Borderline Personality Disorder: A Dysregulation of the Endogenous Opioid System?

Borderline Personality Disorder: A Dysregulation of the Endogenous Opioid System?

Psychological Review                                                                                                                                                                                          © 2010 American Psychological Association

2010, Vol. 117, No. 2,  623– 636                                                                                                                                                                      0033-295X/10/$12.00    DOI: 10.1037/a0018095

 

Borwin Bandelow

University of Gottingen

Christian Schmahl

Central Institute of Mental Health, Mannheim, Germany

Peter Falkai and Dirk Wedekind

University of Gottingen

 

The neurobiology of borderline personality disorder (BPD) remains unclear. Dysfunctions of several neurobiological systems, including serotoninergic, dopaminergic, and other neurotransmitter systems, have been discussed. Here we present a theory that alterations in the sensitivity of opioid receptors or the availability of endogenous opioids constitute part of the underlying pathophysiology of BPD. The alarming symptoms and self-destructive behaviors of the affected patients may be explained by uncon- trollable and unconscious attempts to stimulate their endogenous opioid system (EOS) and the dopami- nergic reward system, regardless of the possible harmful consequences. Neurobiological findings that support this hypothesis are reviewed: Frantic efforts to avoid abandonment, frequent and risky sexual contacts, and attention-seeking behavior may be explained by attempts to make use of the rewarding effects of human attachment mediated by the EOS. Anhedonia and feelings of emptiness may be an expression of reduced activity of the EOS. Patients with BPD tend to abuse substances that target µ-opioid receptors. Self-injury, food restriction, aggressive behavior, and sensation seeking may be interpreted as desperate attempts to artificially set the body to survival mode in order to mobilize the last reserves of the EOS. BPD-associated symptoms, such as substance abuse, anorexia, self-injury, deper- sonalization, and sexual overstimulation, can be treated successfully with opioid receptor antagonists. An understanding of the neurobiology of BPD may help in developing new treatments for patients with this severe disorder.

Borderline personality disorder (BPD) is a common disorder with an estimated lifetime prevalence of 5.9% (B. F. Grant, Chou, et al., 2008). Patients with BPD often are hospitalized, mainly due to self-injury, suicidality, or drug abuse (Zanarini, Frankenburg, Hennen, & Silk, 2004). Current treatments for BPD are far from satisfactory. Most inpatients with BPD receive some kind of psy- chopharmacological treatment (Heinze, Andreae, & Grohmann, 2005; Zanarini et al., 2004). According to a Cochrane analysis of

current pharmacological treatments (Binks et al., 2006a), only improvements of a few symptom complexes can be achieved, and complete remission is rare (Paris, 2008). Polypharmacy is com- mon, which may be indicative of the lack of satisfactory drug treatments (Wedekind, Bandelow, & Ruther, 2005).

According to another Cochrane analysis, there is also room for improvement of psychological treatments (Binks et al., 2006b). For dialectical behavior therapy and standard cognitive behavioral therapy (Davidson et al., 2006; Linehan, Tutek, Heard, & Arm- strong, 1994; Weinberg, Gunderson, Hennen, & Cutter, 2006), some effects on self-harm and suicidality but fewer effects on overall severity were found. For psychoanalytically oriented treat- ment, studies using an adequate control group are lacking.

Therefore, there is need for improvement of BPD treatments. An understanding of the neurobiology of BPD may help to develop novel treatment options and to improve the quality of life of patients with this severe disorder.

 

Etiology

The etiology of BPD remains unclear. According to several studies, female and male patients with BPD, when compared with patients with other psychiatric disorders, reported higher rates of childhood sexual abuse and other kinds of developmental trauma (Ludolph et al., 1990; Paris, Zweig-Frank, & Guzder, 1994; Tim- merman & Emmelkamp, 2001). Also, in the only study in which patients with BPD were compared with a healthy control group regarding early childhood traumatization, a higher rate of child- hood traumatic events was found in the patient sample: 74% of the respondents retrospectively reported some kind of sexual abuse, in contrast to only 6% in the healthy control group (Bandelow et al., 2005). However, there has been some skepticism about trauma as the sole cause of BPD (New, Triebwasser, & Charney, 2008). Twenty to forty-five percent of BPD patients report no history of sexual abuse, and 80% of individuals with sexual abuse have no personality pathology (Goodman & Yehuda, 2002). In a sample of patients with different personality disorders, childhood physical and sexual abuse were not specific predictors for BPD (Bierer et al., 2003). Meta-analyses showed little relationship between child- hood sexual abuse and BPD or self-injury (Fossati, Madeddu, & Maffei, 1999; Klonsky & Moyer, 2008).

BPD runs in families (Bandelow et al., 2005; Zanarini, Fran- kenburg, Hennen, Reich, & Silk, 2006). According to a large twin study, 69% of the variance is based on genetic factors (Torgersen et al., 2000). It is not yet understood why patients with BPD, having such a high genetic risk, also seem to have an increased risk of childhood traumatic events. Apparently, these factors are inter- related. If the parents of BPD patients also had symptoms of the disorder, there is a higher chance that they had limited child- rearing abilities, possibly because of substance abuse, frequent absence as a result of hospitalizations, unfavorable family and social environment conditions, or a tendency toward sexual devi- ations. In a logistic regression, a method that is able to control for the complex interdependencies among various risk factors, a fa- milial risk was a stronger predictor for BPD than was childhood sexual abuse (Bandelow et al., 2005).

 

Neurobiology

Neurobiological findings about the disorder have been reviewed elsewhere (Bohus, Schmahl, & Lieb, 2004; Friedel, 2004; New, Goodman, Triebwasser, & Siever, 2008; Silk, 2000). According to recent work, the neurotransmitter domain of greatest interest in BPD is the serotonin system. In BPD patients, laboratory data showed decreased cerebrospinal fluid concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA), decreased plate- let paroxetine binding, gender differences in the prolactin response to fenfluramine challenge in BPD, and other changes. Genetic studies found abnormalities of the 5-HTT, the tryptophan hydrox- ylase, and the 5-HT2A receptor gene (New, Goodman, et al., 2008). As dopamine activity plays an important role in emotion informa- tion processing, impulse control, and cognition, a dopamine dys- function theory has been proposed, which is derived from the efficacy of antipsychotic agents in some BPD symptoms and from provocative challenges with amphetamine and methylphenidate of subjects with the disorder (Friedel, 2004). Laboratory data about the disorder further suggest a role of adrenergic dysfunction or dysregulations of the HPA axis (New, Goodman, et al., 2008).

Neurobiological changes in BPD patients may be genetically determined, a direct cause of early emotional trauma, or a conse- quence of the elevated activity of stress-associated neurobiological systems. Some research lines examined the linkage between early trauma and later neurobiological dysfunctions (Kaffman & Meaney, 2007). In rats, it was demonstrated that prolonged expo- sure to stress leads to loss of neurons, particularly in the hippocampus (McEwen & Sapolsky, 1995). In a longitudinal study, in which children were followed over 4.5 years after birth, it was shown that exposure to early maternal stress may sensitize the children’s pituitary-adrenal responses to subsequent stress exposure (Essex, Klein, Cho, & Kalin, 2002).

In a review of brain imaging studies in BPD (Schmahl & Bremner, 2006), a number of abnormalities were summarized, including reduced volumes, decreased baseline metabolism, and abnormal activity in response to affective pictures, abandonment and trauma scripts, or pain stimuli in some brain regions, including the hippocampus, amygdalae, anterior cingulate cortex, and medial orbital dorsolateral prefrontal cortex.

Unlike in schizophrenia or depression, it cannot be deduced which neurobiological dysfunctions underlie BPD from the mech- anism of action of certain drugs. Affected patients are mostly treated with antidepressants, followed by antipsychotics, hypnot- ics, antihistamines, and mood stabilizers (Bellino, Paradiso, & Bogetto, 2008; Herpertz et al., 2007; Wedekind, Becker, Bande- low, & Falkai, 2009). Serotonergic antidepressants, such as selec- tive serotonin reuptake inhibitors, have only a moderate influence on some symptoms, and from these unspecific effects it cannot be concluded that dysregulations of serotonin systems are a central cause of BPD. Likewise, from the efficacy of dopamine D2 recep- tor antagonist antipsychotics or mood stabilizers, the etiology of BPD cannot be concluded ex iuvantibus. Compliance with antide- pressants, antipsychotics, or mood stabilizers is poor, perhaps because of their only moderately symptom-relieving effects. How- ever, substance abuse is common in BPD, and from the receptors that are modulated by abused drugs, conclusions on the neurobi- ology of BPD may be drawn. Therefore, it seems warranted to examine whether the neurobiology of BPD is at least partially based on molecular systems that are affected by drugs of abuse.

 

The Reward System and the Endogenous Opioid System (EOS)

Olds and Milner established in the 1950s that there are specific dopamine reward circuits (“pleasure centers”) in the brain that respond to positive stimuli by using microelectrodes that could be self-stimulated by laboratory animals (Olds & Milner, 1954). The nucleus accumbens is a target of the mesolimbic reward system, which arises in the ventral tegmental area (VTA), where mainly dopamine is released. Primary rewards include those that are necessary for the survival of the species, such as food, water, and sex. In humans, secondary rewards derive their value from the primary reward and include money, pleasant touch, warm water, pleasant smells, perceiving respect and attention, and many other pleasurable stimuli. The involvement of the nucleus accumbens in secondary reward could be demonstrated with brain imaging tech- niques for monetary reward (Knutson, Adams, Fong, & Hommer, 2001), charitable donations (Moll et al., 2006), viewing beautiful faces (Aharon et al., 2001), or listening to delightful “shivers- down-the-spine” music (Blood & Zatorre, 2001). In depressed patients, anhedonia was successfully treated with deep brain stim- ulation of the nucleus accumbens (Schlaepfer et al., 2008).

The EOS (Hughes et al., 1975; Pert & Snyder, 1973) consists of three classes of opioids (r3-endorphins, enkephalins, and dynor- phins) that activate three types of receptors (µ-, 8-, and K-opioid receptors; Dhawan et al., 1996). Rewarding and addictive properties of endorphins are similar to those displayed by morphine (van Ree, 1979). One of the most important endogenous opioids, r3-endorphin, is synthesized in the pituitary gland, the nucleus arcuatus of the hypothalamus, and the nucleus tractus solitarius and is released into the blood, the brain, and the spinal cord (Roth-Deri, Green-Sadan, & Yadid, 2008). When the protein pro- opiomelanocortin (POMC) is split into different peptide hormones, adrenocorticotropin (ACTH) and r3-endorphin are among the cleavage products. r3-endorphin has the highest affinity for the µ1-opioid receptor.

The EOS and the reward system are  closely  linked  (see  Figure 1). r3-Endorphinic cell bodies terminate in various regions, including the VTA and the nucleus accumbens. Opioids modulate mesolimbic dopamine pathways in the VTA by activating µ1- opioid receptors on secondary interneurons, causing hyperpolar- ization and inhibition of GABA release on dopaminergic output neurons with consequent increased dopamine release (De Vries & Shippenberg, 2002; Roth-Deri et al., 2008). Reward sensitization is reversed by intracerebroventricular infusion of naltrexone (Carr, 1996). There is also a reverse interaction: Intracranial administra- tion of dopamine into the nucleus accumbens increases r3-endorphin levels (Roth-Deri et al., 2003). It has been suggested that brain dopamine tends to code for the preparatory aspects of reward behavior, whereas brain opioids seem to mediate the per- ception of the hedonic properties of rewards (Barbano & Cador, 2007).

r3-Endorphin is an endogenous opioid peptide that is released during stress (Roth-Deri et al., 2008). If an animal is fighting for its life and bleeding from many wounds, r3-endorphin helps it to survive by inducing euphoria and analgesic effects. Endorphin release is considered to be the reason why soldiers severely injured in combat or accident victims often do not feel pain in the first moment. Endorphins are also released during childbirth.

Endorphins also play a role in positive experiences like love, kissing, or sexual activities (Esch & Stefano, 2005). Moreover, the placebo effect is probably mediated by endorphins (Johansen, Brox, & Flaten, 2003; Levine, Gordon, & Fields, 1978) and can be antagonized by naltrexone (Hersh et al., 1993). The “runner’s high” resulting from long-distance running, characterized by eu- phoria and lowered pain sensitivity, is mediated by endorphins (Goldfarb & Jamurtas, 1997; Markoff, Ryan, & Young, 1982). In a positron emission tomography (PET) study with athletes, the level of euphoria was significantly increased after running and was inversely correlated with opioid binding in the brain (Boecker et al., 2008). In PET scans in humans, activation of the EOS could be shown while subjects received painful stimuli or exercised (Ravert, Bencherif, Madar, & Frost, 2004). It is most likely that the release of endorphins by long-distance running is mediated by the simu- lation of a flight situation, as endorphins have the role of helping to ensure survival under stress conditions.

In contrast to the effects of endorphins, stimulation of K-opioid receptors—for example, by dynorphins— can induce dysphoria, depersonalization, derealization, and perceptual alterations (Kumor et al., 1986; Walsh, Strain, Abreu, & Bigelow, 2001).

 

Endogenous Opioid Theory of Borderline Personality Disorder

From the available evidence can be derived an endogenous opioid theory of borderline personality disorder, according to which the neurobiological changes in BPD are based on a dys- regulation of the EOS. This dysregulation may consist of a reduced sensitivity of endorphin receptors or too low a level of endogenous opioids. Excessive K-receptor-mediated activity during stressful states may also play a role.

 

To date, there is only limited evidence of alterations of endog- enous opioid levels in BPD patients. Plasma r3-endorphin immu- noreactivity was low in a sample of patients with nonmajor de- pression, many of whom met criteria for BPD (Cohen, Pickar, Extein, Gold, & Sweeney, 1984). Large-scale studies investigating endorphins in patients with BPD are still lacking.

As the EOS and the reward system are closely linked and have an inverse relationship, the primary dysfunction may also lie in a disturbance of dopamine receptors in the mesolimbic dopamine system, a decreased dopamine release, or a disturbed connectivity between the EOS and the reward system. However, a primary disturbance of the dopaminergic reward system is less likely, as patients with BPD do not have a preference for dopamine agonists or antagonists, whereas they have a clear preference for substances affecting the EOS.

In the following article, we attempt to explain how the charac- teristic symptoms of BPD may be caused by a deficiency in the EOS. Most of these mysterious and alarming symptoms seem to have a common denominator: They can be interpreted as a des- perate, albeit mostly unconscious, effort to achieve higher opioid receptor occupancy or normal levels of endorphins in the shortest possible time.

 

Fear of Abandonment and Disrupted Interpersonal Attachment

Partner relationships of BPD patients are often problematical and are commonly characterized by “nearness-distance conflicts.” Although the affected persons  frequently  show  frantic  efforts  to avoid abandonment, they often argue and fight with their part- ners and end relationships easily. This paradox is not yet under- stood, but it is probably due to a complex disturbance of the hormones that modulate human bonding.

The reward system plays a central role in bonding and attach- ment. According to fMRI studies, romantic love is associated with an activation of right VTA and the right postero-dorsal body and medial caudate nucleus (Aron et al., 2005). Endogenous opioid binding to µ-receptors has been proposed to be the basis of infant attachment. In their seminal work, Panksepp and colleagues dem- onstrated that opioids, particularly r3-endorphins, play a central role in forming social bonds (Panksepp, Herman, Conner, Bishop, & Scott, 1978). In many species, including nonhuman primates, opioids are very effective in reducing separation distress vocaliza- tions (Carden & Hofer, 1990; Fabre-Nys, Meller, & Keverne, 1982; Kalin, Shelton, & Lynn, 1995; Knowles, Conner, & Pank- sepp, 1989). Separation distress may reflect a state of endogenous endorphin withdrawal, as it can be alleviated by morphine and potentiated by naloxone. µ-Knockout mice are characterized by deficits in attachment behavior (Moles, Kieffer, & D’Amato, 2004). In infant primates, a variation at the µ-opioid receptor gene (OPRM1) influences attachment behavior (Barr et al., 2008). It may therefore be speculated that reduced opioidergic tone or other disturbances in opioid neurotransmission may be related to diffi- culties of BPD patients in forming stable social bonds or coping with interpersonal distress.

When deeply in love, critical judgments of one’s partner are suspended (i.e., love is blind). This natural deactivation of scrutiny of possible partners to facilitate human bonding is perhaps medi- ated by a connection between reward centers and cortical regions.

In brain imaging studies, increased activity in the VTA when subjects are in romantic love was mirrored by a decrease in the activity of cortical zones that are responsible for negative feelings or critical judgment (Zeki, 2007). The phenomenon of splitting, the sudden changes between idealization and devaluation of close people, and the nearness-distance conflict described in people with BPD may reflect a complex dysregulation of the cooperation between these brain regions.

In humans, sexual attraction and feelings of love, warmth, and security are also modulated by hormones such as vasopressin and oxytocin and the dopamine reward system (Esch & Stefano, 2005). There is evidence in a variety of species that oxytocin and vaso- pressin are involved in reproductive and social behavior, and these effects are mediated by the reward system (Depue & Morrone- Strupinsky, 2005). Both hormones facilitate pair bonding and maternal behavior in laboratory animals. Experiments with two different voles showed remarkable differences: The prairie vole shows lifelong attachment with its first sex partner, whereas the montane vole meets other voles only briefly for sexual contacts. The difference between the two species was shown to be the regulation of oxytocin release. Oxytocin administered centrally facilitates formation of a partner preference (Williams, Insel, Har- baugh, & Carter, 1994). In humans, oxytocin was shown to in- crease trust (Kosfeld, Heinrichs, Zak, Fischbacher, & Fehr, 2005). Activation of the reward system during sexual activity is mediated by oxytocin. Oxytocin injected into the VTA induces penile erec- tion and increases extracellular dopamine in the nucleus accum- bens and paraventricular nucleus of the hypothalamus of male rats (Melis et al., 2007).

 

Frequent and Risky Sexual Contacts

Some patients with BPD have a tendency to have frequent, impulsive, and risky sexual contacts, regardless of possible prob- lems resulting from indiscriminate sexual activity, such as un- wanted pregnancy, venereal diseases, or HIV. They also seem to care less about the problematic social consequences, including problems associated with adultery, a bad reputation, or alimony payments. BPD is common among female and male prostitutes (Brody, Potterat, Muth, & Woodhouse, 2005; Chen, Brown, Lo, & Linehan, 2007). A high rate of BPD was found in HIV-positive men (Perkins, Davidson, Leserman, Liao, & Evans, 1993), but this may also be due to the high rate of intravenous drug abuse in BPD patients. Men with BPD are often found among sexual offenders (Curtin & Niveau, 1998) and sexual murderers (Hill, Habermann, Berner, & Briken, 2007).

One major purpose of the mesolimbic dopamine system is to reward individuals for sexual activity. The neurochemistry of sexual arousal is based on a number of neurotransmitters, includ- ing dopamine, but also other hormones, such as endorphins, oxy- tocin, and vasopressin (Odent, 1999; Pfaus et al., 1990). In hu- mans, the activation of the VTA during orgasm could be shown by positron emission tomography (Holstege et al., 2003). Compulsive sexual behavior can be treated with the opioid antagonist naltrex- one (see Table 1).

Therefore, inconsiderate, risky, and unrestrained sexual activity in BPD may be explained by a frantic attempt to stimulate the EOS and/or the reward system. Moreover, the tendency of some BPD patients to frequently change sexual partners may be a result of their attempts to maximize stimulation of the reward system, as the dopamine release is increased when a reward is unexpected or new (Martin-Soelch, Leenders, et al., 2001; Schultz, 2002).

 

Table 1

Treatment of BPD-Associated Symptoms With Opioid Antagonists

Syndrome                                       Treatment                             Study type                                                          References

Self-injury

In subjects with intellectual disabilities Naltrexone Review of DBPC studies Symons, Thompson, & Rodriguez, 2004
Various diagnoses Naltrexone Open study Roth, Ostroff, & Hoffman, 1996
In BPD Naltrexone Case series Sonne, Rubey, Brady, Malcolm, & Morris, 1996
In BPD Naltrexone Case report McGee, 1997
Dissociation in BPD Naltrexone

Naloxone

Open study

DBPC

Bohus et al., 1999

Philipsen, Schmahl, & Lieb, 2004

Depersonalization disorder Naltrexone Open study Simeon & Knutelska, 2005
  Naloxone Open study Nuller, Morozova, Kushnir, & Hamper, 2001
Anorexia or bulimia nervosa Naltrexone DBPC Marrazzi, Bacon, Kinzie, & Luby, 1995
  Naltrexone

Naltrexone

DBPC

DBPC

Huseman, Pearson, Madison, & Leuschen, 1990

Mitchell et al., 1989

  Naltrexone Open study Jonas & Gold, 1986
  Naltrexone Case report Chatoor, Herman, & Hartzler, 1994
Compulsive food restriction Naltrexone Case report Gade, Haussinger, & Bandelow, 2009
Heroin dependency Naltrexone Systematic review of DBPC studies Adi et al., 2007
Alcohol dependency Naltrexone Meta-analysis of DBPC studies Streeton & Whelan, 2001
Pathological gambling Naltrexone DBPC Kim, Grant, Adson, & Shin, 2001
  Naltrexone DBPC J. E. Grant, Kim, & Hartman, 2008
  Nalmefene DBPC J. E. Grant et al., 2006
  Naltrexone Open Kim & Grant, 2001
Compulsive buying Naltrexone Case series Bullock & Koran, 2003
Kleptomania Naltrexone DBPC J. E. Grant, Kim, & Odlaug, 2009
  Naltrexone Open study J. E. Grant & Kim, 2002
Kleptomania and compulsive sexual behavior Naltrexone Case report J. E. Grant & Kim, 2001
Compulsive sexual behavior Naltrexone Case reports Raymond, Grant, Kim, & Coleman, 2002
  Naltrexone Case report Bostwick & Bucci, 2008
Sexual overstimulation in sexual offenders Naltrexone Open study Ryback, 2004

Note. BPD = borderline personality disorder; DBPC = double-blind, placebo-controlled; CBT = cognitive behavior therapy. All studies showed global improvement, except two, which are identified by a †.

 

Attention-Seeking Behavior 

Although not listed among the Diagnostic and Statistical Man- ual of Mental Disorders (4th ed.; DSM–IV; American Psychiatric Association, 1994) symptoms for BPD, a typical behavior of BPD patients is described by the psychoanalytical term acting out, that is, performing an action to garner attention, sometimes in a child- ish manner (e.g., throwing a tantrum, insulting the therapist, threat- ening to commit suicide, or behaving promiscuously). These at- tempts to gain attention are possibly motivated by an urgent need for any kind of awareness, even in a negative way, when positive means of attracting interest from other people are not available. Clinicians are aware that persons with BPD often wear outfits designed to attract other people’s attention, like provocative “un- derground chic” dresses. Individuals with BPD also frequently find positive ways of attracting the attention of other people, such as by being creative artists, musicians, or actors. The highly increased mortality rate in famous rock stars, mostly due to accidental overdoses owing to polysubstance abuse (Bellis et al., 2007), may lead to the conclusion that there is a link between the rewarding effects of increased attention-seeking behavior and substance abuse.

For some reason, some BPD sufferers have a strange way of fascinating other people, perhaps because of their increased activ- ity in attracting attention. Some people with BPD may have an unusually high degree of interpersonal sensitivity, insight, and empathy and engage in charity or work as health care profession- als. Although neurobiological studies are lacking, it is very likely that the reinforcing power of social attention from other people is mediated by the EOS and the reward system.

 

Anhedonia

 

Feelings of emptiness are characteristic for BPD. According to the description of BPD patients, these states are not exactly the same as depression but are better described as anhedonia, dyspho- ria, or tediousness. Frequently, these feelings can suddenly alter- nate with short-lasting euphoric or high feelings. These changes in mood, which may last only a few hours, are often independent of positive or stressful precipitating events but occur more or less out of the blue, which is why BPD patients are often characterized as unpredictable, hot-tempered, or moody. It is possible that these sudden mood changes are triggered by rises and falls in endoge- nous opioid levels. Feelings of emptiness and boredom may be explained by a reduced hedonic tone caused by a subsensitivity of opioid receptors. Studies with mice deficient in dopamine recep- tors suggest that endogenous opioid peptides maintain a basal level of positive affect (Narayanan et al., 2004). Another component of the opioid circuitry that is of interest in BPD is the K-receptor system, overactivity of which may be related to anhedonic feelings (Kumor et al., 1986; Schlaepfer et al., 1998).

Suicidality is common in patients with BPD and is partly due to chronic anhedonia. Between 5 and 10% of BPD patients commit suicide. Among adolescents committing suicide, a personality dis- order was present in half of the cases (Halfon, Laget, & Barrie, 1995). In a postmortem study, an up to ninefold increase in µ-receptor density was found in young suicide victims with de- pression (Gross-Isseroff, Dillon, Israeli, & Biegon, 1990).

Typical features of BPD include reduced frustration tolerance and an inability to wait for positive reinforcement. Because of their failure to tolerate the delay of a reward, the affected patients often do not finish their education or vocational training. The urge for immediate satisfaction may also be understood as an expression of an understimulated reward system.

 

Drug Addiction

Perhaps the strongest evidence supporting a dysregulated EOS derives from the high rate of substance abuse in BPD. Up to 75% of BPD patients have substance abuse problems (Hatzitaskos, Soldatos, Kokkevi, & Stefanis, 1999), and 45% of heroin addicts have BPD (Darke, Ross, Williamson, & Teesson, 2005). Substance abuse in BPD is often self-destructive. Hard drugs, such as heroin or cocaine, are frequently consumed by BPD patients, in spite of the deleterious consequences. Many patients have polysubstance dependency, and many die from accidental overdoses as a result of complex interactions between various illegal and prescription drugs and alcohol.

GABAergic, dopaminergic, glutamatergic, and cholinergic sys- tems within the mesocorticolimbic circuitry are involved in drug addiction (Ikemoto & Wise, 2004; Kelley & Berridge, 2002). However, although many drugs of abuse, including heroin, co- caine, amphetamines, alcohol, cannabis, nicotine, and others, have different primary molecular targets, they all increase dopamine transmission in the nucleus accumbens (Nestler, 2005). Lower levels of mesolimbic dopamine D2 receptor availability have been reported in abusers of cocaine, alcohol, heroin, and methamphetamines (Volkow et al., 2001).

Heroin directly stimulates µ-opioid receptors. It causes “kicks” (euphoria) and “flushes” (a pleasant, cozy feeling of warmth and happiness). The levels of r3-endorphin in the limbic system are reduced immediately prior to a scheduled drug administration in animals that self-inject heroin or cocaine (Sweep, Van Ree, & Wiegant, 1988). After chronic heroin use, tolerance to the drug develops because of decreased sensitivity of µ-opioid receptors and reduced endorphin production.

Cocaine induces a “rush,” which is sometimes described as being like an intense orgasm, combined with sexual interest, sociability, exhilaration, and euphoria. Smoking crack, the more rapidly acting base form of cocaine, more easily leads to addiction. Cocaine increases extracellular dopamine levels (Nomikos, Damsma, Wenkstern, & Fibiger, 1990). Blockade of opioid recep- tors by naltrexone decreases the reinforcing effects of cocaine (Roth-Deri et al., 2008). Increased µ-opioid receptor binding de- tected by PET in cocaine-dependent men was associated with cocaine craving (Zubieta et al., 1996). Abnormalities in regional blood flow were also found in PET studies with opioid addicts when other kinds of reward were investigated, for example, mon- etary incentives (Martin-Soelch, Chevalley, et al., 2001a).

Amphetamines, drugs that modulate the dopaminergic reward system, but also serotonin and norepinephrine, cause euphoria and exhilaration. In double-blind studies with amphetamine adminis- tration, it was shown that BPD patients appear to be pharmacody- namically separable from controls. Patients with both borderline and schizotypal disorder developed psychotic symptoms with the drug, whereas patients with only the borderline diagnosis im- proved (Schulz, Cornelius, Schulz, & Soloff, 1988; Schulz et al., 1985).

Benzodiazepines are often abused by BPD patients. They exert their effects by increasing the inhibitory activity of )I-amino- butyric acid (GABA). The EOS is modulated by GABA-ergic neurons (Eichenberger et al., 2002). GABA neurons in the VTA appear to be critical regulators of mesocorticolimbic dopamine neurotransmission (Ishikawa, Ambroggi, Nicola, & Fields, 2008). Severe alcohol dependency is common in BPD. Opioid antag- onists have been shown to reduce alcohol consumption by animals. Alcohol triggers endorphin release via the interaction between ethanol and GABAA receptors in the reward pathway (Enoch, 2008; Steffensen et al., 2009).

The involvement of the EOS also extends to impulse control disorders, including pathological gambling, kleptomania, or com- pulsive buying, which may be considered non-substance-related addictions (Brewer & Potenza, 2008), and are also common in patients with BPD (Sacco, Cunningham-Williams, Ostmann, & Spitznagel, 2008). During the playing of Pachinko, a popular Japanese addictive game of chance, r3-endorphin plasma levels are increased (Shinohara et al., 1999). It is assumed that pathological gambling is also mediated via dopamine receptors, as patients with Parkinson’s disease receiving dopamine agonists sometimes de- velop pathological gambling; in some patients, this reaction is accompanied by other abnormal behaviors such as pathological shopping and hypersexuality (Lader, 2008).

Not only the amount of EOS stimulation but also the speed of action seem to be important components. Patients with BPD prefer drugs that have an immediate onset of action, such as crack or “speedballs” (a combination of heroin and cocaine). When being treated with the µ-agonist/K-antagonist buprenorphine as a heroin replacement, some patients dissolve and inject the tablets to get a kick (which can be prevented by combining buprenorphine with naloxone in one tablet).

 

Antagonizing BPD Symptoms With Opioid Antagonists

Not only heroin addiction but also other addictions and symp- toms of BPD can be treated with opioid antagonists, including the orally effective drug naltrexone and the intravenously adminis- tered naloxone. These drugs block opioid receptors but do not have an intrinsic effect. Indirectly, they modulate mesolimbic dopamine (Matthews & German, 1984; Stewart, 1984).

Table 1 summarizes studies with opioid antagonists showing efficacy in symptoms and syndromes that are part of the borderline spectrum. However, these studies were not conducted exclusively with BPD patients. There are no controlled studies investigating the effects of opioid antagonists on overall BPD symptomatology.

Acute administration of naltrexone may be effective in self- injury because it blocks the rewarding effects of endorphin release after wrist cutting. But naltrexone may also have long-term effects. If a heroin addict has been treated with naltrexone for some weeks or months, then discontinues this treatment and restarts consuming heroin at the same dose as before naltrexone treatment, this may result in a potentially life-threatening opioid overdose, because he or she may now be more sensitive to lower doses of opioids. There have been reports of fatal outcomes in such cases. Therefore, it can be assumed that chronic administration of naltrexone increases the sensitivity of opioid receptors. Thus, the positive effects of opioid antagonists may result from a normalization of a pathological subsensitivity of opioid receptors. Alternatively, naltrexone, by blocking K-opioid receptors, may act by suppressing dysphoric and dissociative states.

However, the positive effects of opioid antagonists in BPD- associated symptoms are not yet fully understood. Their efficacy seems paradoxical, as one would expect anhedonic feelings result- ing from opioid receptor blockade. However, according to clinical experience, BPD patients treated with naltrexone for self-injury reported neither anhedonia nor increased feelings of emptiness. In clinical studies, depression was reported as a side effect, but it did not occur more frequently than in the placebo groups (Naltrexone hydrochloride tablets package insert, 2003).

 

Self-Injury

Some form of self-injurious behavior occurs in 70 – 80% of BPD patients, mainly in women. This striking and disturbing symptom is usually initiated with the intention of reducing dysphoric states (Herpertz, 1995; Kleindienst et al., 2008). According to their reports, patients mostly do not feel pain at the moment when they cut their arms but instead have feelings of relief or well-being (Bohus et al., 2000; Kemperman et al., 1997; Russ et al., 1992). Some patients also report an addictionlike urge to continue with their self-injurious behavior. This strange, not-yet-understood be- havior is sometimes repeated several times in one session because of the only short-lived relieving effects. Pain perception was shown to be reduced in BPD patients (Schmahl et al., 2004, 2006). It was typical for BPD patients to have tattoos and piercings long before these types of body art became a mass phenomenon (Inch & Huws, 1993). This may also be interpreted as some form of self-injury. A bizarre form of self-injury is Munchausen syn- drome, which is often associated with BPD (Ehlers & Plassmann, 1994). Male persons with BPD only rarely show self-cutting, but it has also been speculated that the tendency of male patients to be involved in fights can be interpreted as a form of self-injury. Patients with BPD seem to artificially put their body into survival mode to take advantage of the endorphin rush generated during self-harm. A complex dysfunction of the opioid system in BPD may explain why healthy persons only feel pain when they cut themselves, whereas BPD patients report euphoria and no pain. Decreased r3-endorphin levels were found in one study involv- ing subjects with mental retardation who practiced self-injury (Barrera, Teodoro, Selmeci, & Madappuli, 1994). In another study, self-injuring behavior was not associated with changed r3-endorphin levels, but a POMC dysregulation was found showing that r3-endorphin was elevated in relation to the coreleased POMC fragment ACTH (Sandman, Touchette, Marion, & Chicz-DeMet,

2008). Met-enkephalin levels were elevated in patients who habit- ually mutilated themselves. The patients did not feel pain but reported feelings of relief of tension or dysphoria (Coid, Allolio, & Rees, 1983).

Self-injury can be treated with opioid antagonists (see Table 1). According to a review of 27 research articles of naltrexone treat- ment in people with mental retardation or autism, 80% of subjects were reported to improve (Symons, Thompson, & Rodriguez, 2004). A hypothesis has been proposed that autistic children who have a lack of social-emotional interest in other people and a tendency to self-mutilate have a disturbance of the brain opioid system (Sahley & Panksepp, 1987). The use of naltrexone as a treatment for self-injury in BPD patients has not yet been inves- tigated in a double-blind study, but case reports have shown positive results.

Whereas patients with BPD seem to have reduced pain during self-injury, they seem to have reduced pain tolerance when suf- fering from headache, toothache, or other forms of non-self- inflicted pain, as they require higher doses of pain medications than are normally used (Saper & Lake, 2002). This seems para- doxical, but the difference between these sources of pain and cutting or burning wounds is that headache and toothache are not associated with tissue damage as is the case with bleeding, which seems to be a prerequisite for endorphin release. Therapeutic attempts to replace self-cutting with ice cubes are often described as less helpful by patients with BPD, probably because it does not cause tissue damage or bleeding. If bleeding was not a necessary condition, other pain-inducing methods that do not leave scars behind, such as head banging, would be more popular than cutting. In an MRI study, it was found that antinociceptive mechanisms in patients with BPD were associated with an increased pain-induced response in the dorsolateral prefrontal cortex and deactivation in the anterior cingulate and the amygdala (Schmahl et al., 2006).

 

Eating Disorders

Although anorexia or bulimia do not belong to the list of symptoms required for a DSM–IV (American Psychiatric Associ- ation, 1994) diagnosis of BPD, 54% of patients with BPD also meet criteria for an eating disorder (Zanarini, Reichman, Franken- burg, Reich, & Fitzmaurice, 2009). These behaviors are addic- tionlike and self-destructive, difficult to control, and often refrac- tory to all kinds of treatments.

Binge eating may easily be explained as an uncontrolled attempt to stimulate the reward system, as food is a primary reward. Naloxone may attenuate binge-eating behavior (see Table 1). Thus, overeating may be interpreted as a desperate, uncontrollable attempt to stimulate the EOS and the reward system. Also, the preference of some BPD patients for children’s candy, which is commonly attributed to regression, can be explained by the fast- acting effects of high-caloric glucose-containing food on the re- ward system.

However, for anorexia nervosa, it seems paradoxical to explain the addictionlike tendency to restrict food by the same mechanisms as for binge eating. According to the reports of patients with anorexia, food restriction provides a temporary respite from dys- phoric mood (Kaye, 2008). Possibly, excessive dieting can also be explained as an effort to stimulate opioid receptors. It was shown in rats that endogenous opioids are mobilized in states of prolonged food deprivation (Marrazzi & Luby, 1986). First, they increase food intake to correct the starvation. Second, they adapt the organism to survival in the face of starvation until nutritional repletion can occur. Sensitivity to rewarding brain stimulation varies inversely with declining body weight in rats (Carr, 1996). Also, in healthy persons, plasma r3-endorphin is elevated in the early phase of fasting (Komaki et al., 1990).

There is some evidence of an EOS dysregulation in eating disorders. In patients with anorexia nervosa, higher levels of cerebrospinal fluid opioid activity were found than in the same patients after weight restoration or in normal controls (Kaye, Pickar, Naber, & Ebert, 1982). Also, endogenous opioids were elevated in the plasma of anorectic patients (Marrazzi, Luby, Kinzie, Munjal, & Spector, 1997). Naltrexone may improve an- orexia and bulimia nervosa (see Table 1). Moreover, there is a high comorbidity of eating disorders with substance abuse. Reinforcing effects of food and drugs are mediated by related neural circuits. Food restriction increases the reinforcing efficacy of abused drugs (Carr, 1996). Rats that binged on sucrose and then fasted demon- strated signs of opiatelike withdrawal (Avena, Bocarsly, Rada, Kim, & Hoebel, 2008). An autoaddiction opioid model of anorexia has been proposed, according to which endogenous opioids are released during an initial period of dieting and reinforce a state of starvation dependence (Marrazzi et al., 1997). Binge eating and intense craving for food in anorexia and bulimia nervosa may be due to a periodic breakthrough of the appetite-stimulating proper- ties of opioids. An increased pain threshold is a consistent finding in eating disorders (Papezova, Yamamotova, & Uher, 2005), thus further supporting the link between eating disorders and a distur- bance of the EOS.

Excessive, addictive exercise is a problematic behavior of many patients with anorexia nervosa (Klein et al., 2004). Although addictive running in anorexia is generally explained as a way of decreasing body weight, it also may support the theory that pa- tients with anorexia unconsciously try to stimulate their EOS by striving for a runner’s high (see The Reward System and the Endogenous Opioid System [EOS] section above). Again, food restriction and excessive exercise appear to be unconscious efforts to switch the body to an artificial survival mode.

 

Frustration Intolerance and Aggressive Behavior

Poor social adaptation is a common feature of BPD. In a way, patients with BPD tend not to know or understand the rules regarding social interactions or performance in job and academic settings. Although patients with BPD impose intense expectations on others with respect to support and caring, they are often unfriendly, sullen, hurtful, or confrontational toward partners, friends, or therapists, thus trying the patience of persons who want to support them. BPD is often associated with inappropriate, intense anger; violence; aggression; or recurrent physical fights (Fountoulakis, Leucht, & Kaprinis, 2008). These behaviors are often impulsedriven, uncontrolled, and characterized by frustration intolerance, regardless of the problematic social consequences, but embarrass the patients later. In a study of prison inmates, BPD was present in 29.5% of the subjects, the percentage of women being more than twice that for men (Black et al., 2007). Also, in forensic settings, BPD is one of the most frequent personality disorders (Coid & Cordess, 1992).

Aggressive behavior can be reinforcing in many species, as it is necessary to obtain resources such as food, mates, or territory. There is some evidence that dopamine receptors in the ventral striatum are involved in the rewarding properties of aggression (Couppis & Kennedy, 2008). r3-Endorphin deficient mice show more aggression than do wild type mice without this deficiency (Vaanholt, Turek, & Meerlo, 2003). Mouse strains with high aggression scores had lower endorphin levels than did those with lower aggression scores (Tordjman et al., 2003). After agonistic encounters, increased extracellular dopamine was found in the nucleus accumbens in rats (van Erp & Miczek, 2000). Therefore, it seems plausible that uncontrolled aggressive behavior in BPD patients is motivated by an (unconscious) effort to stimulate the EOS by artificially creating a “fight for survival” situation.

 

Sensation-Seeking Behavior

BPD patients often show sensation-seeking behavior (e.g., reck- less motorcycle driving, balancing on bridge railings, performing dangerous stunts with skateboards, or placing a noose around their neck). According to their reports, they often seek excitement and adventure to fill their constant boredom and emptiness. Dangerous games in BPD patients have often been explained by an uncon- scious death wish in chronically suicidal patients, but the tendency to search for kicks also extends to other risky behaviors, such as shoplifting, which are not associated with a risk to life.

Not only in BPD patients but also in healthy subjects, coming out of a dangerous situation unhurt may be associated with eu- phoric feelings (this also applies to only virtually dangerous situ- ations, such as riding on a roller coaster). In bungee jumpers, an increase of more than 200% in r3-endorphin immunoreactivity was observed after the jump (Hennig, Laschefski, & Opper, 1994). This phenomenon may be explained by special properties of the reward system. Dopamine neurons increase their firing relative to the predictability of reward. They are activated when rewards occur without being predicted or are better than predicted. In a situation where a punishment is expected but does not occur, there is also a release in the reward system (Martin-Soelch, Leenders, et al., 2001; Schultz, 2002; Shizgal & Arvanitogiannis, 2003). There- fore, dangerous experiments of BPD patients are probably driven by the (unconscious) wish to stimulate the reward system to compensate for a pathological down-regulation in this condition.

 

Dissociation and Depersonalization

Dissociation, derealization, and depersonalization are possibly mediated by a dysregulation of K-opioid receptors, as agonists at these receptors may cause depersonalization (Pfeiffer, Brantl, Herz, & Emrich, 1986; Walsh et al., 2001). These phenomena are associated with decreased pain sensitivity (Kemperman et al., 1997; Luda¨scher et al., 2007). One study showed improvement of dissociative states in BPD with naltrexone, whereas naloxone did not show clear effects. Both naltrexone and naloxone were effec- tive in the treatment of depersonalization disorder (see Table 1).

 

Discussion

The puzzling symptoms and alarming self-destructive behaviors of patients with BPD may be explained by desperate, unconscious attempts to stimulate a dysregulated EOS in the shortest possible time. Anhedonia and feelings of emptiness may be an expression of reduced activity of the EOS. Frequent and risky sexual contacts and attention-seeking behavior can be explained by efforts to make use of the rewarding effects of human attachment mediated by the EOS, which are also the reason why patients show frantic efforts to avoid abandonment. Substance abuse directly addresses the EOS. Self-injury, food restriction, aggressive behavior, and sen- sation seeking may be interpreted as desperate attempts to artifi- cially set the body to survival mode to mobilize the last reserves of a maladaptive EOS. Although healthy persons experience pain during cutting and hunger during food restriction, patients with BPD seem to have a dysregulated EOS, which makes them prefer the emergency state of the system. There seem to be similarities between patients with BPD and religious fanatics who fast or flagellate their backs with whips to cause heavy bleeding to achieve heightened states of religious ecstasy.

All individuals want to stimulate their reward system, but healthy humans impose certain limits on themselves and prefer to satisfy their instinctual needs such as sex and food in a controlled way, so as to not to break social rules or to avoid dangerous situations. The reward system is antagonized by a social fear system that usually warns people not to behave impulsively, un- controllably, shamelessly, or impudently. Analogous to Freud’s models of the ego and superego, the reward system and the anxiety network (a system described by Charney & Bremner, 1999; Gor- man, Kent, Sullivan, & Coplan, 2000; LeDoux, 1998) counteract each other to keep satisfaction of needs, on the one hand, and social restraint and consideration, on the other, more or less in balance. Patients with BPD, however, have a tendency to reinforce immediate satisfaction of their primary drives, behaving in an impulse-driven manner regardless of the harmful consequences, indicating an imbalance between the reward and the anxiety systems.

If the stated hypothesis is correct, understanding the often in- comprehensible, perplexing, and self-destructive behavior of BPD patients will be easier. It is likely that their often perplexing behavior is under the control of subcortical, unconscious mecha- nisms. The term unconscious should not be understood in a psy- choanalytical sense: What is meant is that the behavior is being controlled by overpowering neurobiological mechanisms and not by the free will of the affected person. The EOS theory may also explain why many patients with BPD are often incompliant with treatment protocols, when they surrender to the overwhelming power of a disturbance in a system designed to help to ensure the survival of the individual. When there is enough evidence to support this theory, health care providers who treat patients with the disorder will have to bear in mind that the many bizarre behaviors of their patients and their unfriendly and off-putting attitude toward people who try to help them is partly due to neurobiological abnormalities, over which they have significantly less control than do healthy persons.

BPD is a highly symptomatic mental illness rather than a per- sonality variant. When clear neurobiological dysfunctions are identified in BPD, this will be one more reason why the disorder should be moved to Axis I in the newest version of the Diagnostic and Statistical Manual of Mental Disorders (DSM–V), as has already been proposed by some researchers (New, Triebwasser, & Charney, 2008; Paris, 2009).

 

Limitations

It may be argued that it is too simple to attribute so many behavioral dimensions to just one neurobiological system. An illness as complex as BPD most likely involves multiple neuro- transmitter systems (New, Goodman, et al., 2008), and future research should focus on the complex links of the EOS and the reward system to other neurotransmitter systems, including sero- tonin and dopamine.

The hypothesis has limitations, as r3-endorphin plasma or cere- brospinal fluid levels have not yet been studied extensively in patients with BPD. However, blood levels do not necessarily correlate with brain levels, as endorphins do not easily pass the blood– brain barrier. Both ACTH and r3-endorphin are among the cleavage products of POMC. This means that under stress condi- tions, not only ACTH but also r3-endorphin will be found in the plasma. It is possible that brain and plasma levels of r3-endorphin do not correlate highly. Therefore, it may be difficult to confirm or refute the hypothesis in the near future by means of direct mea- surement of endorphins. However, opioid antagonists, such as naltrexone, can be used to indirectly measure the release of en- dorphins in that researchers can observe the changes that occur when endorphin activity is blocked.

Another limitation of the endogenous opioid theory for BPD is that opioid receptors have not yet been studied in patients with BPD using brain imaging techniques. Now, quantitative PET im- aging of µ-, 8-, and K-opioid receptors is possible in the brain. Moreover, radioligands are under development for single photon emission computed tomography of opioid receptors (Lever, 2007). Genetic studies that target µ-opioid receptor gene polymor- phisms and related candidate genes are required to test the validity of the hypothesis. As there are large gender differences in terms of prevalence rates and symptomatology, future research should also focus on possible genetic or neurobiological reasons for these differences. Future studies will also have to elucidate why BPD symptomatology is worst when patients are in their 20s and 30s and then gradually improves (Paris, 2009; Zanarini, Frankenburg, Hennen, & Silk, 2003).

 

Therapeutic Implications

If this theory receives more support from new findings in the future, there will be implications for improvement of treatments for BPD. Future options for the investigation of medications for BPD include double-blind studies with opioid antagonists like naltrexone to control self-injury and other self-destructive behav- iors in the affected patients or the development of new drugs that have intrinsic activity at endogenous opioid receptors without causing addiction. Moreover, deep brain stimulation of the nucleus accumbens, which has led to improvement in treatment-refractory depression (Schlaepfer et al., 2008), might be an option in desper- ate, life-threatening cases of BPD. Furthermore, psychotherapy should aim at substituting dangerous, unhealthy, or aggressive ways of stimulating the EOS with socially accepted, healthy, and safe methods, such as exercise in moderation, artistic activities, engagement in social work, or the establishment of safe and reliable interpersonal relationships.

 

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Received March 18, 2009

Revision received September 30,  2009

Accepted October 1, 2009 ■

 

Borwin Bandelow, Peter Falkai, and Dirk Wedekind, Department of Psychiatry  and  Psychotherapy,  University  of  Go¨ttingen,  Go¨ttingen,  Ger- many; Christian Schmahl, Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany. In the last five years and in the near future, Borwin Bandelow has been/will be on the speakers/advisory board for AstraZeneca, Cephalon, Bristol-Myers-Squibb, Dainippon Sumitomo, Janssen-Cilag, Jazz, Lilly, Lundbeck, Pfizer, Roche, Sanofi-Aventis, Servier, Wyeth, and Xian- Janssen. Christian Schmahl was on the speakers/advisory board of Astra- Zeneca, Pfizer, Lilly, and Lundbeck. Peter Falkai was on the speakers/ advisory board of AstraZeneca, Bristol-Myers-Squibb, Janssen-Cilag, Lilly, Lundbeck, and Wyeth. Dirk Wedekind was on the speakers board of

AstraZeneca, Essex Pharma, Lundbeck, Wyeth, and Servier. Correspondence concerning this article should be addressed to Borwin

Bandelow, von-Siebold-Str. 5, Department of Psychiatry and Psychother- apy,  University  of  Go¨ttingen,  D-37075  Go¨ttingen,  Germany.  E-mail: sekretariat.bandelow@med.uni-goettingen.de

 

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