaust survivors and combat veterans as well as by survivors of natural disasters, airplane crashes, acts of terrorism, and mass shootings. While some survivor guilt may be natural, when excessive or prolonged, it can lead to other problems.

Here’s an example of a man who survived the Oklahoma City bombing while working inside the Federal Building. When the blast occurred, he had been turning on a light switch. He developed the irrational belief that his switching on the light had somehow triggered the bomb, although he knew intellectually that this was not the case. He escaped the devastated building with no physical injuries, but many coworkers perished. He did not escape psychic injuries. Along with considerable survivor guilt, he developed PTSD and a substance use disorder, complicating his treatment and recovery, and died a few years later of cardiovascular disease.

Survivor guilt has been described in the psychoanalytic literature. Freud described a broader conceptualization of a more universal guilt that individuals feel when they survive another’s death.

 Hartman recently re-examined Anna Freud’s dreams, exploring the interplay of mourning and survival guilt. Her immediate family escaped the Holocaust but her aunts were lost in Nazi concentration camps. While she never wrote directly about her family’s Holocaust experiences, her grieving was seen to be complicated by survivor guilt, with the possibility that her mourning may have affected her views on trauma and attachment. Anna later worked with child concentration camp survivors although she had a conservative view of altruism.

Survivor guilt has been recognized in combat veterans with PTSD and has been one of 5 factors significantly related to suicide attempts, along with depression, anxiety, severe PTSD, and intense combat guilt as the number one factor.

 Survivor guilt may vary among veterans of different wars. Vietnam veterans had more severe symptoms of PTSD, depression, hostility, survivor guilt, and work impairment as well as earlier onset of alcoholism compared with World War II veterans, although more time had passed since combat experiences for the latter group.

 Hospitalized Nigerian army veterans who had served as peacekeepers in Liberia and Sierra Leon had higher rates of survivor guilt (38%) than PTSD (22%), with survivor guilt associated with avoidance of trauma stimuli and PTSD linked with alcohol and cannabis use.

Traumatic bereavement or grief may occur after a sudden or unexpected death of a loved one if the response is severe or prolonged or interferes with functioning. It differs from survivor guilt in having predominant grief rather than guilt. According to the National Center for PTSD, with traumatic bereavement there is preoccupation with or a longing for the deceased; avoidance or being drawn to reminders of the lost one; feeling bitter, dazed, or angry; seeing the deceased or hearing the loved one’s voice; difficulty with relationships, upsetting memories, or feelings of emptiness.

Other psychiatric, behavioral, or medical problems may also occur with prolonged traumatic grief. Risk factors complicating recovery after witnessing sudden death include survivor guilt, having one’s own life threatened, and being confronted with massive, shocking deaths. For children, having many losses or viewing death is especially difficult. To help the traumatically bereaved individual recover hope and comfort, recommendations include providing information about grief, assessing the bereaved person’s distress while helping solve practical problems, and managing intense feelings.

In light of recent events, mass shootings of youth have become increasingly a concern. What have we learned over the years? Much of the focus has understandably been on PTSD, with some assessments of grief. One year following a 1984 sniper attack at an elementary school, surviving children had more grief symptoms if they were better acquainted with the deceased child and had had more exposure to the violence; grief and PTSD symptoms sometimes presented independently, and at other times they were interconnected.

Four months after a 2007 high school shooting in Finland, half of the girls and a third of boys had posttraumatic distress; intense exposure and female gender increased the risk for PTSD.

 After a 2007 classroom shooting in an Illinois university, an assessment of female undergraduates in a sexual revictimization study found many (42.1%) to be resilient, with 11.9% having probable PTSD acutely and 8 months later.

 More PTSD symptoms at 8 months was associated with higher prior trauma exposure, post-trauma emotional dysregulation, and peritraumatic dissociation.

The impact of school shootings extends far beyond the directly affected school and community. The widespread emotional effects of 69 deaths (average age 19 years) in a 2011 summer camp mass shooting in Norway were revealed in an assessment of over 10,000 Norwegian high school students. One in five respondents knew individuals directly exposed, over 50% felt the event threatened their own or a close one’s lives, and almost 80% had changed views of the world. Higher levels of PTSD symptoms were associated with personal proximity to the events, perceived threat, and being a female or immigrant.

Looking at the widespread effects of mass school shootings, a national US survey of high school students not directly involved in the event was conducted a month before and two months after the 1999 Columbine High School shootings. Results showed that more students felt too unsafe to go to school after the catastrophe, but they were less likely to consider suicide.

So, what can we do to help survivors and family members of school shootings? No studies have systematically studied interventions to help these individuals with specific problems of survival guilt alone. See 

 for recommendations that may be helpful in the immediate aftermath of a community disaster and over time.

Treatments for diagnosed PTSD cited by the National Center for PTSD as having the strongest evidence for efficacy are prolonged exposure, cognitive processing therapy, and eye movement desensitization and reprocessing (EMDR). Four antidepressants with demonstrated effectiveness in adults only are sertraline, paroxetine, fluoxetine, and venlafaxine. Similarly, psychotherapy and some antidepressants may be helpful for children or adolescents who have major depression in the aftermath of mass violence.

Providing a sense of safety and normalcy is important. A recent study of children and teens who presented to an ER in the UK after traumatic incidents were followed for two months. The findings suggest that youths with more PTSD symptoms made more efforts to deliberately process their trauma, as if they perceived that there was something wrong with them. PTSD symptoms were not associated with severity of physical injuries, other life stressors, or social support.

The reactions of caregivers also plays a role in number of PTSD symptoms. More PTSD symptoms were seen in traumatized youths who had families who exaggerated their child’s emotional response or whose parents reported more family over-involvement and accommodation behaviors.

School shootings have taken direct and secondary victims and appear to be increasing. While limiting access to weapons among at-risk youth and monitoring social media for potential threats may help prevent future incidents, as mental health professionals we must deal with the emotional toll on innocent survivors and among youths in general, to restore mental health and a sense of safety.

 is Professor and Vice Chair of Education, Ungerman Endowed Chair, Department of Psychiatry and Behavioral Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK. Dr Lastrapes is PGY-1, Department of Psychiatry and Behavioral Sciences, University of Oklahoma Health Sciences Center. She is also an Editorial Board Member for

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 Davidson JRT, Kudler HS, Saunders WP. Symptom and comorbidity patterns in World War II and Vietnam veterans with posttraumatic stress disorder. 

 Okulate GT, Jones OBE. Post-traumatic stress disorder, survivor guilt and substance use: a study of hospitalized Nigerian army veterans. 

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https://www.ptsd.va.gov/professional/treat/type/manage_grief_disaster.asp

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 Miron LR, Orcutt HK, Kumpula MJ. Differential predictors of transient stress versus posttraumatic stress disorder: evaluating risk following targeted mass violence. 

 Nordanger DO, Hysing M, Posserud M-B, et al. Posttraumatic responses to the July 22, 2011 Oslo terror among Norwegian high school students. 

 Brener ND, Simon TR, Anderson M, et al. Effect of the incidence at Columbine on students’ violence- and suicide-eelated behaviors. 

 Meiser-Stedman R, McKinnon A, Dixon C, et al. A core role for cognitive processes in the acute onset and maintenance of post-traumatic stress in children and adolescents. 

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The impact of school shootings extends far beyond the directly affected school and community. What can we do to help survivors and family members?

The Aftermath of School Shootings

This activity offers CE credits for:
1. Physicians (CME)
2. Other

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

To understand the role of inflammation and immune function in the risk of schizophrenia.

At the end of this CE activity, participants should be able to:

• Define the mechanisms responsible for a healthy immune system

• Describe the effects of higher levels of inflammation on the CNS to promote mood disturbances and psychosis

• Describe variable responses to antipsychotics and the connection to the anti-inflammatory properties of these medications

• Recognize anti-inflammatory treatments that might be used as adjunctive therapy to mitigate symptoms

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and 

. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 

 ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants: AANPCP and AAPA accept certificates of participation for educational activities certified for 

It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer-review process.

The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.

Erin Walling, MSIV, has no disclosures to report.

Phebe Tucker, MD, has no disclosures to report.

Brian Miller, MD, (peer/content reviewer) reports that he has received grant support from Augusta University, National Institute of Mental Health, Stanley Medical Research Institute, and Brain and Behavior Research Foundation; he has received research support from Alkermes and Acadia; and he has received honoraria from 

Applicable Psychiatric Times staff and CME Outfitters staff have no disclosures to report.

Faculty of this CME/CE activity may include discussion of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

Schizophrenia affects an estimated 1% of the population worldwide. Its prominent positive and negative psychotic symptoms and adverse effects on cognitive functioning lead to low levels of global functioning and increased morbidity and mortality.

Historically, research has focused on dopaminergic theories to explain the pathophysiology of schizophrenia, supported by years of clinical evidence that typical and atypical antipsychotic drugs can benefit patients. In practice, however, limitations of the clinical efficacy of antipsychotic medications suggest that the dopaminergic theory is not an entirely adequate explanation. Current research investigates new pathophysiologic mechanisms and lays the groundwork for redefining schizophrenia based on distinct medical subclasses-which may lead to more targeted and effective treatments.

The association between autoimmunity, chronic inflammation, and psychosis is not new. It was first postulated by German neuropsychiatrist Hermann Lehmann-Facius in 1937 and further expanded by P.R.J. Burch in the early 1960s. More recently, scientists have expanded this theory, prompted by repeated findings of elevated inflammatory markers in patients with schizophrenia (

). Elevated serum levels of nonspecific proinflammatory markers such as prostaglandin E2 and C-reactive protein have been noted across multiple studies, in addition to elevated inflammatory cytokines such as interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-Î±).

Within a healthy immune system, these factors are essential in promoting immunological responses through febrile reactions, phagocyte activation, leukocyte recruitment, and activation of the complement system in response to physiological insult. However, over-activation of this protective mechanism can damage host tissues with excessive production of nitrogen monoxide and superoxide anion, which are toxic to healthy proteins, mitochondria, and DNA. Increased levels of proinflammatory mediators can also cross the blood-brain barrier, where they damage polyunsaturated fatty acids that comprise the neuronal membrane. They are known to disturb brain function and to affect cognition, perception, mood, and behavior.

Higher levels of inflammatory markers have also been linked to increased catabolism of tryptophan, an essential amino acid required for the production of serotonin.

 Furthermore, over-activation of proinflammatory CNS cells can produce a kynurenic acid by-product, a substance known as a potent glutamatergic antagonist associated with both positive and negative symptoms of schizophrenia. Hence, increased inflammation can directly contribute to decreased serotonin levels and increased glutamatergic activity in the CNS, factors associated with both mood disturbances and symptoms of schizophrenia in previous studies.

In addition to known peripheral effects of proinflammatory proteins, other changes noted in the CNS involve actions of astrocytes and microglial cells. These 2 cell types serve as the immunocompetent cells of the CNS. Astrocytes exhibit stimulatory effects on microglia, which act as macrophages within the brain, consuming damaged cells and infectious agents. This process is essential to protecting the CNS from infection and buildup of unwanted cellular debris. However, as with peripheral stimulation, too much activity within this system can damage healthy host tissues, which ultimately leads to cognitive dysfunction.

In support of this, researchers have identified an astrocyte-specific protein, S100B, found to be elevated in cerebrospinal fluid samples of patients with schizophrenia. Elevations of this protein not only indicate astrocyte overactivity, but S100B also causes microglial cells to be more active. Positive emission tomography (PET) studies of patients with schizophrenia have shown increases in microglial cell activity, which lends further support to the link between dysfunctional immunomodulation of the CNS and the pathophysiology of schizophrenia.

Note, however, that additional research using PET has produced vastly diverse results; therefore, this area requires further exploration and analysis.

Schizophrenia has a strong genetic component-studies of monozygotic twins show concordance rates of up to 48% to 50%.5 Use of advanced technologies such as genome-wide association studies have enabled researchers to examine precise heritable biomarkers in schizophrenia. In addition to others, the major histocompatibility complex region has been most strongly associated with schizophrenia.

 This complex is considered one of the key regulators of immune function, contributing to HLA genes, TNF production, and production of components of the complement cascade.

The association between major histocompatibility complex and schizophrenia is composed, in large part, by the complement component 4 (C4) alleles that produce increased levels of C4A and C4B in the CNS. In mice, C4 has been credited with postnatal synapse destruction, implicating the role of C4 in the reduced number of synapses found in patients with schizophrenia.

This finding clarifies both the heritability of mental disorders like schizophrenia and a possible genetic link between this disorder and excessive activation of the immune system.

Epidemiological studies support a link between overt autoimmune disorders and schizophrenia. In one study, the presence of an autoimmune disorder indicated a 45% increase in the risk of schizophrenia, with strong associations of this mental disorder with rheumatoid arthritis, intestinal malabsorption, autoimmune thyroid disease, dermatomyositis, acquired hemolytic anemia, interstitial cystitis, and SjÃ¶gren syndrome.

 The same study also found an overall increase in the presence of familial autoimmune disease in patients with schizophrenia, which suggests that in many cases schizophrenia shares a genetic diathesis with familial autoimmune disorders. Overall, this evidence implies a heritable link between these disease processes, but further research is needed to identify specific genes or loci.

Immune priming and neurodevelopmental insults

Immune priming refers to a theory that specific environmental factors that take effect during formative prenatal or early postnatal developmental windows can cause permanent changes to physiological, emotional, or physical functionality later in life. Recent studies suggest that early exposure to infection may induce sensitizing or preconditioning effects that lead to intensified reactions to infectious or noninfectious insults as an adult. One study showed that prenatal increases in the proinflammatory cytokine IL-8 were associated with an increased risk of schizophrenia in the offspring.

 This link could not only explain early susceptibility to mental illness but also illuminate the disruption during formative developmental periods that can change lifelong physiology.

Other theories of developmental predisposition to psychosis suggest that early prenatal insults can disrupt neurodevelopment, which leads to permanent changes in neuroanatomy, cognitive processing, and behavior-thus predisposing individuals to psychiatric disorders.

 Although it is difficult to make a direct correlation between a prenatal or early postnatal insult and a disease that typically is not diagnosed until the second or third decade of life, more extensive studies are needed to explore additional risk factors or environmental insults that could produce such neurodevelopmental differences.

-methyl-d-aspartate (NMDA) glutamate receptor involvement has long been suspected in the pathophysiology of psychosis. In one study, autoantibodies to the NMDA receptor caused decreased rates of glutamate transmission, resulting in psychotic symptoms secondary to encephalitis.

 This supports not only the premise of glutamatergic modulation as a possible contributor to psychosis in schizophrenia, but also that the modulation can be provoked by atypical immunological function. Moreover, animal studies have found that excessive activation of proinflammatory cells of the CNS such as astrocytes and microglia can produce a kynurenic acid by-product, a substance that serves as a potent antagonist of glutamatergic NMDA receptors.

 Therefore, the possibility of multiple pathways of immunological disruption could contribute to an NMDA receptor component of schizophrenia.

Recent research into the increased numbers of inflammatory cells in patients with schizophrenia offers additional support for inflammatory theories. In one study, cell lines in affected patients were compared with those of healthy, matched participants. Patients with schizophrenia had higher levels of natural killer cells, monocytes, naive B cells, and memory T cells than healthy controls. These differences were particularly prominent in patients with primarily negative and cognitive symptoms, and in those with treatment-resistant disease.

 The results demonstrate a link between immune dysregulation and schizophrenia, and suggest that such dysregulation may contribute to symptoms that may not be easily treated by traditional dopamine antagonists.

Furthermore, the immune system’s monocytes and macrophages, controlled by toll-like receptors (TLRs) that mediate inflammatory responses, have been implicated. In a double-blind study, patients with schizophrenia and matched, healthy controls were exposed to a lipopolysaccharide to mimic bacterial infections and to polyI:C to mimic viral infections. Patients with schizophrenia showed an increase in TLR-3 and TLR-4 on flow cytometry and increased overall numbers of monocytes.

 These findings support the hypothesis of an increased inflammatory response and an abnormal response to normal environmental insults.

Anti-inflammatory properties of antipsychotics

One potential explanation for variable responsiveness to antipsychotics could be differences in the anti-inflammatory properties of these medications. Research on this topic shows variable results. Some studies have found increased levels of inflammatory markers with antipsychotic treatment, while others have found decreased levels or no change in levels. Findings suggest that antipsychotic drugs may have both direct anti-inflammatory and indirect inflammatory effects, depending on the weight gain associated with treatment.

A longitudinal study of patients treated with risperidone noted an initial decrease in IL-1Î² and IL-6 in the first 6 weeks, followed by a subsequent increase in levels, which mimics patients’ weight gain patterns.

 This could explain discrepancies among previous studies and demonstrates the importance of measuring timing of metabolic dysfunction when inflammatory markers and immune dysregulation are evaluated. Future studies should incorporate this information when investigating anti-inflammatory properties of medications that are currently first-line treatments for schizophrenia.

Cyclooxygenase (COX) is a critical-step enzyme in the inflammatory process, which results in the direct production of inflammatory mediators. Specifically, COX-2 is responsible for the conversion of arachidonic acid to active prostaglandins that are direct mediators of fever, leukocyte recruitment, and vascular permeability.

In a double-blind, randomized trial, patients treated with COX-2 inhibitors (celecoxib) in conjunction with amisulpride (an atypical antipsychotic available in Europe) showed statistically significant improvement in both positive and negative symptoms of schizophrenia compared with patients treated with amisulpride and placebo.

 In another double-blind, randomized trial, patients with first-episode schizophrenic psychosis were treated with risperidone plus celecoxib or risperidone plus placebo. Those treated with the combination of an antipsychotic and a COX-2 inhibitor benefited particularly in negative and cognitive symptoms.

Studies that used other atypical antipsychotics have replicated these results, which supports the utility of this treatment with a variety of antipsychotics. However, one meta-analysis that compared NSAIDs with placebo for adjunctive treatment of schizophrenia showed only minimal and/or small effect size for positive symptoms.

 Although this finding suggests that NSAIDs adjunctive to first-line antipsychotics may not benefit patients with schizophrenia, further controlled studies are needed.

Minocycline is a second-generation tetracycline with both anti-inflammatory and antimicrobial effects through its inhibition of protein synthesis. In a double-blind, placebo-controlled trial, patients treated with antipsychotics in combination with minocycline showed statistically significant improvement in both negative symptoms and cognitive symptoms of schizophrenia, compared with patients who received antipsychotics plus placebo.

Specific anti-inflammatory benefits in the treatment of schizophrenia may involve decreased activation and proliferation of microglia, which mediate CNS inflammation and subsequent cytokine production. Other theories propose that minocycline as an adjunctive therapy could benefit patients with schizophrenia because of its inhibition of nitric oxide synthase in the glutamatergic system.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the 2 principal omega-3 fatty acids found in fish oil. They are thought to exhibit anti-inflammatory properties through proteins known as resolvins, which bind to G-protein–coupled receptors on the surface of leukocytes and block their production of inflammatory substances. Resolvins also prevent migration of leukocytes and block expression of inflammatory mediators on microglial cells.

A double-blind, randomized, controlled trial compared EPA, DHA, and placebo treatment in patients who were receiving antipsychotics but had residual symptoms. The results showed that EPA combined with antipsychotics was more beneficial than antipsychotic treatment combined with either placebo or DHA.

Additional studies with other antipsychotics are needed to further define possible benefits of such combined treatments.

Old theories of schizophrenia, although widely accepted, do not completely explain its pathophysiology or effective treatments. With decades of antipsychotic treatment still associated with persistence of symptoms or subsequent relapse into psychosis, clinical research strives to increase novel treatment options. Although research into autoimmune and inflammatory theories of schizophrenia is in its infancy, it shows some promise in addressing more resistant problems, such as negative symptoms and cognitive deficits.

Future research should expand on pioneer studies of anti-inflammatory treatments, with a focus on efficacy in treating symptom types, first-onset psychosis, and treatment-resistant disease. Medications that block inflammatory pathways are safe and currently available to treat other disorders; thus, they offer the potential to treat mentally ill patients in desperate need of new options.

As evidenced by patients’ variable response rates to current antipsychotic treatments, the pathophysiology of schizophrenia should be reconsidered and broadened. The field of psychiatry has recognized for decades that mental illness is multifactorial in nature. It is time that we think beyond the traditional genetics, physiology, and social history of a patient.

There is strong evidence that a multitude of different pathways or combinations of pathways in schizophrenia could produce distinct subclasses of patients who respond variably to different therapeutic modalities. In the distant future, we may be further classifying schizophrenia into subtypes such as inflammatory, dopaminergic, glutamatergic, or genetically mediated. Identifying these subtypes could serve to create specialized treatment plans that reduce the rates of relapse and persistence of symptoms. Moreover, it could allow for earlier diagnosis of disease and identification of high-risk individuals, which could provide opportunities for earlier intervention and better patient outcomes.

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An Update on the Diagnosis and Treatment of Bipolar Disorder, Part 1: Mania

Philip G. Janicak, MD and Joseph Esposito, MS, MD

Update on Bipolar Disorder, Part 2: Bipolar Depression and Cyclothymic Disorder

Philip G. Janicak, MD and Joseph Esposito, MD, MS

Erin Walling is a fourth-year medical student at the University of Oklahoma College of Medicine, Oklahoma City; Dr. Tucker is Professor and Vice Chair of Education, Department of Psychiatry, University of Oklahoma Health Sciences Center, Oklahoma City.

 Tomasik J, Rahmoune H, Guest PC, Bahn S. Neuroimmune biomarkers in schizophrenia. 

 MÃ¼ller N, Schwarz MJ. Immune system and schizophrenia. 

 Meyer U. Anti-inflammatory signaling in schizophrenia. 

 Van Berckel BN, Bossong MG, Boellaard R, et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. 

 Tsuang M. Schizophrenia: genes and environment. Biol Psychiatry. 2000;47:210-220.

Current research investigates new pathophysiologic mechanisms and lays the groundwork for redefining schizophrenia based on distinct medical subclasses-which may lead to more targeted and effective treatments. Details here.

Inflammation, Immune Function, and Schizophrenia: An Overview

Mrs Dalton, a 53-year-old, presents to the emergency department, complaining of numerous small insects that have been crawling under her skin. She has created multiple excoriations on her arms, chest, neck, legs, and face in an attempt to remove the parasites. She also complains of a larger organism in her abdomen that she can feel moving through her organs. Mrs Dalton reports that she first experienced these phenomena 1 week after watching a television program that featured a patient with similar complaints who was infected with a rare parasite. Approximately 6 months before this presentation, Mrs Dalton had traveled to a rural area of Honduras.

Mrs Dalton had previously visited her primary care physician as well as a dermatologist, a cardiologist, and 2 emergency departments to seek treatment for these complaints. Testing of substances removed from the site of her excoriations showed only skin debris. She had tried a topical antiparasitic agent to eliminate the causal organism and alprazolam to reduce anxiety associated with her symptoms, but she reports that neither medication improved her condition. 

She has a history of depressive symptoms, which emerged 2 years before her current presentation. The depression had been effectively controlled for a year and finally remitted a year ago with citalopram. She has no history of 

. She is admitted to the internal medicine service with consultation from both the infectious disease and neurology services. Workup for medical causes of this presentation include culture from the site of her excoriations; chest films; CT of the head; and laboratory tests, including complete blood cell count, basic metabolic panel, thyroid-stimulating hormone level, vitamin B12 level, folate level, urinalysis with culture, urine drug screen, and HIV screen. No evidence of a medical cause for her symptoms is detected.

The differential includes a number of medical and psychiatric diagnoses. Several species of parasites can cause an infestation that results in pruritus and lesions caused by migrating organisms 

 (hookworms or roundworms), and members of the genus 

 (nematodes). These infections are commonly seen in patients who have traveled to tropical areas as Mrs Dalton had done. Scabies (the mite 

Dermatological conditions can be associated with pruritus and subsequent excoriation, including contact dermatitis, eczema, psoriasis, and impetigo. Psychiatric diagnoses to rule out include skin picking disorder, trichotillomania, obsessive-compulsive disorder, body dysmorphic disorder, delusional disorder, or any number of conditions that could cause psychosis or delusions. Intoxication with illicit drugs such as methamphetamine and cocaine commonly leads to self-excoriation as well.

Diagnostic criteria for parasitosis include:

• Symptoms that last a month or longer that do not meet criteria for schizophrenia

Delusional parasitosis can be difficult to recognize, but timely diagnosis and psychiatric treatment can improve quality of life and reduce medical costs.

Author | Phebe Tucker, MD

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