Genetics

Nature-nurture arguments about the cause of physical and mental disease have raged for decades, of course, but with the expansion of knowledge of heritability, gene mapping, and molecular genetics over the past quarter century, the role of nature has become better understood. One approach to this controversy is through the use of “twin studies”: in this type of study, identical twins (possessing the same genetic makeup) who are adopted into different households are examined years later for the presence of the disease. If one twin exhibits BPD, the likelihood that the other, reared in a different environment, will also be diagnosed with BPD is as much as 35 percent to almost 70 percent in some studies, thus giving greater weight to the nature argument.¹ Specific borderline traits, such as anxiety, emotional lability, suicidal tendencies, impulsivity, anger, sensation-seeking, aggression, cognitive distortions, identity confusion, and relationship problems, can also be highly genetic.

Heritability also extends to family members. Relatives of borderlines exhibit significantly greater rates of mood and impulse disorders, substance abuse, and personality disorders, especially BPD and antisocial personality.²

Our humanness emerges from the elaborate and unique chain of chromosomes that determine the individual. Although one specific gene alone does not determine our fate, a combination of DNA codings on different chromosomes do contribute to vulnerability for illness. Individual genes have been associated with Alzheimer’s disease, breast cancer, and other maladies; however, other chromosomal loci and environmental factors also contribute. Molecular genetics has identified specific gene alterations (polymorphisms) that are associated with BPD. Interestingly, these genes are involved with production and metabolism of the neurotransmitters, serotonin, norepinephrine, and dopamine. These neurotransmitters facilitate communication between brain cells and influence which genes are turned on or off. Alterations in these neurotransmitters have been associated with mood disorders, impulse dysregulation, dissociation, and pain sensitivity.

Neuroendocrinology

Other endocrine (hormone) neurotransmitters have been implicated in borderline pathology. NMDA (N-methyl-D-aspartate) dysregulation has been noted in BPD (as well as in some other illnesses) and implicated with dissociation, psychotic episodes, and impaired cognition.³ Disruptions in the body’s opioid (endorphin) system has been demonstrated in BPD and associated with dissociative experiences, pain insensitivity (particularly among self-mutilating individuals), and opiate abuse.⁴ Acetylcholine is another neurotransmitter affecting memory, attention, learning, mood, aggression, and sexual behavior, which has been linked to BPD.⁵

Chronic or repeated stress can also disrupt the neuroendocrine balance. Stress activates the hypothalamic-pitiutary-adrenal (HPA) axis, which secretes cortisol and activates the body’s immune system. In the usual acute stress situation, this system activates the “fight-flight” mechanisms of the body in a productive way. An internal feedback mechanism acts like a thermostat to then turn down the axis and return the body to equilibrium. However, ongoing stress dismantles the regenerative circuit and the stress alarms continue unabated, inflicting negative impact on the body, including shrinkage in characteristic areas of the brain. This pattern has been observed in several disorders, including BPD, PTSD, major depression, and certain anxiety disorders.

Neurological Dysfunction

Disturbances in brain function have been frequently associated with BPD. A significant subset of borderline patients have experienced a history of head trauma, encephalitis, epilepsy, learning disability, EEG (electroencephalogram, or brain wave) abnormalities, sleep pattern dysfunction, and abnormal, subtle neurologic “soft signs.”⁶^,⁷

Sophisticated brain imaging—such as fMRI (functional magnetic resonance imaging), CT (computerized tomography), PET (positron emission tomography), and SPECT (single photon emission computed tomography)—has elucidated some of the anatomical and physiological deviations associated with BPD. As already noted (see chapter 3), these studies seem to imply overactivity of those parts of the brain involved with emotional response (the limbic system), which includes such deep brain structures as the amygdala, hippocampus, and cingulate gyrus, while demonstrating underactivity of the outer parts of the brain involved with executive thinking and control, such as the prefrontal cortex.⁸

Future Considerations

With these advances in genetics and neurobiology, scientists will eventually be able to subtype more discretely different presentations of pathology, and, based on this knowledge, doctors may be able to more precisely “customize” a particular drug to a particular patient. To use an analogy: Our current understanding of psychiatric illnesses is roughly similar to our understanding of infections in the early and mid-1900s, before doctors could adequately culture the infecting agent. At that time, it was generally acknowledged that all antibiotics were equally beneficial—penicillin was just as effective, among all patients with infections, as any other antibiotic. However, when scientists discovered how to culture individual strains of bacteria and establish their sensitivities to particular antibiotics, doctors could prescribe a specific drug with the greatest likelihood of success. In other words, doctors were not simply treating infection or pneumonia; they were treating the specific strain, staphylococcus aureus. Similarly, in the future, the hope is that we will be able to “culture” the psychiatric illness and determine the best treatment. We will be treating the individual’s unique biology, not simply the diagnosis. As a result, the concept of “off-label” (in which a medicine is prescribed for a condition not formally approved—see page 200) will become moot, since the medicine will be directed toward a specific biological process, rather than a particular diagnosis.

Medications

Discoveries in the exploding fields of genetics and brain physiology have led to new drugs for many physical and mental conditions. Great advances have been achieved in pharmacology, especially in the area of biotechnology; in short, numerous psychotherapeutic drugs have been developed in the last twenty years, and the evidence suggests that some have proved effective in treating BPD. Although no medication is targeted specifically for BPD, research has demonstrated that three primary classes of medicines—antidepressants, mood stabilizers, and neuroleptics (antipsychotics)—ameliorate many of the maladaptive behaviors associated with the disorder.⁹

Antidepressants

Most research has examined the use of antidepressants, particularly serotonin reuptake inhibitors (SSRIs or SRIs). These medicines include Prozac (fluoxetine), Zoloft (sertraline), Paxil or Pexeva (paroxetine), Luvox (fluvoxamine), Celexa (citalopram), and Lexapro (escitalopram—related to citalopram). Predictably, these drugs have been effective for mood instability and related symptoms of depression, such as feelings of emptiness, rejection sensitivity, and anxiety. Additionally, SRIs have been shown to decrease inappropriate anger and temper outbursts, aggressive behavior, destructive impulsivity, and self-mutilating actions, even in the absence of depressive symptoms. In many studies, higher than usual doses of these medicines (for example, >80 mg of Prozac; >200 mg of Zoloft per day) were necessary to have a positive effect. A related group of drugs, serotonin-norepinephrine reuptake inhibitors (SNRIs), have not been as extensively studied, but may have similar positive effects. These include Effexor (venlafaxine), Pristiq (desvenlafaxine—related to venlafaxine), and Cymbalta (duloxetine).

Older antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), have also been studied. TCAs include Elavil (amitriptylene), Tofranil (imipramine), Pamelor or Aventyl (nortriptylene), Vivactil (protriptylene), Sinequan (doxepin), Norpramin (desipramine), Asendin, (amoxapine), Surmontil (trimipramine), and others. These drugs have generally been less effective and in some cases have decreased emotional control. Therefore, the patient diagnosed with BPD should be wary of prescribed drugs in the TCA class.

MAOIs—Nardil (phenelzine) and Parnate (tranylcypromine) being the most commonly used in the United States—have shown efficacy in BPD comparable to that of SRIs. However, MAOIs tend to have more side effects, are more dangerous in overdose, and require dietary and concurrent medication restrictions, and are therefore utilized much less.

Mood Stabilizers

This group of medications includes Lithium, a naturally occurring element, and antiseizure drugs—Depakote (valproate), Tegretol (carbamazepine), Trileptal (oxcarbazepine—related to carbamazepine), Lamictal (lamotrigine), and Topamax (topiramate). APA guidelines recommend this group as adjunctive treatment when SRIs or other interventions are ineffective or only partially effective. These medicines, in typical doses, help stabilize mood, decrease anxiety, and better control impulsivity, aggression, irritability, and anger. Neurontin (gabapentin), Dilantin (phenytoin), Gabatril (tiagabine), Keppra (levetiracetam), and Zonegran (zonisamide) are also in this class of drugs, but studies testing their effectiveness in BPD patients have been limited.

Neuroleptics

These drugs are recommended for initial treatment of cognitive-perceptual distortions in borderline patients. Paranoia, dissociative symptoms, and feelings of unreality (criteria 9 in the DSM-IV-TR—see chapter 2) are primary targets. In combination with SRIs, these medicines, usually in lower than common doses, relieve feelings of anger and aggressiveness; stabilize mood; and decrease anxiety, obsessional thinking, impulsivity, and interpersonal sensitivity.

Early studies were done with older neuroleptics, such as Thorazine (chlorpromazine), Stelazine (trifluoperazine), Trilafon (perphenazine), Haldol (haloperidol), Navane (thiothixene), and Loxitane (loxapine). Newer medicines, called atypical antipsychotics, have also demonstrated efficacy with generally less complicated side effects. These include Zyprexa (olanzapine), Seroquel (quetiapine), Risperdal (risperidone), Abilify (aripiprazole), and Clozaril (clozapine). Other medicines in this class—Invega (paliperidone—related to risperidone), Fanapt (iloperidone), Saphris (asenapine), and Geodon (ziprasidone)—have either not been studied or have yielded contradictory results.

Anxiolytics

Antianxiety agents, although acutely helpful for anxiety, have been shown to increase impulsivity and can be abused and addictive. These tranquilizers, primarily in the class known as benzodiazepines, include Xanax (alprazalom), Ativan (lorazepam), Valium (diazepam), and Librium (chlordiazepoxide), among others. Klonopin (clonazepam), a longer-acting benzodiazepine that may have greater effect on serotonin, has had success in treating symptoms of aggression and anxiety and so is perhaps the only benzodiazepine that may be useful for BPD.

Opiate Antagonists

Revia (naltrexone) blocks the body’s release of its own endorphins, which induce analgesia and euphoric feelings. Some reports suggest that this medicine may inhibit self-mutilating behavior.

Other Treatments

Homeopathic or herbal treatments have generally been unsuccessful, with the exception of omega-3 fatty acid preparation. One small study found that the substance did decrease aggressiveness and depression among women.¹⁰

Two substances that modulate the neurotransmitter glutamate have been investigated in BPD. The amino acid N-acetylcysteine and Rilutek (riluzole)—a drug used for the treatment of amyotrophic lateral sclerosis (Lou Gehrig’s disease)—were reported to significantly diminish self-injurious behavior in two borderline patients.¹¹

The APA’s Practice Guideline recommends that medications target a specific symptom cluster. Guidelines divide BPD symptoms into three primary groups: Mood Instability, Impulse Dyscontrol, and Cognitive-Perceptual Distortions. An algorithm of recommended treatment approaches, with alternative tactics if the previous choice is ineffective, is summarized in Table 9-1.

TABLE 9-1. Pharmacotherapy for treating BPD symptoms

A Word About “Off-Label” Use

The FDA (Food and Drug Administration) has not formally approved any drug for the treatment of BPD, so all of the medicines commonly used for treating BPD are considered “off-label.” Though the term “off-label” may be off-putting, if not seem downright risky to the uninitiated, off-label prescribing is quite common for a wide variety of conditions. Because a pharmaceutical company spends almost $1 billion on average to bring a drug to market, many companies do not seek approval for a wide range of conditions or outside narrow dosage ranges, as these strategies might narrow the chances for FDA approval and greatly increase the cost of development. For example, even though it is known that SRIs benefit several conditions, including depression, PTSD, anxiety illnesses, and some pain disorders, the drug manufacturer may not want to absorb the extra expense of gaining FDA approval—nor risk FDA rejection—by applying for label use for all of these indications and/or broad dosage ranges. Whenever a physician prescribes a medicine for an unapproved condition, or at a dose outside of recommendations, it is considered “off-label.” Unfortunately, managed care agencies may refuse approval of these (sometimes expensive) “off-label” prescriptions.

Generic Drugs

In simplest terms, a generic drug contains the same primary or active ingredient as the original formulation; generally speaking, it is almost always less expensive. However, this does not mean that a generic medication is identical to its brand-name counterpart. The FDA considers a generic drug “equivalent” to a branded medicine if blood levels in healthy volunteers are within 20 percent variation, a significant difference in some patients. A generic may also differ from the original in its inactive ingredients and its delivery system (e.g., tablet or capsule). Moreover, one generic may vary widely from another (theoretically, up to a 40 percent variation in blood level). The lesson here is that if a switch to a generic drug will result in significant savings, it may be worth trying. However, if symptoms recur, it is best to return to the brand medicine. Additionally, if you are taking a generic medicine that is working, do not change to a different generic. Also, be aware that some pharmacies and some doctors receive bonuses for switching patients to generic drugs.

Split Treatment

Many patients receive care from more than one provider. Often, therapy may be administered by a nonmedical professional (psychologist, social worker, or counselor), while medications are administered by a physician (psychiatrist or primary care doctor). Advantages of this protocol include less expense (thus accounting for its encouragement by managed care companies), involvement of more professionals, and separation of therapy and medication issues. But this separation can also be a disadvantage, since it allows the potential for patients to split providers into “good doctors” and “bad doctors” and to become confused about the treatment. Close communication among professionals treating the same patient is essential for the process to be successful. In most cases, a psychiatrist skilled in both medical management and psychotherapy techniques may be the preferred approach.

Can Borderlines Be Cured?

Much like the disorder itself, professionals’ opinion about the prognosis for those afflicted with BPD has whipsawed from one extreme to the other. In the 1980s Axis II personality disorders were generally thought to be enduring and stable over time. DSM-III asserted that personality disorders “begin in childhood or adolescence and persist in stable form (without periods of remission or exacerbation) into adult life.”¹² This perception was in contrast to most Axis I disorders (such as major depression, alcoholism, bipolar disorder, schizophrenia, etc.), which were thought to be more episodic and responsive to pharmacological treatment. Suicide rates in BPD approached 10 percent.¹³ All of these considerations suggested that prognosis for BPD was likely to be poor.

However, longer-term studies published over the last several years demonstrated significant improvement over time.¹⁴^,¹⁵ In these studies, tracking borderlines over a ten-year period, up to two-thirds of the patients no longer exhibited five of the nine defining criteria for BPD, and therefore could be considered “cured,” since they no longer fulfilled the formal DSM definition. Improvement occurred with or without treatment, although treated patients achieved remission sooner. Most patients remained in treatment, and relapses diminished over time. Despite these optimistic findings, it was also discovered that although these patients no longer could be formally designated as “borderline,” some continued to have difficulty with interpersonal functioning that impaired their social and vocational relationships. This suggests that the more acute and prominent symptoms of BPD (which primarily define the disorder), such as suicidal or self-mutilating behaviors, destructive impulsivity, and quasi-psychotic thinking, are more quickly responsive to treatment or time than the more enduring temperamental symptoms (fears of abandonment, feelings of emptiness, dependency, etc.). In short, although the prognosis is clearly much better than originally thought, some borderlines continue to struggle with ongoing issues.

Those who conquer the illness display a greater capacity to trust and establish satisfactory (even if sometimes not very close) relationships. They have a clearer sense of purpose and a more stable understanding of themselves. In a sense, then, even if borderline issues remain, they become better borderlines.