Stress can trigger former drug users to begin taking drugs again. In clinical trials, the bonding hormone oxytocin has been found to reduce stress-induced cravings for certain drugs, including alcohol and marijuana. A new study in animals suggests that oxytocin may be able to reduce stress-induced cocaine cravings as well.
Brandon Bentzley and colleagues combined an unpredictable shock to the foot with an alkaloid called yohimbe that comes from a particular tree bark to apply stress to animals who had previously developed a cocaine self-administration habit that had since been extinguished. The combination of the foot shocks and yohimbe brought back robust reinstatement of the animals’ cocaine seeking behaviors, but pretreatment with oxytocin (at doses of 1 mg/kg) prevented this reinstatement.
This research suggests that oxytocin has potential to prevent stress-induced cocaine cravings in people.
Deaths from opiate abuse are occurring in the US at about the same rate as automobile fatalities. At a recent talk, researcher Richard Ries discussed treatment of opiate addictions and the current epidemic of unintended opiate overdoses. Most opiates being abused come from other people’s leftover prescriptions. The best way to prevent opiate abuse is to throw out unused painkillers when they are no longer needed.
Many overdoses from opiates also involve alcohol and benzodiazepines, which can contribute to breathing difficulties.
There are several treatments available that can help patients abstain from using opiates. Treatment with opioid receptor antagonists (such as naltrexone (Rivia or long-acting Vivitrol, which is taken as an injection and lasts for 1 month), partial agonists (like buprenorphine), or full agonists (like methadone) results in, on average, an 80% decrease in the rate of hospitalization and an 80% reduction in crime, as well as a marked decrease in AIDS transmission. Without treatment, it is very difficult for people with opiate addictions to maintain abstinence, and relapse rates are extraordinarily high.
Treatment of Alcohol Abuse and Benzodiazepines
Ries also discussed data on treatment of alcohol abuse. He emphasizes that some aspects of withdrawal, such as sleep disturbance, can last a month or more after a parient’s last drink, putting the patient at high risk for relapse. Gabapentin, which is most often prescribed to prevent seizures, helps patients with this phase. Ries endorsed the combination of gabapentin and naltrexone as especially helpful. Carbamazepine is widely used in Europe for the treatment of alcohol abuse, and Ries also strongly endorsed the drug as another way of avoiding benzodiazepines. Several large placebo-controlled trials suggest that the anticonvulsant topiramate is also effective for long-term alcohol avoidance.
Editor’s Note: Another researcher, Mark Frye, found that women with bipolar disorder are more than seven times more likely than women in the general population to abuse alcohol, often in an attempt to self medicate their residual anxiety and depression. Excellent treatment of mood in bipolar disorder may have the double benefit of helping patients avoid alcohol abuse. The nutritional supplement n-acetylcysteine (NAC) also helps improve mood in bipolar disorder and has positive placebo-controlled data in heroin, cocaine, and alcohol avoidance.
Note: The following article discusses “off-label” treatments for the treatment of PTSD or traumatic brain injury, i.e. those which are not FDA-approved for these purposes. In some of these instances, there is no controlled research to support the use of these drugs in patients with PTSD. Thus the ideas noted here cannot be taken as anything more than anecdotal information from personal experience. Patients and physicians must make their own decisions about any of the strategies reported in this or other issues of BNN.
At a recent scientific conference, Vaishali P. Bakshi, a renowned Canadian psychopharmacologist, shared a novel treatment strategy he has developed for patients with exceptionally profound degrees of post-traumatic stress disorder (PTSD), which, particularly among military veterans, can be compounded by traumatic brain injury.
Treatment options based on placebo-controlled clinical trials are sometimes insufficient for the treatment of seriously ill patients. FDA-approved treatment for PTSD consists of serotonin-selective antidepressants, while exposure therapies (in which the patient is gradually exposed to more of the stimuli that triggered symptoms) are the recommended psychotherapy, but these methods often leave patients highly disabled.
Bakshi’s typical treatment algorithm goes well beyond these treatment guidelines to find solutions for hard-to-treat patients. He first addresses sleep disturbance, which often occurs in PTSD. He suggests the anticonvulsant levetiracetam (Keppra), starting at doses of 150mg per night and increasing to 500–1000mg as tolerated. This highly sedating anticonvulsant not only improves sleep but may also help cognition, since it is structurally similar to other cognitive enhancers such as piracetam. Levetiracetam also decreases the hippocampal hyperactivity associated with some forms of cognitive dysfunction, as we’ve noted before. In order to further enhance sleep effects, Bakshi adds trazodone at 50–150mg per night as needed.
Instead of selective serotonin reuptake inhibitors (SSRIs), Bakshi recommends the selective serotonin and norepinephrine reuptake inhibitors (SNRIs). Among these, he prefers desvenlafaxine (Pristiq) over venlafaxine, as desvenlafaxine has fewer interactions with other drugs. Theoretically, duloxetine (Cymbalta) is another SNRI that could be used.
Another component of Bakshi’s treatment plan is topiramate (Topamax), which can target many comorbidities of PTSD, including alcohol and substance abuse, particularly stimulant abuse. In addition, topiramate has efficacy in anger attacks, which often accompany PTSD.
In patients with ongoing problems with depression and/or cognition, Bakshi adds bupropion (Wellbutrin). Read more
Patients with PTSD often struggle with nightmares, but a treatment normally used for high blood pressure may also be able to prevent these sometimes horrific dreams. In a study that marks the third replication of this finding, Murray Raskind, a researcher from the University of Seattle, reported that prazosin was significantly better than placebo at selectively blocking nightmares in 77 Iraq war veterans with PTSD in a 15-week trial. (Interestingly, normal dreaming is uninterrupted.)
Editor’s Note: Prazosin is a noradrenergic alpha-1 receptor antagonist. Doses of this drug must be titrated upward slowly over a period of 6 weeks to avoid orthostatic hypotension (a sudden fall in blood pressure that occurs when a person stands up). Maximum doses achieved in this study were 5mg mid-morning and 20mg at night (although 10mg at night is often effective). This treatment, although not FDA-approved, is increasingly being used in veteran populations and other patients with PTSD.
At a recent scientific meeting, Thomas Neylan and colleagues reported that post-traumatic stress disorder (PTSD) may be connected to autoimmune illnesses. In this study, 673,277 veterans of the US military who had served in Iraq and Afghanistan were screened for the development of PTSD. The illness was diagnosed in 31% of the veterans, and those individuals had a higher incidence of autoimmune-related disorders including thyroiditis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and systemic lupus erythematosus. Neylan’s research group specifically examined those whose disorders developed after the onset of the PTSD, and found that the statistical relationship between their illnesses and PTSD was strong. However, the researchers also found that there was evidence of a similarly strong relationship in the other direction: veterans who were first diagnosed with some of these same autoimmune difficulties also went on to develop PTSD.
Many previous clinical and preclinical studies have linked altered immune and autoimmune mechanisms to severe stressors such as those that are involved in PTSD. This is the first study to unequivocally demonstrate the relationship in an extraordinarily large number of patients.
Editor’s Note: These findings resemble those that suggest that among the general population, childhood adversity is associated with an increased incidence of a variety of medical disorders in adulthood. Similarly, in the Bipolar Collaborative Network in which this editor (Post) is an investigator, we found that a history of childhood adversity in patients with bipolar disorder was associated with an increased incidence of a variety of medical illnesses in adulthood, including some related to immune and autoimmune function.
More research that would measure inflammatory markers in PTSD and mood disorders is needed. It would also be important to ascertain whether treatment of mood disorders and PTSD reduces the risk of autoimmune disorders.
Adults with bipolar disorder have higher rates of cardiovascular disease and premature death from cardiovascular illness than the general population. At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry, Benjamin Goldstein presented a poster in which he showed that youth with bipolar disorder may also have abnormal cardiovascular function.
When a tourniquet is applied, blood vessels normally expand to make up for the period of oxygen deprivation. This does not happen as readily in patients with mood disorders. This lack of flexibility and compensatory response could be one of the reasons for increased cardiovascular difficulties in those with mood disorders.
In Goldstein’s study, noninvasive ultrasound imaging was used to measure the thickness of the walls of the carotid artery and flow mediated dilation of the artery in adolescents with bipolar disorder and those without the illness. The data was collected by a certified ultrasound technologist who remained blind to the patients’ diagnostic and symptom status.
Goldstein found highly abnormal results in 14 adolescents aged 14 to 19 with bipolar disorder compared to controls. He concluded that reducing cardiovascular risk in bipolar disorder is a pressing clinical and public health challenge and that treating these patients while they are adolescents may offer considerable advantages both for prevention and for understanding the progression of cardiovascular problems in patients with bipolar disorder.
Substance Use Among Canadian Adolescents with Bipolar Disorder: The Critical Need for Intervention and Prevention
At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Antoinette Scavone presented a poster on correlates of substance use disorders among Canadian adolescents with bipolar disorder. Participants were 62 adolescents aged 14 to 19 with bipolar disorder. Twenty-three participants (37.1%) had a substance abuse disorder.
Those with a comorbid substance use disorder were more likely to have a comorbid panic disorder or an oppositional defiant disorder. They also had higher rates of police contact or arrest, were more likely to have been involved in assault, and were more impulsive. In addition they had experienced more stressful life events.
Editor’s Note: These data from a Canadian sample replicate previous findings in the US and again indicate the critical importance of preventing the onset of substance abuse in adolescents at especially high risk because of their bipolar disorder.
At the 2012 annual meeting on pediatric bipolar disorder sponsored by the Ryan Licht Sang Foundation and Massachusetts General Hospital, Timothy E. Wilens gave a plenary talk on “The Explosive Combination of Bipolar and Substance Abuse.”
Wilens cited the statistic that 10% of adolescents in the general US population have at some time received a diagnosis of a substance abuse disorder. The age of onset of substance abuse peaks between ages 15 and 20.
Wilens said that in a recent survey about use in the past month, among participants in the general population aged 12 or higher with substance use, about 50% use marijuana and about 50% use prescription narcotics (often obtained from their parents’ medicine chest).
The rate of mortality from substance abuse has risen dramatically since 1993 and now approximates that from automobile accidents. According to Wilens, rates of emergency room visits and fatalities have increased recently, and this has been linked to opiate overdoses.
Adolescents with bipolar disorder are at greatly increased risk of substance abuse compared to the general population. Most substance abuse follows the onset of bipolar disorder, not vice versa.
Wilens cited the data of researcher Ben Goldstein that on 8-year follow up, 32% of bipolar adolescents developed a substance use disorder. Those treated with antimanic agents were much less likely to develop a substance use disorder. MORAL: Treat bipolar disorder psychopathology in adolescents well and help them avoid substance abuse.
Children with persistent emotion dysregulation were: 1) more likely to develop a substance use disorder; 2) more likely to begin using substances earlier; and 3) more likely to have a more severe form of combined (multiple) substance use disorders.
Treating Substance Use
Wilen suggested that a good interview is better than urine toxicology screens for assessing substance use. He suggested the following treatment paradigm: Read more
Kellen and colleagues presented a poster at the 9th International Conference on Bipolar Disorder (ICBD) held in Pittsburgh in 2011, in which they reported that 21% of patients with rapid cycling bipolar disorder have confirmed sleep apnea. Since many patients who screened positive for sleep apnea on the study’s sleep questionnaire did not undergo follow-up sleep studies to confirm the diagnosis, it is estimated that up to 40% of rapid cycling patients may, in fact, have sleep apnea.
Editor’s note: Given such a high incidence of sleep apnea among rapid cycling bipolar patients, it would be prudent for patients and clinicians to be alert to the possibility of sleep apnea and follow up with appropriate sleep studies. Sleep apnea can cause daytime fatigue, cognitive dysfunction, and treatment resistance, so its identification and treatment with continuous positive airway pressure (CPAP) may be enormously beneficial to a substantial number of rapid cycling bipolar patients. A just-published article by Sukys-Claudino in Sleep Medicine presents findings that compared to placebo, the anti-Alzheimer’s drug donepezil (Aricept) started at 5mg/day for 2 weeks and then increased to 10 mg given twice a day (20 mg/day total) helped all measures of sleep apnea including daytime sleepiness.
Clinical hints that a patient may be suffering from sleep apnea include loud snoring, long pauses between breaths, and non-restorative sleep. The likelihood of sleep apnea increases with age and with overweight or obesity.
Sherwood Brown and colleagues from the University of Texas Southwestern Medical Center have completed a successful placebo-controlled trial of citicoline for bipolar and unipolar depression with comorbid methamphetamine dependence. Forty-eight participants with methamphetamine dependence and either unipolar or bipolar depression were randomized to either citicoline (2000 mg/day) or placebo for 12 weeks. Those receiving citicoline had significantly greater improvement in scores on the Inventory of Depressive Symptoms compared with those who received placebo, and patients receiving citicoline stayed in the study significantly longer, with completion rates of 41% on citicoline and 15% on placebo.
In 2007, the same team of investigators reported in the Journal of Clinical Psychopharmacology that citicoline had positive effects in bipolar patients with cocaine dependence, who experienced significant decreases in cocaine use and fewer cocaine-positive urine tests while taking citicoline.