I use the word “frustrating” because a biological explanation for the disease seems heartbreakingly just out of reach. Schizophrenia has a powerful genetic component (heritability percentage is in the low 80s), something I’ve known for years, something that could make it low-hanging research fruit. There is also a large clinical base on which to do studies: schizophrenia afflicts millions of people (the estimated prevalence rate is about 1% of the global population). Despite these seeming advantages, a molecular mechanism capable of describing all aspects of schizophrenia has almost completely eluded researchers.

There’s a simple reason for this. A deep understanding of schizophrenia at such an intimate level has been hampered by a single technical bottleneck: the lack of a robust in vitro disease model.

That may all be about to change. The results from a study that used cells derived from a deceased patient’s skin tissue has recently been published.¹ Findings from the study may provide just such a model. It is not yet full-fledged schizophrenia-in-a-dish, but the findings portend a powerful future for the field. I’d like to tell you what happened. I’ll start with a brief review of hiPSCs (human inducible pluripotent stem cells), then move to the data.

Pluripotent stem cells

August 2006 is a landmark in the field of regenerative medicine. An article published that month from a group in Kyoto, Japan, described how to take garden-variety mouse skin cells and turn them into pluripotent stem cells.² It was reported that stem cells have an ability to transform themselves into different cell types, depending on the tissue, essentially at the scientist’s whim.

Researchers had been trying to harness this power for a long time, and for good reason. Such technologies could be useful for screening the effects of drugs, valuable as replacement therapies for damaged tissues, and relevant to this article on creating disease models. The cells are formally termed “iPSCs.” I received a further shock when a year later, the same research group did the same trick with human cells.³

Four separate gene sequences are loaded onto genetically reengineered retroviruses (members of the genus lentivirus, which includes HIV). These viruses are allowed to infect a host skin cell, and because they are retroviruses, they immediately integrate into the host cell’s DNA. For reasons not fully understood, this integrated gene combination goes right to work reprogramming the skin, transforming it into a batch of versatile iPSCs. One of the most interesting of the 4 retroviral-stitched sequences is called Myc, which before this work was mostly known for causing cancer.

Once there was a reliable way to manufacture healthy hiPSCs, scientists could turn their attention toward their most important goal: learning how to create the cell type they wanted to study. It did not take long for researchers to discover how to turn hiPSCs into functional neurons. It took a slightly different combination of genes stitched onto their retroviral transports (Figure). iPSCs were infected with this combination and, voilà, functional neurons began to grow in a dish.

With these technologies in mind, I now have the tools needed to understand how to create a dish-bound model of schizophrenia. It involves answering some simple questions: What if you took the skin cells from patients who had schizophrenia and turned them into neurons? Would they exhibit behaviors of typical, healthy cells? Or would they exhibit behaviors reminiscent of previously determined properties of neurons in patients with schizophrenia? If the latter were observed, would you have a robust cellular model of schizophrenia, the missing link in this line of work? A consortium of researchers from Pennsylvania, San Diego, and New York decided to pool their resources and find out.⁴

Experimental protocol

Primary fibroblasts derived from postmortem samples of patients with a formal diagnosis of schizophrenia were obtained and cultured. These were infected with retroviruses using iPSC protocols such as the ones described above. Would skin cells from diseased patients make iPSCs that were similar to fibroblasts obtained from unaffected people? They did indeed. Once obtained, these iPSCs were even reprogrammable, and soon either neurons or NPCs (neural progenitor cells) from deceased schizophrenic individuals were growing in the dish.

The most interesting result came from what happened next. Even though the reprogrammed cells were clearly neural tissue, they did not behave like typically functioning neurons. Several observed differences were eerily similar to previous findings other researchers had seen in tissue samples from patients with schizophrenia.

Dendritic arborization. Neurons derived from patients with previously diagnosed schizophrenia exhibit specific, aberrant properties. Postmortem examination of neural tissue reveals a significant reduction in dendritic arborization in many patients, which may result in aberrant neural connectivity and subsequent behavioral abnormalities.

This same reduction was observed in the reprogrammed cells. The cells showed a decrease in neurite numbers (a neurite refers to any projection from a neuron’s cell body). This resulted in a loss in neural connectivity in these same populations. It is interesting to note that the application of the antipsychotic loxapine(Drug information on loxapine) to these cells significantly restored their neuronal connectivity. (Four other antipsychotics did not.)

It should be noted that these cells were all fully capable of spontaneous neural activity. In response to normal membrane depolarization events, for example, these cells displayed typical inward sodium currents (transient) and more sustained outward potassium currents.

Changes in neuregulin expression. A number of genes whose aberrant expression profiles are associated with the disease state in other individuals showed up in these reprogrammed cells. One of the most dramatic was an increase in NRG1 (neuregulin) expression. NRG1 is part of a group of glycoproteins in the epidermal growth factor family. This elevation was not seen in the cultured fibroblasts or in the iPSCs (nor was it seen in the NPCs). Why is NRG1 important? Previous work has shown that mutations in this gene were highly associated with the prevalence of schizophrenia in Icelandic populations. The specific involvement of neuregulin in these cells thus represents an important finding.

Global gene expression changes. There are techniques that allow researchers to assess the “gross domestic product” of gene expression profiles in given cell populations (essentially a global assessment of class 2 gene expression). Such analysis was performed, and findings were compared with those from nondiseased controls and with genes previously implicated in schizophrenia. It was found that 25% of the genes differentially expressed in the reprogrammed cells had been previously implicated in schizophrenia. These were not trivial genes. Further analysis (gene ontology examinations) demonstrated changes in glutamate signaling, as well as WNT and cyclic adenosine(Drug information on adenosine) monophosphate signaling pathways.

The bottom line is that many of the major cellular and molecular aberrations previously demonstrated in diseased tissues were showing up in these reprogrammed cells. A robust living cell model, derived exclusively from postmortem samples from patients in whom schizophrenia had been diagnosed, seems to have been achieved.

What this means

Although this is truly a significant result, there are specific caveats. Some have to do with the fact that relatively “simple” tissues growing in a dish do not mimic the complex, real world of the living brain. Other objections have to do with the technology.

iPSCs are notorious for carrying mutations that may have very little to do with the real in vivo world. Retroviruses insert at random DNA sites in the genome, which introduces the risk of gene disruption. Moreover, genes such as the aforementioned Myc, greatly increase the efficiency of reprogramming cells, which means they are nice to have around if you are doing this type of research. However, Myc is also an oncogene, which means it is a sequence capable of inducing cancer. Does that introduce any uncontrolled variables? At this point, no one knows.

None of these objections seriously undermine the great potential of this result, of course. Having a dish filled with cells that carry many characteristics of a human disease is a lot like having a flashlight in a dark cave. The greatest utility is in the ability to illuminate molecular mechanisms that might go undetected without such a model. It can go a long way toward relieving the frustration often associated with this line of work. Give it enough time and it might even—someday—illuminate a cure.

References

1. Brennand KJ, Simone A, Jou J, et al. Modelling schizophrenia using human induced pluripotent skin cells. Nature. 2011;473:221-225.
2. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663-676.
3. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861-872.
4. Sendtner M. Regenerative medicine: bespoke cells for the human brain. Nature. 2011;476:158-159.

CASE VIGNETTE

Ms A, a 22-year-old, was brought to the emergency department (ED) by ambulance; she had overdosed on zolpidem. After detoxification in the ED, a psychiatric consultation was requested. Ms A told the consultant that she had had a bad day and simply took 5 extra zolpidem tablets to “go to sleep” and that “it was just a stupid thing to do.” While obtaining the history, the consultant noted that Ms A’s therapist had left for vacation 2 days earlier.

The consultant informed Ms A that her overdose was just a reaction to her therapist’s vacation, that she did not have a major mental disorder, and that she was going to be discharged. In response, Ms A became irate, “No one cares about me; I just tried to kill myself and you just want to get rid of me! If you don’t admit me, I’m going to walk in front of the next bus!”

Feeling manipulated but with no other options, the consultant admitted Ms A to the inpatient psychiatric unit. Once there, the staff noted that Ms A seemed cheerful, childlike, and cooperative. In the morning, however, Ms A angrily demanded to be discharged when she was refused a smoking pass. The inpatient psychiatrist questioned Ms A about the recent overdose and suicide threats; she stated that she never intended to carry out her threats but was just trying to get attention.

Although health care providers may not take the threat of suicide seriously in patients who have BPD, these patients are often serious about suicide. Long-term studies indicate that compared with controls, patients with BPD have an 8% to 10% increased risk of completed suicide, which is comparable to that of patients who have MDD and schizophrenia.² Moreover, minor overdoses frequently represent ambivalent suicide intent, and episodes of non-suicidal self-injury are markers for suicide risk and predict future suicide attempts.^3,4

Conscious “attention-seeking” behavior is rare, although both patients and health care providers may attempt to frame suicidal behavior that way. As with Ms A, patients may minimize the seriousness of their intent, stating it was just “attention-seeking,” or “I was just trying to sleep,” making it easy for health care providers to question the validity of their patients’ actions.

On the other hand, not every gesture or threat is an indication for a prolonged inpatient hospital stay. Patients may threaten suicide as a way of obtaining or extending hospital stays. A study by Gregory and Jindal⁵ of 100 consecutive inpatient admissions showed that factitious production of suicide ideation, gestures, and threats was common among women with BPD at the time of discharge. Suicide threats and behavior served as a means of justifying the seriousness of their condition to providers, and to themselves. Given this information, is the underlying message that we should take suicidal ideation and behavior seriously, but not too seriously? How can we understand suicide risk in BPD?

Understanding the causes of suicide in BPD

The affect, mood, and behavior of patients with BPD can suddenly switch and appear contradictory, causing bewilderment and frustration for their health care providers. Patients can appear very depressed and suicidal at one moment and appear angry and entitled the next. Indeed, affective instability is the feature of BPD most closely associated with attempted suicide.⁶

Many clinicians have found the states of being model of dynamic deconstructive psychotherapy helpful for understanding affective instability in BPD and how it increases suicide risk.⁷ According to this model, patients with BPD can be triggered to switch between different states of being, or pseudo-personalities. In a matter of days, hours, or even minutes, patients can alternately appear helpless and childlike (helpless victim state), angry and self-righteous (angry victim state), or depressed and suicidal (guilty perpetrator state). These states are not methods of manipulation, but rather represent different sets of polarized and poorly integrated attributions of self and others.

When in the angry victim state, patients see themselves as heroic victims. They accept no responsibility for failures and instead blame others for their difficulties. They can become angry, manipulative, or violent in this state, since they perceive their actions as totally justified. This state is a defense against feelings of shame or humiliation and is triggered by situations that provoke such feelings. For example, Ms A reacted with rage when the consultant questioned the seriousness of her condition and the legitimacy of her suicide attempt. Patients are at low risk for suicide while in this state because they see the source of their difficulties as outside of themselves.

On the other hand, when in the guilty perpetrator state, patients with BPD are at significantly increased risk for suicide, especially when there are other risk factors, such as poor social supports, co-occurring alcohol misuse, or poor physical health.³ When in the guilty perpetrator state, patients take on total responsibility for every bad thing that has ever happened to them. They see their lives as a series of failures and bad decisions; they feel ugly, worthless, and evil—a pest that deserves to be exterminated.

In the guilty perpetrator state, the patient preserves an idealized image of others by taking all the badness onto himself or herself. This state is usually triggered by perceived rejection, abandonment, or separation anxiety, but it can also be triggered by any situation that causes the patient to become ambivalent toward major attachment figures. For example, Ms A’s initial presentation of having had a “bad day” was triggered by her therapist’s vacation. Instead of being able to acknowledge anger toward her therapist for abandoning her, Ms A maintained a positive image of her therapist by devaluing herself instead. During that day, Ms A’s self-image was the unlovable and difficult patient who was beyond help and who deserved to be “abandoned.” Despite Ms A’s later protestations, her overdose most likely included some suicide intent, in addi-tion to self-directed anger.

The states of being and rapidity of switching can be exacerbated by circumstances that intensify attachment wishes and fears, such as abusive relationships, prolonged hospital stays, or poor patient-therapist boundaries (physical touching, multiple contacts per week, extended sessions, etc). Patients can regress and become moody and childlike under these conditions: they react strongly to minor provocations and alternate rapidly between different states of being; their risk of suicide varies as well. The childlike qualities and sudden fluctuations in states contribute to health care providers’ confusion and skepticism.

Making the diagnosis

The first step in managing suicide risk in patients with BPD is to correctly identify the disorder. After multiple encounters that end in feeling manipulated or duped, physicians often come to assign the diagnosis of BPD only to patients whom they dislike or view as attention-seeking. Despite the importance of this diagnosis, physicians do not usually screen for BPD because making an accurate diagnosis can be time-consuming; they often come to believe that they can magically sense whether or not BPD is present.

Underdiagnosis of BPD is common, as is a misdiagnosis of bipolar disorder.⁸ Some indicators for systematic diagnostic screening for BPD include meeting criteria for multiple Axis I conditions; taking 3 or more psychiatric medications; or having evidence of behavioral dyscontrol, such as an eating disorder, substance use disorder, or recurrent incidents of self-harm. Routine use of brief self-rating scales, such as the McLean Screening Instrument for Borderline Personality Disorder⁹ and the patient questionnaire portion of the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II),¹⁰ can also greatly enhance diagnostic accuracy.

Summary

The conflict within health care providers over whether their patient’s suicidal behavior and threats are legitimate mirrors a similar conflict within patients with BPD over whether their illness is legitimate, or whether they are totally to blame for their problems, attention-seeking, and needing to get their act together. Patients can rapidly switch states as they take one side of the conflict or the other, switching blame from self to others. Assessing the patient’s current state of being, recent stressors, alcohol misuse, and support system informs the health care provider about immediate risk. The Table provides some management strategies to minimize risk of suicide.

Staying empathic and keeping the conflict within the patient instead of between the patient and health care provider, is a key to successful management. Other keys include maintaining clear expectations and boundaries, building autonomous motivation, and helping patients verbalize experiences and emotions.

Comorbid substance use disorders play a particularly important role in the development of violent behavior in schizophrenia. This was studied in a meta-analysis of violent criminality using data from 18,423 individuals with schizophrenia and other psychoses.³ The odds ratio for violent crime was 2.1 (95% confidence interval [CI], 1.7 – 2.7) without comorbidity, but it increased to 8.9 (95% CI, 5.4 – 14.7) with comorbidity. The difference between odds ratios indicated a marked effect of substance abuse on violent crime.

The clinical importance of this effect is underlined by the fact that risk for substance use disorders in schizophrenia is very high; lifetime prevalence of this comorbidity in schizophrenia is estimated at 47%.⁴ For these reasons, evaluation of comorbid substance use disorders is an important component of the clinical assessment of patients with schizophrenia. Management of comorbid substance use disorders must be an inherent part of the treatment plan.

Violent behavior is heterogeneous in origin, and its development is not limited to the context of mental illness.⁵ Therefore, management approaches that rely exclusively on psychopharmacology are frequently unsuccessful—not only because of incorrect societal context, but also because violent behavior in mental illness frequently results from nonadherence to treatment.⁶

Acute management of agitation and violent behavior

Agitation is a common reason for presentation to an emergency department (ED); it can tip the decision for in-patient care and can be an obsta-cle to hospital discharge. Agitation can easily escalate to aggression and violent behavior, and thus acute agitation is considered a behavioral emergency that requires immediate action. In addition to nonpharmacological interventions related to managing crisis situations, medication approaches are vital.⁵

Although oral medications can be effective, rapidity of onset of action is enhanced with the use of short-acting parenteral formulations that allow for maximal plasma levels to be reached more quickly. Lorazepam(Drug information on lorazepam) can be useful when the cause of the disturbed behavior is unclear and perhaps due to withdrawal from alcohol(Drug information on alcohol). It is reliably absorbed intramuscularly, has no active metabolites, and has a half-life of 10 to 20 hours; the usual dosage is 0.5 to 2 mg every 1 to 6 hours.⁷

Caution is required with lorazepam when respiratory depression is a possibility. In addition, lorazepam should not be used for long-term daily use because of the problems that are associated with benzodiazepine use—tolerance, dependence, and withdrawal.

The combination of intramuscular haloperidol with intramuscular lorazepam is also commonly used and is supported by a double-blind randomized clinical trial that compared intramuscular haloperidol 5 mg, intramuscular lorazepam 2 mg, or a combination of both in psychotic, agitated, and aggressive patients treated in EDs.⁸ However, continued use of haloperidol as a foundational antipsychotic would be suboptimal in schizophrenia or bipolar disorder. Consequently, there has been increased interest in intramuscular formulations of second-generation antipsychotics, of which 3 are available in the US: ziprasidone, olanzapine, and aripiprazole.⁹

Intramuscular ziprasidone’s efficacy in reducing agitation was evidenced in 2 pivotal clinical trials that enrolled patients with schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features, or another psychotic disorder.^10,11 Although the product label recommends a dose of 10 or 20 mg, the best dose appears to be 20 mg; this conclusion is based on the proportion of patients with a clinically relevant reduction in agitation-rating–scale scores.

A naturalistic study of intramuscular ziprasidone in patients who can have more severe levels of agitation than those participating in a randomized controlled study also supports the use of intramuscular ziprasidone as an effective treatment.¹² Product labeling cautions prescribers regarding ziprasidone’s potential to prolong the QT interval and that the cyclodextrin excipient used in the formulation is cleared by renal filtration, which may be an issue in patients who have impaired renal function.¹³

Intramuscular olanzapine was found to be effective in reducing agitation in patients with schizophrenia and in patients with bipolar disorder, manic or mixed.^14-16 The recommended dose of olanzapine is 10 mg, but lower doses of 2.5 to 5 mg can be considered for medically vulnerable patients.¹⁷ Naturalistic studies of intramuscular olanzapine are also supportive of its effectiveness.¹⁸ The product label is cautionary regarding hypotension, bradycardia with or without hypotension, tachycardia, and syncope as reported during the clinical trials. Simultaneous injection of olanzapine and benzodiazepines is not recommended, and this advice is reinforced in a report of a case series in which comorbid medical conditions were noted to increase risk.¹⁹

Study findings indicate that intramuscular aripiprazole reduces agitation in patients with schizophrenia and in patients with bipolar disorder, manic or mixed.^20-22 The recommended dose is 9.75 mg.²³ The product label cautions clinicians regarding greater sedation and orthostatic hypotension with the combination of lorazepam and aripiprazole compared with aripiprazole alone.

Once past the acute phase, patients who are receiving intramuscular ziprasidone, olanzapine, or aripiprazole can be successfully transitioned to the oral counterpart of the medication.^24-27

Long-term management of violent behavior

Most of the evidence on long-term treatment of aggression in mental illness has been collected in patients with schizophrenia. There are very few controlled trials that were a priori designed to test antiaggressive treatments. Most of the data available were obtained in the form of clinical observations, uncontrolled chart reviews, and post hoc retrospective analyses of databases collected primarily for purposes other than the study of aggression. Antipsychotics are the mainstay of the long-term pharmacological treatment of aggression in schizophrenia.

Antipsychotics

Randomized controlled trials of antipsychotics are summarized in the Table. Two randomized, controlled, double-blind trials were designed a priori to study aggression in schizophrenia. The first trial compared clozapine, olanzapine, risperidone(Drug information on risperidone), and haloperidol in 157 patients with schizophrenia or schizoaffective disorder.²⁸ The hostility item of the PANSS (Positive and Negative Syndrome Scale) was used as a proxy measure for aggression in the analyses. Clozapine was superior to risperidone and haloperidol (but not to olanzapine) in reducing hostility.²⁹ Neither risperidone nor olanzapine showed superiority to haloperidol.

In the same randomized controlled trial, incidents of overt physical aggression were also recorded and analyzed.^28,30 The results showed clozapine (and, in some analyses, all 3 atypicals) to be superior to haloperidol in antiaggressive efficacy, particularly after the first 24 days in the trial, when scheduled dose escalation of clozapine was completed. Thus, an important clinical take-home lesson from this study is that full effectiveness of clozapine cannot be expected until the patient has been exposed to an adequate-dose regimen. If aggressive behavior is a problem during the escalation period of clozapine, other medications need to be temporarily coadministered. Discontinuation of clozapine for lack of effectiveness during this period would be premature.

The second randomized double-blind trial compared clozapine, olanzapine, and risperidone in 110 patients with schizophrenia or schizo-affective disorder who were selected for being violent.³¹ For reducing overt physical aggression, clozapine was more efficacious than olanzapine, which was, in turn, more efficacious than haloperidol.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) has yielded important information about antiaggressive effects of antipsychotics.³² In the double-blind phase 1 trial, 1445 patients with chronic schizophrenia were randomly assigned to receive 1 of 5 antipsychotics: risperidone, olanzapine, quetiapine, ziprasidone, or perphenazine(Drug information on perphenazine). They were then followed up for 6 months for violent behavior.³³ Violence declined with all medications. The only difference between medications was that perphenazine showed greater violence reduction than quetiapine(Drug information on quetiapine) in some analyses.

Data acquired in the context of the European First Episode Schizophrenia Trial (EUFEST) were used to compare in post hoc analyses the effects of haloperidol, amisulpride(Drug information on amisulpride), olanzapine, quetiapine, and ziprasidone on hostility (assessed as a PANSS item).^34,35 The results showed that at months 1 and 3, olanzapine was significantly superior to haloperidol, quetiapine, and amisulpride in reducing hostility.

Smaller studies, also summarized in the Table, have shown the superiority of risperidone, quetiapine, and aripiprazole in comparison with placebo in terms of antiaggressive efficacy.^36-38 The effects of ziprasidone could not be distinguished from those of other antipsychotics.³³

Thus, randomized controlled trials as well as uncontrolled studies strongly support the superiority of clozapine over other antipsychotics in reducing violent behavior. Emerging evidence suggests that olanzapine may be a good second choice if clozapine cannot be used. However, metabolic adverse effects of these medications must be taken into account when making individual clinical decisions.

Mood stabilizers (anticonvulsants and lithium(Drug information on lithium))

Although not approved by the FDA for impulsive aggression, valproate is frequently prescribed as an adjunctive medication for patients with schizophrenia, perhaps with the expectation that impulse control will be improved.³⁹ Satisfactory efficacy of adjunctive valproate in schizophrenia has been reported, and post hoc analysis of the hostility item of the PANSS has demonstrated valproate(Drug information on valproate) efficacy during the first week of treatment.^40,41 However, these results could not be replicated; thus, the empirical data available do not support the efficacy of valproate as adjunctive treatment for violent patients with schizophrenia.

Lamotrigine has been tested as adjunctive treatment in schizophrenia, with contradictory results.^42,43 Findings from a recent meta-analysis suggest that lamotrigine(Drug information on lamotrigine) may be useful in the most severely ill patients who are clozapine-resistant.⁴⁴

A recent meta-analysis examined the effects of valproate, carbamazepine(Drug information on carbamazepine), and phenytoin(Drug information on phenytoin) in the treatment of aggression with associated impulsivity in various psychiatric disorders. The researchers found that the evidence is insufficient to allow any firm conclusion to be drawn about the use of antiepileptic medication in the treatment of aggression and associated impulsivity.⁴⁵

Another meta-analysis excluded patients with psychosis, organic brain disorder, and mental retardation and, thus, focused mainly on personality disorders.⁴⁶ The effects of valproate, carbamazepine, phenytoin, levetiracetam(Drug information on levetiracetam), and lithium on aggression were analyzed. Some evidence of antiaggressive efficacy was found for carbamazepine, phenytoin, and lithium.

Lithium has been found to reduce aggressive behavior in mood disorders, particularly in bipolar disorder.⁴⁷ There is some evidence of antiaggressive effects of mood stabilizers in personality disorders.

Although mood stabilizer treatment of aggression in schizophrenia is not supported by adequate empirical evidence and is not approved by the FDA, it is possible that it may be effective in some patients. Such use must be weighed against potential adverse effects. The effectiveness of adjunctive treatment must be closely monitored, and the treatment must be promptly discontinued if it fails to show clear benefits.³⁹

SSRIs were reported to reduce aggressive behavior in patients with personality disorders and in the intellectually disabled.^48,49 Adjunctive citalopram(Drug information on citalopram) showed antiaggressive efficacy in persistently violent schizophrenia inpatients in a study that awaits replication.⁵⁰

Summary

Several studies have been undertaken to test the efficacy of drugs in the management of aggression and hostility in patients with schizophrenia and other mood disorders. Clozapine was found to be most efficacious in reducing violent behavior in agitated patients with schizophrenia. However, clozapine is not likely to be fully effective against aggression before an optimal dose (approximately 400 mg/d) is reached, and dose titration may take several weeks. During the initial escalation period, clozapine should not be prematurely discontinued for apparent lack of effectiveness; if necessary, other medications can be added to clozapine temporarily to reduce aggressive behavior. If clozapine is contraindicated, olanzapine may be the second choice. Other antipsychotics do not show any systematic differences in their antiaggressive effects.

References

1. Volavka J. Neurobiology of Violence. 2 ed. Washington, DC: American Psychiatric Publishing, Inc; 2002.
2. Swanson JW, Holzer CE 3rd, Ganju VK, Jono RT. Violence and psychiatric disorder in the community: evidence from the Epidemiologic Catchment Area surveys [published correction appears in Hosp Community Psychiatry 1991;42:954-955]. Hosp Community Psychiatry 1990;41:761-770.
3. Fazel S, Gulati G, Linsell L, et al. Schizophrenia and violence: systematic review and meta-analysis. PLoS Med. 2009;6:e1000120.
4. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 1990;264:2511-2518.
5. Volavka J, Swanson JW, Citrome LL. Understanding and managing violence in schizophrenia. In: Lieberman JA, Murray RM, eds. Comprehensive Care of Schizophrenia: A Textbook of Clinical Management. 2nd ed. New York: Oxford University Press; 2012.
6. Swartz MS, Swanson JW, Hiday VA, et al. Violence and severe mental illness: the effects of substance abuse and nonadherence to medication. Am J Psychiatry. 1998;155:226-231.
7. Greenblatt DJ, Shader RI, Franke K, et al. Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans. J Pharm Sci. 1979;68:57-63.
8. Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med. 1997;15:335-340.
9. Citrome L. Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: a quantitative review of efficacy and safety. J Clin Psychiatry. 2007;68:1876-1885.
10. Lesem MD, Zajecka JM, Swift RH, et al. Intramuscular ziprasidone, 2 mg versus 10 mg, in the short-term management of agitated psychotic patients [published correction appears in J Clin Psychiatry. 2001;62:209]. J Clin Psychiatry. 2001;62:12-18.

Click here for a full list of references

The therapist’s countertransference is making itself known. Gabbard¹ described countertransference as a hallmark of psychodynamic thinking—the patient and therapist have 2 separate subjectivities that interact in a meaningful way during the course of the therapy. The field of study thus involves 2 complex human beings—2 minds—each interacting and mutually influencing the other. The patient is continuously evoking a variety of feelings in the therapist.

The psychodynamic therapist is not a cold scientist devoid of emotion, objectively scrutinizing a human specimen. Rather, he or she is a fellow human being with his or her own conflicts and emotional struggles. He unconsciously experiences the patient as someone from his past at the same time that the patient experiences him as someone from his past.

What sets psychodynamic psychotherapy apart from other modalities of psychotherapy is its emphasis on the use of transference and countertransference to inform the therapy. While there have been many changes in psychodynamic psychotherapy over time, the evolution of our conceptual model of countertransference is one of the most significant.

The narrow view

Psychodynamic therapists have been of “2 minds” about the origins, usefulness, and management of countertransference. The initial view was identified by Freud^2(pp144-145) in 1910, in one of his rare comments on the subject. He wrote:

We have become aware of the “countertransference,” which arises in [the analyst] as a result of the patient’s influence on his unconscious feelings, and we are almost inclined to insist that he shall recognise this countertransference in himself and overcome it. Now that a considerable number of people are practising psychoanalysis and exchanging their observations with one another, we have noticed that no psychoanalyst goes further than his own complexes and internal resistances permit; and we consequently require that he shall begin his activity with a self-analysis and continually carry it deeper while he is making his own observations on his patients. Anyone who fails to produce results in a self-analysis of this kind may at once give up any idea of being able to treat patients by analysis.

This Freudian view came to be known as the “narrow” view, in that it was essentially the analyst’s transference to the patient. Countertransference was a signal that the therapist needed further analysis because its presence was interfering with analysis of the patient.

From this early view, an ongoing debate emerged and has been present in the psychoanalytic literature for the past 100 years. The original Freudian version of countertransference has a somewhat negative connotation, ie, the therapist has countertransference because of unresolved personal conflicts.¹ The implication is that one who is well-analyzed should not have such distractions. This pejorative tone is now considered a relic of the past.

The broad view

In the middle of the 20th century, the concept of countertransference began to broaden to an expanded view that regarded countertransference as the therapist’s total emotional reaction to the patient. In other words, all emotional reactions did not simply reflect the analyst’s unanalyzed conflicts. Some of the analyst’s feelings were induced by the patient and said more about the patient than the analyst.

This expanded definition also served to normalize the concept so that countertransference was not viewed as simply an obstacle to helping the patient or an interference in the therapy, but rather as a source of important information about the patient. With the “broad,” or “totalistic,” view, it became a major therapeutic and diagnostic tool that could tell the therapist a great deal about the patient’s internal world. This theoretical shift within psychoanalysis from a 1-person to a 2-person psychology has legitimized countertransference as a useful part of the therapist’s daily work.

The joint creation view

In recent decades, the polarization of the narrow view and the broad view has lessened because most contributors to the literature recognize that both views may be relevant. In other words, the idea of countertransference as a joint creation that involves contributions from both the therapist’s past and what is induced by the patient has emerged as a common ground.³ Terms such as “projective identification” and “countertransference enactment” have entered the literature to describe this jointly constructed view. Both of these concepts have worked their way into everyday discourse among psychoanalysts and psychodynamic therapists. Both involve similar processes, but the former is derived from Kleinian and object relations thinking, while the latter developed out of the work of American ego psychologists.

Projective identification. The definition of projective identification that has become the preferred way of viewing the construct and is in common usage, although by no means universal, involves 2 steps. A self or object representation is projectively disavowed by the patient, who then unconsciously projects it onto the therapist. This phenomenon occurs through the patient’s interpersonal pressure on the therapist, thus “nudging” the therapist to experience or unconsciously identify with that which has been projected.¹ The first step is a type of transference, whereas the second step can be regarded as countertransference proper.

In view of the broad consensus that projective identification relies on interpersonal pressure, or nudging, rather than on a mysterious passage of mental contents from one party to another, the countertransference response arising in the therapist must be viewed as having been a latent structure that was present and somehow triggered by the patient’s nudging. The previous nature of the therapist’s own conflicts, defenses, and internal object relations will determine whether or not a projection and its recipient are a good “fit.” While projective identification may feel to the therapist like an alien force sweeping over him, what is actually happening is that a buried self or object representation, typically seen as “not me” by the therapist, has been activated by the interpersonal pressure of the patient. Hence a therapist’s usual sense of a familiar, continuous self has been disrupted by the emergence of the repressed aspects of the self.

Symington⁴ described this process as one in which the patient “bullies” the therapist into thinking the patient’s thoughts rather than the therapist’s own thoughts. Part of the reaction to the patient is based on the therapist’s past relationships brought into the present, as in transference. In addition, other aspects of the therapist’s feelings are induced by the patient’s behavior. Through projective identification, the patient re-creates an old “script” from his unconscious in which the therapist plays a principal character from the patient’s drama.³

CASE VIGNETTE

Annie, aged 25 years, starts therapy at the request of her parents, because she continues to abuse alcohol(Drug information on alcohol), does not perform adequately in the family business, and makes irresponsible financial decisions. Over the course of therapy, the therapist, Dr M, takes on a more directive and authoritarian stance when Annie begins to behave in a manner that is reminiscent of how she behaves with her family. In the midst of a session during which Dr M was trying to control the patient’s behavior, Dr M has a sudden flash to her sister’s face during an argument in childhood. The therapist recognizes that there is some resonance between what is happening with her patient and what happened with her younger sister.

In this scenario, there is a perfect “hook” for the therapist that is triggered by the patient’s behavior because of her past relationship with her sister. A therapist with different life experiences and relationships may be more resistant to the pressure to take on the role of punitive parent. Contemporary experiences in the therapist’s life that mirror what is going on in the patient’s life may also trigger intense countertransference feelings. It is commonplace, for example, for a therapist to feel uncomfortable when a patient’s marital conflicts mirror his own.

The key point here is that not all therapists will have the same countertransference responses to the patient. The notion of a “hook” (or lack of it) in the therapist and a good “fit” between patient and therapist implies that the therapist’s internal world will determine to some extent the nature of the response to the patient’s transference.

Ogden^5(p236) made the following observation: “Projective identification is a universal feature of the externalization of an internal object relationship, ie, of transference. What is variable is the degree to which the external object is enlisted as a participant in the externalization of the internal object relationship.” Hence, some therapists may not have their “buttons pushed” by a particular patient as much as another therapist might. Sometimes transferring a patient to another therapist improves the therapeutic situation because the new therapist has an entirely different subjectivity and is not as easily provoked.

Therapists may begin to appreciate that the projective identification is occurring when they begin to experience that they are not acting like themselves. Behaviors and feelings that are uncharacteristic for the therapist should make the therapist curious about the possibility of projective identification. When a therapist begins feeling that “I’m not myself,” he should carefully consider what might be transpiring between him and the patient.

Countertransference enactment. In the 1990s, a number of American ego psychologists began contributing papers on the topic of countertransference enactment in therapy. The term gradually took on a meaning quite similar to projective identification. The fundamental idea was that “enactments occur when an attempt to actualize the transference fantasy elicits a countertransference reaction.”^6(p629) These enactments were often regarded as involving both the narrow form of countertransference and something induced by the patient. Roughton⁷ described this as actualization: subtle forms of manipulation on the part of the patient that induce the therapist to act or to communicate in a slightly special way or to assume a particular role with the patient that silently gratifies the transference wish or, conversely, defends against such a wish.

It is important to acknowledge that countertransference is present in every second of every session. Since countertransference is initially unconscious, sometimes an action, such as forgetting an appointment or ending an appointment early, may be the first sign of it. American ego psychologists have emphasized that there can be acting in by the therapist that parallels the acting in by the patient. The therapist’s actual behavior influences the patient’s transference, while the patient’s actual behavior influences the therapist’s countertransference.

Shifts in countertransference

Because countertransference is ubiquitously present, it is logical that a therapist’s countertransference to a patient shifts over time, rather than remaining static. Just as we now think of multiple transferences instead of “the” transference, we now also think of countertransferences rather than “the” countertransference. In the course of therapy, the countertransference shifts as the therapist plays different roles in the patient’s internal drama.

CASE VIGNETTE

Mr T, a divorced 40-year-old attorney, comes to therapy with Dr K, who sees Mr T as charming and attractive. Dr K feels protective toward him—she sees him as a victim when he describes the dissolution of his romantic relationships. As his sadistic and narcissistic modes of relating are revealed during the course of therapy, her countertransference transitions to a more balanced view. It occurs to Dr K that her transition from a charmed and sympathetic observer to a disenchanted and cynical party to his mistreatment of women parallels the way women in his life experience him.

Thoughtful disclosure of the therapist’s feelings toward the patient can be helpful, although self-disclosure is not generally regarded as a dynamic psychotherapeutic intervention. Most therapists refrain from disclosures about their private lives or about personal problems. However, a specific type of disclosure involving feelings that emerge in the here and now of the therapeutic situation may be highly effective in helping the patient see the effect that he has on others.¹

Because we cannot always be sure what our intentions are when we disclose our feelings to a patient, self-disclosure should be used only when we have reflected on possible consequences that cannot necessarily be foreseen. Talking with a supervisor or consultant to discuss potential unforeseen consequences is generally a wise course of action. Some feelings, however, should probably not be disclosed for fear of burdening the patient unnecessarily or collapsing the analytic space in which the perception of the therapist is in the “as if” realm.¹ Some of these include sexual feelings for a patient and feelings of hate or disgust.

Transference and countertransference are the enactment of the unconscious worlds of 2 minds in the analytic space. Psychodynamic therapists must be aware of these processes at work, accept them, and understand their therapeutic utility. They are what defines what we do as psychodynamic therapists.

Acknowledgment—The author wishes to offer special thanks to Glen O. Gabbard, MD, for his helpful contributions to this article.

References

1. Gabbard GO. Long-Term Psychodynamic Psychotherapy: A Basic Text. Arlington, VA: American Psychiatric Publishing, Inc; 2010.
2. Freud S. The future prospects for psycho-analytic therapy (1910). In: Strachey J, ed. The Standard Edition of the Complete Psychological Works of Sigmund Freud. Vol 11. London: Hogarth Press; 1961:139-151.
3. Gabbard GO. Countertransference: the emerging common ground. Int J Psychoanal. 1995;76(pt 3):475-485.
4. Symington N. The possibility of human freedom and its transmission (with particular reference to the thought of Bion). Int J Psychoanal. 1990;71(pt 1):95-106.
5. Ogden TH. The concept of internal object relations. Int J Psychoanal. 1983;64(pt 2):227-241.
6. Chused JF. The evocative power of enactments. J Am Psychoanal Assoc. 1991;39:615-639.
7. Roughton RE. Useful aspects of acting out: repetition, enactment, and actualization. J Am Psychoanal Assoc. 1993;41:443-472.

Anil is manic with mood-driven behaviors that are so out of control that he meets criteria for an involuntary hospitalization. Janice presents with psychosis—a delusion of impersonation, or Capgras syndrome. For both patients, a factor that will heavily influence treatment decisions, length of stay, medication adherence, need for extra support in the community—indeed the ultimate course of illness—is the patients’ level of insight.

CASE VIGNETTE

Anil, a 20-year-old from India, now a college student in the United States, was involuntarily admitted to the psychiatric inpatient unit in a florid manic state, with rapid speech, flight of ideas, and sleeplessness. Before admission, he had been clocked driving at 100 mph. The intercepting police, noting his abnormal mental status, brought Anil to the emergency department. Mood stabilizer and antipsychotic medication settled him over a week, but he still persisted in believing the police “must have been drunk themselves,” since they assessed him as needing psychiatric help. “I’m not bipolar. Everybody has mood swings!” he insisted. He added, “I will take the medications while I am here, but I am not sure I really need them after I leave.”

Anil clearly does not accept the bipolar disorder diagnosis. Is this part of his illness and a sign that he is not yet stable? Should we trust him in a partial hospital or outpatient program or should he remain on a locked inpatient unit? In view of his lack of insight, does he need a change of medication? What should his family be told about his prognosis, especially if he persists in his denial of illness? Understanding insight is paramount for answering these questions.

CASE VIGNETTE

Janice, a 27-year-old with schizophrenia, stopped taking her prescribed antipsychotic consistently. Within 2 months, her psychotic symptoms returned with full force, and she required hospitalization. She told the admitting psychiatrist that the woman who brought her to the emergency department was not her real mother, but rather “an actress playing her mother.” This misperception had likely played a role in threats she had made toward her mother on the day of admission. Questioned by the psychiatrist as to the plausibility of someone resembling her mother so precisely, she responded, “I don’t know how they did it, but somehow they were able to find someone!” A week after restarting her medication, Janice allowed that her imagination had been “playing tricks on her” and happily embraced her real mother.

Is Janice ready to go home after her week in the hospital? Does she really understand her illness well enough to be allowed to manage her own medications again? Does the risk of violence change the assessment? Should a long-acting injection be prescribed, given her history of nonadherence?

What’s insight got to do with it?

Deficits in insight have implications for numerous clinical inpatient hospitalization issues, including the decision to hospitalize a patient voluntarily or involuntarily in the first place. Other insight-related issues include adherence to treatment after discharge, guardianship/capacity assessments, readiness for discharge decisions, the choice of oral medications versus long-acting depot medication, recommendations for placement in a structured setting after discharge, and the referral of patients to appropriate psychotherapy on hospital discharge.

The etiology of lack of insight has been variously conceptualized as¹:

• Stemming from neuropsychological (brain) deficits

• Part of the primary psychiatric illness itself (eg, poor insight as a symptom of mania)

• A form of defensive denial protecting the patient against the distress of awareness of illness

Regardless of the theoretical model—and it is likely that all apply in different circumstances—the assessment of insight should be detailed and well documented in the clinical record.

A sizable group of clinical researchers, within both psychology and psychiatry, have studied and clarified the concept of insight and its application to clinical states. There is abundant literature on the design and validation of rating scales of insight, and there are studies that correlate deficits in insight with psychiatric diagnoses and with various states of illness.^2,3

A moment’s insight is sometimes worth a life’s experience.
—Oliver Wendell Holmes Jr

Impaired insight is intrinsic to many, if not most, severe psychiatric conditions. Poor insight is a prevalent feature of schizophrenia, and lack of awareness of schizophrenic symptoms is correlated with poor medication adherence and higher rates of recidivism.^4,5 Poor insight is also common in bipolar disorder, and although insight is more state-dependent in bipolar disorder than in schizophrenia, it correlates with poor treatment outcomes.^6,7

Poor insight in mania is not necessarily related to the presence or absence of psychotic symptoms.⁸ Multiple studies have shown correlations between poor medication adherence and lack of insight across diagnostic groupings.³ Assessment of insight has a pivotal role in the decision to give a psychotic patient a long-acting depot medication.⁹

Finally, recent research has expanded into the neuropsychological underpinnings of insight. For instance, the literature suggests that insight deficits in schizophrenia show a greater correlation to the degree of cognitive impairment than to acute psychopathology.¹⁰

Understanding insight

In a general context, meanings assigned to insight generally combine some metaphorical use of terms related to seeing and perception, or words that imply comprehension and self-knowledge. For instance, synonyms for the word “insight” include vision, understanding, awareness, intuition, perception, acumen, comprehension, discernment, and perceptiveness. To illustrate this further, one needs only to note that “insight-oriented psychotherapy” and “insight therapy” are often used interchangeably with other terms for psychodynamic therapies, eg, psychoanalytic psychotherapy, psychodynamically oriented psychotherapy, and even “uncovering therapy.” The insight gained in these therapies can be considered a product of working through of psychological conflict and a concomitant awareness of the self that was previously preconscious or unconscious (the dictionary’s “glimpse or view beneath the surface”).

In contrast to the more comprehensive psychoanalytic concepts, insight has a more circumscribed meaning in the psychiatric mental status examination, especially with severely ill inpatients. In this context, insight refers to awareness of one’s current psychiatric condition or illness, the ramifications of said illness, attribution of the cause of illness, and appreciation of the need for treatment.¹¹ This emphasis on insight into illness is especially fitting in the more severe mental disorders, since much of the research, including the development and validation of rating scales, has centered on schizophrenia, bipolar disorder, dementia and, to a lesser extent, depression.^3,8 Some insight rating scales, which are reviewed in the following section, have only been fully validated for psychotic states.

Patients with Axis II disorders are frequently admitted to acute inpatient units, but the concept of insight in this group is considerably less developed in the general psychiatric insight literature. Assessment of insight in patients with personality disorder can be related to psychodynamic concepts of ego-dystonic and ego-syntonic character traits. Defense mechanisms are also important to consider, since lower-level defenses such as splitting, projection, and externalization lead to the patient’s distorted views of the treatment team, poor recognition of internal emotional states, and lack of awareness of his or her own role in the difficulties that led to hospitalization.

Standardized insight rating scales

Standardized scales of insight have been used in the research setting but are not currently used in common clinical practice. The majority of practicing psychiatrists may not even be aware of the myriad scales that have been developed and validated. Scales are widely used to evaluate levels of insight across various stages of illness, because insight relates to extent of brain pathology (eg, dementia) and correlates with treatment outcomes.^11-13 Although too time-consuming to administer to every patient, a well-chosen insight rating scale could be useful for formally documenting a patient’s insight deficits. Even informally, awareness of the types of questions found on these scales allows a more meaningful assessment of insight than the current general practice in the hospital setting (Table 1).

Sanz and colleagues¹⁴ concluded that there are considerable correlations among the scales; this indicates the construct validity of the concept of insight. Marková³ provides a comprehensive and detailed account of the scales, including historical, philosophical, and clinical dimensions of the entire concept of insight and analysis of the virtues and shortcomings of various insight ratings. Many rating scales are available with which to assess a patient’s insight. The following 7 scales may be useful on the acute psychiatric unit (Table 2).

Item G12. Part of the General Psychopathology section of the Positive and Negative Syndrome Scale (PANSS),¹⁵ Item G12 (lack of judgment and insight), is used separately as an insight scale. The PANSS was developed for use in patients with schizophrenia, and it measures severity of illness and subsequent improvement in trials of new antipsychotic medications. Similar to the other PANSS items, Item G12 is rated on a 7-point scale ranging from “Absent” to “Extreme.” “Mild” applies to patients who recognize their illness but downplay its seriousness and the need for ongoing treatment, ie, have a “mild” lack of insight. “Extreme” applies to patients with blanket denial of illness, delusional interpretation of hospitalization, and lack of cooperation with treatment staff. Item G12 is closely tied to awareness/acknowledgment of psychiatric illness and the need for treatment. Although formally validated in patients with schizophrenia, the anchor points of item G12 can also describe other psychotic illnesses, including severe manic states.

While Item G12 provides brevity and ease of administration, it is neither comprehensive nor practical. However, because it is so brief, this scale could be used at several points during an inpatient admission as a gauge of improvement in insight during the course of treatment.

Schedule for the Assessment of Insight (SAI).¹⁶ Using a semistructured interview, the SAI scores the patient’s insight along 3 dimensions: recognition of illness, recognition of need for treatment, and ability to see that psychotic symptoms (delusions/hallucinations) are not “real” but rather part of the illness. As such, it is also particularly useful in psychotic patients. Using this approach, a psychiatrist might ask questions related to the patient’s interpretation of his psychosis as part of an assessment of insight: “Mr Jones, do you think your voices are coming from a real person or place, or are they related to your illness?”

In the expanded version of the SAI (SAI-E), items are added to more fully address the patient’s awareness of change, practical problems, and symptoms.¹⁴ The original, with 8 items, lends itself to relatively efficient use on the inpatient unit. The longer update is likely a bit unwieldy for day-to-day use but may be appropriate if closer examination is needed. Even if the SAI-E is used occasionally, the 8-item subset of original items could be compared with previous scores for longitudinal assessment.

The Insight and Treatment Attitudes Questionnaire (ITAQ). Developed by McEvoy and colleagues^13,17 specifically for use in patients with schizophrenia, the ITAQ has 11 questions, each scored between 0 (no insight) and 2 (maximum insight). The ITAQ focuses on the patient’s agreement with the assessment of illness and the treatment plan as laid out by the psychiatric treatment team. The psychiatrist’s understanding of the patient’s illness is viewed as the “ideal” and the patient’s degree of congruence with this determines the level of insight. Consultation-liaison psychiatrists may recognize that the concept underlying this approach is similar to that of Appelbaum’s¹⁸ assessment of capacity, in which patients are asked to explain their understanding of the rationale for a given medical procedure and the reasoning behind their refusal of such.

The premise behind the concept of insight in the ITAQ, with its circumscription to the actual treatment situation, can readily be applied to the evaluation of an acutely hospitalized patient. Specifically, this scale would be especially useful in documenting the extent to which the patient agrees with the treatment plan. This domain is increasingly important because of the close scrutiny of third-party payers (sometimes on a daily basis) and the growing emphasis on patient-centered care.

The Patient’s Experience of Hospitalization (PEH). The PEH scale focuses on a hospitalized patient’s position on a continuum from denial of illness to acknowledgment of illness.¹⁹ This component of insight is highly correlated with treatment adherence. The PEH is an 18-item self-report questionnaire that uses a 4-point Likert scale. It is not too unwieldy for occasional use on an inpatient unit. In addition, many of the items can be rephrased as questions and used in the initial clinical evaluation or subsequent progress notes; for example, Item 16: “I think my condition requires psychiatric treatment” rephrased as “Do you think you have a condition that . . . ?”

The primary advantage of the PEH is that because it is self-administered, it takes relatively little of the clinician’s time. Unlike evaluation of symptoms or adverse effects, evaluation of insight really lends itself to self-assessment. Finally, unlike many of the other scales, the PEH has been validated for diagnoses besides psychotic disorders.

The Scale to Assess Unawareness of Mental Disorder (SUMD).^20,21 The SUMD has been validated in schizophrenia and schizoaffective disorder and uses a structured interview administered by trained raters. The SUMD derives from Amador’s complex model of insight and includes a symptom checklist in addition to general items related to awareness of illness, attribution of symptoms to a mental disorder, awareness of effects of medication, and awareness of social consequences of illness. Furthermore, SUMD scoring includes subscales that relate the general items to specific symptom constellations.

This scale is widely used in the literature; however, the complexity of the SUMD, when administered in its entirety, limits its practical application in nonresearch situations. Fortunately, there is an array of studies in which the SUMD was abridged to fit the needs of specific research protocols. One of these abridged SUMDs could be useful on the inpatient unit.

The Beck Cognitive Insight Scale (BCIS).²² The BCIS is a 15-item self-report questionnaire in which patients are asked to rate the degree of their agreement with specific statements. In contrast to other insight scales that focus on awareness of illness, the BCIS assesses the patient’s capacity to evaluate his unusual experiences. Drawing on principles of cognitive-behavioral therapy, the BCIS sees inability to distance oneself from distortions (lack of self-reflectiveness) and difficulty in accepting corrective feedback (self-certainty) as fundamental issues in psychosis.

A cross-comparison study of BCIS scores in schizophrenic spectrum illness and bipolar mania compared with nonpsychotic major depression yielded the expected result of lower index scores (poorer insight) in the former 2 groups.²³ A number of BCIS items can be incorporated as questions into a general insight assessment of psychiatric inpatients. This may be particularly helpful in assessing whether a treated patient is “integrating” or “sealing over” the resolving psychotic experiences²⁴: “Do you think that some of your experiences that have seemed very real may have been due to your imagination?” “Do you think that some of the ideas that you were certain were true may have turned out to be false?”

As with the PEH, the primary advantage of the BCIS is that it is self-administered. It also has been validated over a variety of diagnostic categories. In the scoring scheme (Table 2), the BCIS has the highest score, only losing a point for brevity and a point for practicality. The brevity issue is less relevant, since the patient completes the form on his own.

The Insight Scale (IS). The IS, developed by Marková and colleagues,²⁵ in its most recent form, is a self-report instrument validated for use with patients with schizophrenia. The IS consists of 30 “yes/no” items that are scored as 1 for insight and 0 for no insight, yielding a maximum score of 30. The IS items focus on the patient’s awareness of the changes in subjective experience that occur with psychosis (self-knowledge) and how these changes might affect his interactions and functioning within his environment.

The self-report aspect is useful, and the scale’s seemingly unwieldy length is somewhat tempered by the simple yes/no question structure. The primary limitation of this scale on an inpatient psychiatric unit is the exclusion of items related to the need for treatment. This one issue consumes more clinical time and energy than any other. While some research studies may be better served by this “clean” approach, daily clinical work must consistently include assessment of the patient’s willingness to adhere to treatment recommendations.

Conclusion

The level of insight is virtually always a crucial issue in hospitalized psychiatric patients. Assessment and documentation of insight is thus an important part of the inpatient psychiatric assessment. This determination should include all the components of insight: awareness of illness and its effects, attribution of symptoms to a mental disorder, perception of need for ongoing treatment, and awareness of the achieved effects of current treatment. Insight can be assessed in the course of a typical evaluation or follow-up interview with augmentation by questions borrowed from any of the validated insight rating scales.

Psychodynamic psychotherapy is a widely used treatment for panic disorder, but it has received little systematic assessment.¹⁶ The authors have developed a manualized version of psychodynamic psychotherapy called panic-focused psychodynamic psychotherapy (PFPP).¹⁷ PFPP differs from nonspecific psychodynamic psychotherapy in its focus on symptoms and dynamics of panic disorder. In a recent randomized controlled trial,¹⁸ PFPP demonstrated efficacy for panic disorder in comparison to a less-active psychotherapy called applied relaxation training (ART).¹⁹ This study was the first randomized controlled trial of a manualized psychoanalytical treatment as a sole intervention for panic disorder. This article will describe this treatment and PFPP research studies.

Psychoanalytical concepts

PFPP is based on core psychoanalytical concepts, including the existence and centrality of the unconscious, the relation of defense mechanisms and conflicted wishes to symptom formation, differences between signal and traumatic anxiety, and the importance of transference phenomena. We will discuss these concepts specifically as they relate to the psychodynamic treatment of panic disorder.

From a psychodynamic perspective, symptoms develop in part from unconscious fantasies and conflicts.²⁰ For example, patients with panic disorder often struggle with angry feelings and fantasies, which they experience as threats to important attachment figures.^17,21,22 Although patients are usually aware of some angry feelings, which they commonly find uncomfortable, other unconscious angry or vengeful fantasies that are less tolerable emerge in the course of treatment.

Feelings and fantasies that are experienced as threatening or dangerous are often avoided by unconscious mental processes called defense mechanisms.²³ Certain defense mechanisms are used more frequently by patients with panic disorders. These are reaction formation, undoing, and denial.²⁴ These mechanisms permit the patient to avert recognition of angry feelings toward important love objects and intensify affiliative efforts, with the aim of reducing threats to attachments.

Many aspects of people’s lives, including fantasies, behavior, and symptoms, come about as the result of compromise formations, which are a com- promise between a conflicted wish, often unconscious, and the defense against that wish (also unconscious).²⁰ Panic attacks can represent a compromise between angry and dependent wishes that are expressed through a coercive demand for help and a presentation of helplessness to avoid having to acknowledge rage.

As described by Freud, signal anxiety is a small dose of anxiety that alerts the ego to the presence of wishes and impulses that are felt to be dan-gerous, typically triggering defense mechanisms.²⁵ The failure of defenses to modulate the threat leads to traumatic levels of anxiety, akin to what we call panic attacks. In PFPP, therapists work to help patients recognize and reappraise frightening wishes and fantasies.

In the course of psychotherapy, unconscious conflicts and expectations that the patient has developed with others in the past emerge in the relationship with the therapist (transferance).²⁶ A focus on transference during the course of therapy facilitates articulation of overarching fantasies, permitting the patient to gain more understanding and control of them.

A psychodynamic formulation for panic disorder

A psychodynamic formulation for panic disorder was developed for the purpose of identifying core conflicts to be addressed in a panic-focused psychodynamic treatment. The construction of this formulation from psychoanalytic theory and concepts, including those described above, clinical observations, and more systematic psychological studies, is described in detail elsewhere.^17,21,27,28

The formulation suggests that individuals prone to panic have a fearful dependency on significant others, which is derived from a biochemical vulnerability or traumatic and/or ambivalent relationships with early caregivers that broadly affects their psychological functioning.²⁹ They have a sense of personal inadequacy, and their attachments feel insecure. They often feel they must depend on others to provide a sense of safety, leading separation to be experienced as traumatic. Many patients with panic disorder dread becoming angry at people they love and are frightened that this anger will damage these relationships. A vicious circle of fearful dependency, anger, and anxiety can develop, often triggered by stressors, such as interpersonal loss (Figure 1).³⁰

Panic-focused psychodynamic psychotherapy

Based in part on this formulation, the authors developed a manualized treatment, PFPP.¹⁷ In the PFPP research studies, the treatment consists of 24 twice-weekly sessions. This manualized approach targets core conflicts about anger recognition, ambivalent feelings about autonomy, and fears

of loss or abandonment commonly found in panic disorder. Characteristic psychodynamic techniques of clarification, confrontation, and interpretation are used to elucidate and address these conflicts.

The treatment is divided into 3 phases (Figure 2). In the initial phase, the therapist focuses on identifying the meaning and content of panic symptoms, derived from exploring the circumstances, stressors, and feelings surrounding panic onset. Elucidation of a developmental history, including previous panic episodes, helps determine early life experiences and self and object representations that may play an active part in panic. The initial phase aims at relief of panic symptoms.

In the second phase, the therapist works with the patient to identify core conflicts underlying panic disorder. Conflicts surrounding anger and autonomy, as well as other contributing dynamics, are brought to the patient’s attention. Defense mechanisms, including reaction formation, undoing, and denial, are addressed as efforts—often unconscious—to avoid facing emotional contributions to panic symptoms. Emergence of the transference allows for exploration of these conflicts and defenses in the relationship between therapist and patient. This phase focuses on addressing vulnerability to panic and relapse.

In the third (termination) phase, mixed feelings surrounding anger, autonomy, and separation are addressed as they emerge in ending the therapeutic relationship. The therapist helps the patient articulate feelings about the loss of the therapist, allowing for further recognition of conflicts and a reduced risk of panic recurrence. Increased assertiveness, encouraged by this patient-directed approach, and an increased sense of safety in being more able to tolerate mixed feelings, helps improve psychosocial function.

Although indications for psychodynamic psychotherapy have been described as good verbal skills, psychological mindedness, and a curiosity about the origins of symptoms, panic patients tend to focus on bodily experiences as a way of avoiding frightening feelings and the verbal articulation of conflict. In studies of PFPP, patients have generally responded well despite often limited psychological mindedness.³¹ Patients become engaged in the treatment as the therapist identifies links between feelings and circumstances surrounding panic onset and patients’ emotional lives.

Research on PFPP

PFPP was initially studied in an open trial of 21 patients with primary DSM- IV panic disorder,^32,33 diagnosed on the Anxiety Disorders Interview Schedule for DSM-IV, Lifetime Version (ADIS-IV-L).³⁴

Four patients dropped out of the study. At the end of treatment, 16 of the remaining 17 patients met remission criteria established by the multicenter study of treatments for panic disorder.¹ Patients experienced significant improvements in psychosocial function, depression, and nonpanic anxiety. These improvements were maintained at 6-months follow-up without intervening treatment. Notably, 8 patients who entered the study meeting DSM-IV criteria for comorbid major depression experienced resolution of depression as well as panic.

Our group recently completed a landmark study in which we demonstrated efficacy of PFPP for panic disorder with and without agoraphobia.¹⁸ This was a randomized controlled trial comparing PFPP to a less-active psychotherapy, ART.¹⁹ Inclusion criteria were a diagnosis of primary DSM-IV panic disorder with or without agoraphobia (ADIS-IV-L), with at least 1 panic attack per week. Patients entering the study agreed to stop all nonstudy psychotherapy and to hold their medication constant if they were taking medication (15% of the sample). Patients with comorbid severe agoraphobia, major depression, and DSM-IV personality disorders were included. Exclusion criteria were psychosis, bipolar disorder, and substance abuse (6-months remission necessary).

The Panic Disorder Severity Scale (PDSS) was the primary outcome measure.³⁵ Response was defined as a 40% reduction from baseline on the PDSS.¹ Patients were assessed with the Sheehan Disability Scale (SDS),³⁶ the Hamilton Rating Scale for Anxiety (HAM-A),³⁷ and the Hamilton Rating Scale for Depression (HAM-D).³⁸ Both therapies were of 12 weeks’ duration, with twice-weekly (24 session) interventions. ART included a cognitive explanation about panic disorder, progressive muscle relaxation, cue-controlled relaxation, twice-daily homework, and an exposure protocol.

Psychotherapy sessions were videotaped for adherence monitoring. Both groups demonstrated high levels of adherence to the manualized treatments based on an assessment of 3 videotapes of each therapy using condition-specific adherence measures: the PFPP Adherence Rating Scale (available from the authors) and the ART Adherence Scale.³⁹

No significant demographic or clinical differences were found between the 2 treatment groups at baseline besides sex—more men were in the ART group: 47% versus 15%; 2-tailed Fisher’s exact P < .05 (Table 1). There were no baseline differences between randomized groups in severity of panic disorder, PDSS score, or baseline severity ratings. PFPP had a significantly higher response rate than ART: 73% versus 39%; P = .016 (Table 2); and significantly greater improvement in symptoms of panic disorder: PDSS, P = .002 (Figure 3) and psychosocial function: SDS, P = .014. The 2 treatments did not differ significantly in changes on the HAM-D (P = .07) or in nonpanic anxiety (HAM-A, P = .58).

Only 2 patients in the PFPP group dropped out (7%), an unusually low attrition rate for a randomized controlled trial of panic disorder in the United States, compared with 8 dropouts in the ART group (34%). Patients had good response to treatment despite the inclusion of severe agoraphobia and comorbid depression, making this sample relatively more generalizable than subjects in some other panic disorder outcome studies.^1,2,7,40,41 PFPP performed comparably to clinical trials of cognitive-behavioral therapy (CBT) and medication, but these treatments were not directly compared with one another. Currently, a 2-site study (Cornell, New York and University of Pennsylvania, Philadelphia) is under way comparing PFPP with CBT and ART.

Preliminary moderator analyses of the efficacy study showed that patients with primary DSM-IV panic disorder with comorbid SCID-II-diagnosed Axis II cluster C disorders responded better to PFPP than patients without this comorbidity.⁴² Because panic patients with cluster C comorbidity have not always responded well to CBT,⁴³ PFPP may be of particular value for this population.

Although the results of the PFPP studies are promising, further studies are needed to determine which treatment interventions are most appropriate for any given patient with panic disorder.

Case Vignette

Mr B had onset of severe panic disorder 2 days after his 39th birthday and presented with a score of 12 on the PDSS. In the first phase of treatment, the therapist explored the circumstances surrounding panic onset. Although Mr B acknowledged that he had been “stressed,” he was puzzled about the source of the panic attacks. He focused initially on problems at work: he was not comfortable with the pressure at work since being promoted to leader of his division. As therapy progressed, he started to realize that he had been having some of the symptoms of his subsequent panic attacks for several weeks before their onset when having to reprimand or fire employees. Specifically, he felt tremors in his arms and a sense of loss of control.

Mr B described a difficult background. His father was a temperamental man who was especially intolerant of his son’s early reading and writing difficulties. He described his mother as self-absorbed, often neglecting him. On 3 occasions, his parents sent him away from home, once to relatives and twice to boarding schools, for reasons he did not understand at the time. As a child, he assumed he was sent away because he was “bad,” or he was being punished for losing his temper with his mother. His parents often fought and ultimately divorced.

Although his relationship with his father improved over the years, his mother became a lonely embittered woman who viewed herself as a victim of unfair life circumstances. She pressured Mr B to take care of her, which he experienced as efforts to draw him away from his wife and job. Although he was angry at his mother’s refusal to make efforts to take better care of herself, he felt guilty saying no to her.

Mr B’s panic attacks resolved within the first 6 sessions of PFPP, as he began to recognize that his panic arose as a result of intense fears about confronting his employees that were related to his early separation experiences.

In phase 2, his difficulty in tolerating his anger and his fears of abandonment were explored in more depth. It emerged that Mr B felt frightened about reprimanding his employees, because even though he was the boss, he feared that he would be abandoned or punished, just as he felt would happen if he confronted his mother about her selfish behavior. Mr B’s panic attacks were also triggered by his rage at his employees, particularly one whose victimized stance reminded him of his mother. Unconsciously, he feared both loss of control of his anger (Mr B’s shaking arms during his anxiety and panic) and being abandoned and punished for its expression, which he linked to his being sent away as a child. He had avoided his anger heretofore with reaction formation, taking greater care of his mother while fending off his rage.

In the final phase of treatment, Mr B discussed his frustration and abandonment fears as they emerged in the transference with the therapist. He expressed a concern that the therapist would not be able to tolerate his feelings about leaving the treatment and would become angry with him. Recognizing this transference fear as a fantasy deepened his understanding of the conflicts that had been identified earlier in the treatment. As his fears subsided, Mr B became more effective in his functioning as a boss, and was able to set better limits with his mother. On completion of his 24-session treatment, he had a score of 1 on the PDSS.

References
1. Barlow DH, Gorman JM, Shear MK, Woods SW. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder. JAMA. 2000;283:2529-2536.
2. Craske MG, Brown TA, Barlow DH. Behavioral treatment of panic: a two-year follow-up. Behav Ther. 1991;22:289-304.
3. Craske MG, DeCola JP, Sachs AD, Pontillo DC. Panic control treatment for agoraphobia. J Anxiety Disord. 2003;17:321-333.
4. Otto MW, Tuby KS, Gould RA, et al. An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder. Am J Psychiatry. 2001;158:1989-1992.

Click here for full list of references.

Time is the wisest counselor of all.  —Pericles (495 bc to 429 bc)

This discussion focuses on approaches to improve medication adherence, particularly in reference to helping adolescents remain on recommended psychopharmacological regimens when transitioning from acute to long-term maintenance.

Improving adherence

For physicians, improving patient adherence to medication recommendations has proved to be a complex task. Even patients who have been court-ordered to treatment show limited follow-through.⁴ There is no established evidence-based strategy that improves medication adherence in all cases.⁵ Poor treatment response is a warning sign of nonadherence. When clinical progress is not seen, counseling an adolescent patient about the need for the medication, getting the patient to “buy-in” to the recommended medication(s), and working on the therapeutic alliance will usually result in better adherence than simply switching to another medication, increasing the dosage, or adding another medication.

While the adult literature on nonadherence is considerable, there is a dearth of publications regarding this dilemma in children and adolescents. Two recent articles have proposed theoretical models to help us understand the origins of nonadherence in this population, with suggestions on strategies to improve it.^6,7 Most authors propose similar strategies to improve medication adherence, which generally include discussing with patients the importance of medication, setting up rewards, providing handouts, increasing education of both patient and parents/caregivers, sending reminders about appointments, and using supplementary health care workers in the education process (eg, nurses, social workers, primary care clinicians).⁸ In addition to specific techniques, the regular day-to-day clinical encounters psychiatrists and patients have can do much to augment adherence.

Building patient rapport

Limited communication may contribute to nonadherence; therefore, efforts to build a mutually beneficial rapport should begin during the initial evaluation. Allow enough time to establish an effective communication pattern with the patient. Minimal time spent may lead to the patient’s lack of respect for the clinician and to problems with treatment recommendations. If the initial clinician is not overseeing the long-term maintenance management, the new clinician who becomes involved will need to start building rapport from the beginning.

Therapeutic approaches

Successful treatment requires engaging the young patient in the health care process according to his or her cognitive level and psychiatric diagnosis. The 6 A’s of basic outpatient care are availability, accessibility, approachability, acceptability, appropriateness, and affordability.⁹ Competent caring for an adolescent with a chronic condition will not occur if the clinician is not readily accessible. Evening hours often work well for saturnine youths who may not be appreciative of an early morning visit, when circadian rhythms are not well aligned. If the clinician is not—or does not appear to be—approachable, he or she will not be successful in dealing with a youth’s intimate and complicated mental health issues over the long term. It is difficult to establish a beneficial alliance if the youth finds it difficult to see the clinician or is forced to see one that he does not trust.

The patient should feel that he is liked. Adolescents need a warm and accepting milieu. Malignant attitude problems may come from the young patient or his parents, but they should never arise from the office personnel. Because cost is an increasingly common barrier, the care should be affordable to the patient and family.

Trust of the clinician and the profession in general is a major component for acceptance (and adherence) of psychotropics by children and adolescents.¹⁰ The patient’s parents may also resist use of psychotropics for their child.¹¹ As trust builds, the clinician can more clearly and succinctly explain the need for medications and can overcome the family’s intrinsic distrust of them.^10,11 Failing to engage patients in treatment decisions will often result in treatment nonadherence and, thus, negative outcomes. A power struggle might ensue and result in patients who sabotage treatment efforts.^10,12

As with adult patients, shared decision making is an important component in effectively managing symptoms in young patients.^13,14 Although this may be more complex in psychiatry than in general medicine, shared decision making is necessary for optimal results.¹⁵ More research is clearly needed to understand an adolescent’s experience with and perceptions of recommended psychotropic medications.¹⁶

Western medicine comes out of the Hippocratic tradition, which granted rights to the treating physician on the basis of the long-held belief that the physician would unselfishly and professionally act in the best interests of the patient.^17-20 Twentieth century medicine, based on earlier historical developments in the United States, emphasized the rights of patients. This concept was strongly stimulated by the Nuremberg trials in 1946. The term “informed consent” was first used in a medical malpractice trial in 1957.¹⁷ Even if minors cannot legally provide consent to solidify trust and openness, clinicians should make sure that their patient understands the treatment options and agrees to the choices.¹⁸

It is vital that the patient consents to the treatment or he may sabotage the treatment, refuse to take the recommended medication(s), and weaken the critical therapeutic alliance. Principles of confidentiality must be clearly established and continuously followed for the benefit of all involved—the pediatric patient, his parents/caregivers, and the psychiatrist.^19,20 HIPAA (Health Insurance Portability and Accountability Act) rules must be followed²¹; however, confidentiality is not absolute, and the clinician’s judgment is important.

Adherence-enhancing techniques

Intermittent evaluation of the clinician-patient conversation (ie, the nature of the conversation versus specific therapy) is important and will improve adherence.²² Antagonistic actions, such as coercion and compulsion, can have long-lasting, disastrous results on the therapeutic alliance.²³ Understanding the patient and his motivations for using or not using a medication is important in devising strategies to ameliorate fragile medication adherence.²⁴ Patient education is a key factor in motivating depressed adults to feel better about themselves; the same strat-egy can be used for adolescents.²⁵

New technology (eg, answering questions via e-mail), embraced by most youths, is a powerful communication tool.²⁶ Young patients are often forgetful; thus, strategies such as texting reminders can improve medication adherence.²⁷

The presence of comorbid conditions such as ADHD (Table 2 presents suggestions for management of ADHD), severe family dysfunction, and chronic medical problems complicate medication adherence.²⁸ Comorbidities need to be addressed simultaneously with the presenting disorder.

Inevitably, conflicts arise between the adolescent and the treating clinician—conflicts between adolescents and society have been noted for thousands of years and are not necessarily pathological.²⁹ Plato (427 bc to 347 bc), the great classical philosopher and mathematician, said, “The son feels equal to his father, he has no respect for his parents anymore . . . all he wants to be is free . . . students insult their teachers . . . and on top of this situation, in the name of liberty and equality, sex is everywhere!”³⁰ This master philosopher was simply articulating a classic, yet dour, description of normal, yet inevitable, aspects of adolescence.

CASE VIGNETTES

John, an 11-year-old with ADHD, is readmitted to the psychiatric inpatient unit because of impulsive behaviors that “do not respond to treatment.” His family reports that medications work well in the beginning but soon after they “lose power,” which leads to relapse. On the unit, John is uncooperative, angry, and agitated; does not follow directions; and gets into fights with other patients. He is given a stimulant he had not tried before, and he shows a spectacular improvement. He becomes helpful to staff and his fellow patients to the point that he gets the title of “honorary mental health worker.” Discharge plans involve returning home in 48 hours. On the day before discharge, John begins to exhibit the same type of behaviors that brought him to the unit. These behaviors are initially interpreted as decreased medication effectiveness, and the dose is increased. On the day of discharge, the behaviors become so impulsive that John needs quiet time.

How could it be that such initially spectacular improvement faded away so quickly?

***

Angela, a 12-year-old with ADHD, is on a regimen of a long-acting stimulant in the morning and a short-acting stimulant in the afternoon to help her complete her homework. This regimen has worked well for many months. The child of divorced parents, Angela spends part of the week with her father and part with her mother. She feels very good about taking her medication. However, for the past several weeks, Angela’s performance at school has declined because she has not handed in some of her homework. This has led to an increase in the dose of the short-acting stimulant in the afternoon, which consequently has caused insomnia. Psychotherapeutic work was started to help Angela overcome some oppositional behavior toward certain teachers.

What made a long-stable situation suddenly worsen?

Treatment failures in both cases are related to nonadherence. In John’s case, even when confined to the psychiatric unit, he still managed to avoid taking medication. He had become close to his “fellow” mental health workers, so when they confronted him with the possibility that he may not have been taking his medication, he opened up and shared that he felt “stupid and ashamed” to have to take medicine. This was supportively addressed in the inpatient setting for 2 days and followed up by the outpatient psychiatrist, with good results and improved outcome.

Angela, as it turns out, was cared for by a maternal grandmother on certain days who “did not believe” in medication and would not administer the short-acting stimulant on days that coincided with math and history homework—the two subjects Angela was failing. Once the grandmother was involved in the treatment effort and offered education as well as support, she resolved her opposition to medications and Angela returned to her usual good level of functioning.

References

1. Greydanus DE, Patel DR, Feucht C. Pediatric Psychopharmacology in the 21st Century. New York: Saunders; 2011.
2. Greydanus DE, Calles JL Jr, Patel DR, et al, eds. Clinical Aspects of Psychopharmacology in Childhood and Adolescence. New York: Nova Science Publishers Inc; 2011.
3. World Health Organization. Adherence to long-term therapies: evidence for action; 2003. http://www.who.int/hiv/pub/prev_care/lttherapies/en. Accessed February 22, 2012.
4. Kaplan G, Pannullo D, Brodzinsky D, Hitt JC. Noncompliance with family court mandated evaluations in a juvenile justice clinic. Bull Am Acad Psychiatry Law. 1994;22:31-38.

Click here for full list of references

Jose Miyar and Clive Adams, University of Nottingham, United Kingdom, came to their view through a wide-angle assessment of 10,000 controlled trials conducted in the past 60 years. They suggest that the use of fewer, but standardized, scales to measure outcomes in larger study populations, through multisite collaboration, would have “greater clinical utility and direct value to people with the illness and their families or carers.”

In their analysis of the first 10,000 trials in the Cochrane Schizophrenia Group Register, for which Adams is a coordinating editor, the reviewers characterized most as small (median study population of 60). Many employed new and often nonvalidated outcome scales (2194 different scales, with every fifth trial introducing a new rating instrument).

“Although the trial-to-new-scale ratio has declined,” the reviewers remarked, “we get no impression that it is as a result of exhaustion of the subspecialty to invent and reinvent new scales.”

Miyar and Adams also found that single trials have increasingly been used as a basis for multiple reports, noting that one trial yielded 122 separate “full articles.” While acknowledging that separate reports may be necessary to present complex data sets, to separate the discussion of study protocol from results, or to present follow-up data, the reviewers nevertheless fault what they take to be excessive reporting. Too many reports, they argue, can make it difficult to identify which originate from which trial; can make it appear that there are more data than the trial produced; and can separate and highlight favorable findings from a context of less favorable outcomes.

In addition to advocating larger trials with fewer reports and selected outcome measure instruments, Miyar and Adams suggest that the measures could be selected through collaborative initiatives to determine standardized sets of outcomes. They offer an example in the UK of the COMET (Core Outcome Measures in Effectiveness Trials) initiative.² In that program, the organizers do not preclude the use of unique measures in separate studies. They propose that a “core outcome set” could be evaluated across studies to facilitate results being compared, contrasted, and possibly combined for meta-analysis.

Despite the development and widespread use of several novel pharmacological, psychosocial, and neuromodulatory approaches for bipolar disorder during the past decade, outcomes remain rather disappointing. For example, results from efficacy as well as effectiveness studies indicate that the majority of individuals with bipolar disorder who receive guideline-concordant measurement-based care fail to achieve symptomatic, syndromal, or functional recovery. Moreover, phenomenological studies indicate that the longitudinal course in bipolar disorder largely consists of depressive symptoms and episodes.

Research into bipolar depression symptoms is particularly important because bipolar depression symptoms carry a much higher illness burden—these symptoms are by far more prevalent than manic symptoms.^2-4 This latter observation provides the impetus for developing genuinely novel disease-modifying treatment strategies.

Except for lithium(Drug information on lithium), most treatments for bipolar disorder symptoms were not primarily developed as “antibipolar therapies” (eg, anticonvulsants, conventional unimodal antidepressants). Most were initially used off-label and only later were evaluated in bipolar disorder (eg, atypical antipsychotics). Still others continue to be frequently prescribed off-label (eg, antidepressants). A major limitation to genuinely novel drug discovery in bipolar disorder is the absence of a consensually agreed-on neuropathology as well the unavailability of a sufficient animal model with appropriate face, construct, and pathological and pharmacological validity.⁵

Although the field continues to be preoccupied with the monoamine hypothesis, it is abundantly clear that monoamine dysregulation has never been established as a central disturbance in bipolar disorder and that targeting monoamines is not sine qua non for symptom relief. Other models that have been proposed to exist alongside the monoamine hypothesis include the excitotoxicity, neurotrophic/neuroplasticity, neuroinflammatory, metabolic, and cellular redox (ie, oxidative stress to the cell) models. Novel treatments for bipolar disorder that are a focus of clinical research attempt to target one or more of the effector systems within these pathophysiological models.

Currently, only quetiapine(Drug information on quetiapine), quetiapine XR, and an olanzapine(Drug information on olanzapine)/fluoxetine combination are FDA-approved for the acute treatment of bipolar depression. Although these agents are highly beneficial for some individuals, most fail to sufficiently benefit and/or are intolerant of these agents, which underscores the need for novel alternatives. This article aims to provide a succinct summary of novel pharmacological treatment avenues that are under investigation as treatment for bipolar depression. We present some of these novel treatments according to the overarching disease model that they derive from.

Excitotoxicity

Several lines of evidence suggest that glutamatergic system dysfunction (eg, N-methyl d-aspartate [NMDA] receptor complex) may play a critical role in the pathophysiology of bipolar disorder. In keeping with this view, the use of glutamatergic modulators may be predicted to alleviate symptoms and modify the disease process. Postmortem studies indicate that altered NMDA receptor complexes are observed in the brain tissue of patients with bipolar disorder. Moreover, genetic polymorphisms for genes implicated in the glutamate receptor complex have been associated with this disorder.⁶

Riluzole, an inhibitor of glutamate release, is approved by the FDA for the treatment of amyotrophic lateral sclerosis. This agent, at a dosage of 50 to 200 mg/d, was evaluated in an 8-week add-on study in combination with lithium in 14 adults with bipolar depression, 6 of whom had bipolar I disorder, and 8 of whom had bipolar II disorder. Eight patients completed the 8-week trial.6 Significant improvement in depressive symptoms was noted in weeks 5 through 8 as measured by the Montgomery Asberg Depression Rating Scale (MADRS).

Ketamine is a noncompetitive NMDA antagonist that has been evaluated in subanesthetic doses in persons with bipolar disorder.⁷ Results from a double-blind, randomized, placebo-controlled, crossover study indicate that a single intravenous infusion of ketamine(Drug information on ketamine) combined with lithium or valproate(Drug information on valproate) was capable of alleviating depressive symptoms within 40 minutes of administration when compared with placebo.⁷ The benefit of ketamine was sustained through day 3. Overall, 71% of patients responded to ketamine and 6% responded to placebo at some point during the trial. Ketamine was not associated with significant increases in hypomania or mania but was associated with dissociative symptoms.

Inflammatory network

Abnormal activation in function of the inflammatory network has been implicated as causative and consequential in bipolar depression symptomatology. For example, elevated concentrations of proinflammatory cytokines (interleukin-6 and tumor necrosis factor [TNF]-a) have been implicated in bipolar depression and mania.^8,9 Conventional pharmacotherapy for bipolar disorder (eg, lithium) exerts a modulatory effect on the proinflammatory–anti-inflammatory network.⁸ Proinflammatory cytokines are known to induce behavioral symptoms (eg, anorexia, psychomotor retardation) in humans that are thought to mimic sickness behavior described in animals.⁸

Cyclooxygenase-2 (COX-2) inhibitors have been shown to protect against glutamate-induced neurotoxicity; to prevent normal aging-related increases of cytokines, prostaglandins, and TNF in neurons; and to modulate the hypothalamic adrenal axis.10 The COX-2 inhibitor celecoxib(Drug information on celecoxib) was evaluated as a potential antidepressant in adults with bipolar I/II depression (N = 28).¹⁰ This drug was administered at a dosage of 400 mg daily in combination with a mood stabilizer or antipsychotic medication as part of a 6-week, randomized, double-blind, placebo-controlled study. Depressive symptoms in both the treatment group and the placebo group improved, with a statistically significant (P = .01) advantage at week 1 in patients treated with celecoxib compared with patients who received placebo. Although there was an advantage in favor of the treatment group at week 1, both the active-treatment and placebo groups had similar reductions for each of the remaining observation points.

Taken together, the results suggest that an anti-inflammatory approach may offer a rapid onset of antidepression action in bipolar disorder. More work is needed to replicate/extend or refute these findings, however.

Metabolic action

Neuronal insulin mediates multiple biological actions characterized as metabolic (eg, increases in glucose uptake), neuromodulatory (eg, inhibition of neuronal reuptake of noradrenaline), growth regulatory (eg, promotion of neurite outgrowth and synaptogenesis), and neuroendocrine. For example, insulin modulates the CNS concentration of neuropeptides, monoamines, and other neurotransmitters (eg, acetylcholine) implicated in the pathophysiology of mood disorders, schizophrenia, and Alzheimer disease. Insulin inhibits the firing of neurons in the hippocampus and hypothalamus, inhibits the reuptake of noradrenaline in rat brains, modulates catecholamine turnover in the hypothalamus, stimulates phosphoinositide turnover in the hippocampus, and regulates the noradrenaline and dopamine(Drug information on dopamine) transporter messenger RNA concentration in neurons.

Insulin is transported into the CNS across the blood-brain barrier by a saturable insulin receptor–mediated transport process.^11-13 Long-term potentiation, the neurobiological model of learning, is partially modulated by insulin. Insulin deficiency in diabetic rats triggers a retraction of dendrites and reduces NMDA transmission of hippocampal neurons, with associated decrements in memory performance. Taken together, cellular, molecular, and physiological data indicate that insulin is important for normal (and pathological) memory processes.¹²

Several case reports and case series suggest that insulin sensitizers (eg, rosiglitazone(Drug information on rosiglitazone)) may offer an antidepressant effect in persons with major depressive disorder. Studies are currently under way in bipolar disorder. For example, several studies are evaluating the antidepressant effects of intranasal insulin and insulin secretagogues (eg, incretins) in bipolar disorder. Moreover, there is ongoing research to determine whether weight loss, bariatric surgery, and dietary modification (eg, ketogenic diet) improve depressive symptoms in persons with bipolar disorder.

Antioxidant implications

Available evidence implicates oxidative stress and abnormalities in cellular redox in the pathophysiology of bipolar disorder. Evidence also indicates that lithium and valproate may protect neurons from oxidative stress. Glutathione is an antioxidant distributed throughout multiple tissues; levels of this antioxidant have been reported to be abnormal in individuals with bipolar disorder. Glutathione production rate is limited by its precursor, cysteine(Drug information on cysteine).¹⁴

N-acetylcysteine is the acetylated derivative of cysteine and is more efficiently bioavailable. N-acetylcysteine has been reported to be neuroprotective in preclinical neurodegenerative disease models. Results from a randomized, double-blind, multicenter, placebo-controlled study of adults with bipolar disorder (N = 75) indicate that N-acetylcysteine (1 g bid) adjunctive to usual medications was capable of alleviating depressive symptoms as measured by the MADRS.¹⁴ The benefit on depressive symptoms was noted at week 20 as part of this 24-week study. Benefits were noted by week 8 on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale. N-acetylcysteine did not induce hypomania or mania and was well tolerated. Adverse events reported in more than 15% of the N-acetylcysteine group included change in energy, headaches, heartburn, and increased joint pain.

Modafinil

Modafinil is currently approved by the FDA for improving wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea-hypopnea syndrome and shift work sleep disorder. This drug’s mechanism of action is not fully characterized but is thought to involve multiple neurochemical systems that include dopamine signaling.¹⁵ Modafinil(Drug information on modafinil) at a dosage of 100 to 200 mg/d has been shown to alleviate depressive symptoms when compared with placebo in adults with bipolar disorder across 6 weeks of treatment.¹⁶ Improvement in depressive symptoms was statistically significantly greater (P = .01) in the modafinil group by week 2, with greater response and remission rates. Modafinil was not associated with treatment-emergent hypomania or mania.

Armodafinil is the longer-lasting isomer of modafinil, and its therapeutic indications are similar to those of the racemic agent modafinil. Armodafinil at a dosage of 150 mg/d was evaluated as an antidepressant in adults with bipolar disorder who received either olanzapine, lithium, or valproic acid as part of an 8-week double-blind placebo-controlled study.¹⁷ Patients who received armodafinil exhibited greater improvement of depressive symptoms as measured by the 30-item Inventory of Depressive Symptomatology, Clinician-Rated score. The rate of new-onset hypomania or mania did not differ between groups. The most frequently reported adverse events among armodafinil recipients were headache, diarrhea, and insomnia.

Conclusions

The treatment of adults with bipolar depression may begin with an FDA-approved agent such as quetiapine or an olanzapine/fluoxetine combination. The evidence-based approach to bipolar depression includes treatment with lithium, conventional unimodal antidepressants, lamotrigine(Drug information on lamotrigine), or divalproex. The evidence base does not provide sufficient guidance for next treatment steps in bipolar disorder and, as such, treatment decisions are made empirically. Pharmacological options that are commonly considered are pramipaxole, modafinil, and armodafinil.

Although ketamine and riluzole(Drug information on riluzole) are not considered standard treatments for bipolar depression, they are proof of concept of the role of glutamate systems. These proof of concept studies provide indirect pharmacodynamic support for safer and easier to use treatments that also target glutamate (eg, lamotrigine) in bipolar depression. Results with N-acetylcysteine look promising and could be considered; however, replication in other studies is warranted. Results with omega-3 (not reviewed in this article) are equivocal in bipolar depression but can be considered. The role of exercise, weight loss, and dietary modification are research vista for the future.

Remember that electroconvulsive therapy is a highly effective treatment in bipolar depression and is probably underused in some centers. Results with transcranial magnetic stimulation look promising in bipolar depression; several academic centers are evaluating the role of deep brain stimulation.

As for all patients with bipolar disorder, the pharmacological treatment of bipolar depression is part of a multicomponent chronic disease management approach. A critical component of this model includes psychoeducation and in many cases the provision of manual-based psychotherapy, such as cognitive-behavioral therapy, interpersonal therapy, social rhythm therapy, or family-focused therapy.

References

1. McIntyre RS, Konarski JZ. Bipolar disorder: a national health concern. CNS Spectr. 2004;9(11 suppl 12):6-15.
2. Judd LL, Schettler PJ, Solomon DA, et al. Psychosocial disability and work role function compared across the long-term course of bipolar I, bipolar II and unipolar major depressive disorders. J Affect Disord. 2008;108:49-58.
3. Judd LL, Akiskal HS, Schettler PJ, et al. Psychosocial disability in the course of bipolar I and II disorders: a prospective, comparative, longitudinal study. Arch Gen Psychiatry. 2005;62:1322-1330.
4. Judd LL, Schettler PJ, Akiskal HS, et al. Long-term symptomatic status of bipolar I vs. bipolar II disorders. Int J Neuropsychopharmacol. 2003;6:127-137.
5. Krishnan V, Nestler EJ. Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry. 2010;167:1305-1320.
6. Zarate CA Jr, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57:430-432.
7. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-d-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793-802.
8. Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry. 2009;70:1078-1090.
9. Soczynska JK, Kennedy SH, Goldstein BI, et al. The effect of tumor necrosis factor antagonists on mood and mental health-associated quality of life: novel hypothesis-driven treatments for bipolar depression? Neurotoxicology. 2009;30:497-521.
10. Nery FG, Monkul ES, Hatch JP, et al. Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum Psychopharmacol. 2008;23:87-94.
11. McIntyre RS, Kenna HA, Nguyen HT, et al. Brain volume abnormalities and neurocognitive deficits in diabetes mellitus: points of pathophysiological commonality with mood disorders? Adv Ther. 2010;27:63-80.
12. McIntyre RS, Soczynska JK, Konarski JZ, et al. Should depressive syndromes be reclassified as “metabolic syndrome type II”? Ann Clin Psychiatry. 2007;19:257-264.
13. McIntyre RS, Soczynska JK, Lewis GF, et al. Managing psychiatric disorders with antidiabetic agents: translational research and treatment opportunities. Expert Opin Pharmacother. 2006;7:1305-1321.
14. Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64:468-475.
15. Andersen ML, Kessler E, Murnane KS, et al. Dopamine transporter-related effects of modafinil in rhesus monkeys. Psychopharmacology (Berl). 2010;210:439-448.
16. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164:1242-1249.
17. Calabrese JR, Ketter TA, Youakim JM, et al. Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry. 2010;71:1363-1370.

After detailing what is known concerning the epidemiology of substance abuse among military members and veterans and how substance abuse relates to these other disorders, this article offers some thoughts about the assessment and management of substance use disorders in these populations.

Epidemiology

Considerable knowledge exists about alcohol(Drug information on alcohol) use among military members, some knowledge exists about tobacco use, but only scant data inform us about use of other substances. Even before there were extensive deployments to Iraq and Afghanistan, a large-scale survey found that prevalence of frequent, heavy drinking in the military from 1980 through 2005 ranged from 15% to 20%.¹ A subsequent survey of 88,205 soldiers recently deployed to Iraq showed that 12% to 15% screened positive for alcohol problems.² Rates of binge drinking were 53% in a sample of recently deployed personnel with combat exposure.³

In a 2-item survey of 6527 US Army soldiers who were screened after returning from deployment to Iraq, 27% screened positive for alcohol misuse, and rates of drinking and driving and reporting late to duty because of hangovers were high.⁴ In a separate survey of 1120 recently deployed soldiers, 25% screened positive for alcohol misuse and 12% for alcohol-related behavioral problems. Exposures to life-threatening situations and to atrocities were significantly associated with a positive screen.⁵

A survey of 156 military members deployed to Iraq also found that among men, 51.9% used tobacco before being deployed, and 58.3% used tobacco during deployment. For women, 41.7% used tobacco before being deployed and 51.2% used tobacco during deployment. Stress served as the primary motivating factor for tobacco use among 47.7%; 25.1% blamed boredom and 22.7% blamed addiction. A majority indicated an intention to stop smoking on returning from deployment.⁶ A longitudinal study of 48,304 military members showed deployment as a risk factor for ex-smokers to resume smoking.⁷ Among military veterans, the rate of tobacco smoking in 2007 was estimated at 25% compared with 21% in the general population. For younger veterans, those born between 1975 and 1989, the rate of tobacco smoking was 36% to 37%.⁸

Little information exists on illicit substance use among military members because such use is a crime. If illicit substance use is detected, it typically results in discharge from military service. A large survey suggests that while illicit drug use was common among active duty military members in 1980, it dropped to very low levels by 1992 and has remained low.¹ Articles in the lay press report that opioids are frequently prescribed for pain in active duty military members and that some proportion of the individuals for whom these medications have been prescribed have become addicted to them.⁹ Supporting these anecdotal reports, a survey of 28,546 active duty military members indicated that 11.1% reported misuse of prescription medications in 2008.¹⁰

Data also show increasing use of opioids by veterans. One study found that in 2% of veterans who had received opioid therapy for chronic pain, opioid addiction subsequently developed; this addiction was predicted by the presence of a psychiatric disorder.¹¹ Another study found increasing rates of opioid use for pain among veterans aged 18 through 30 years between 2003 and 2007.¹² Consistent with these data, the number of veterans in whom opioid addiction has been diagnosed has increased in recent years (Table 1).

Table 1 also shows rates of diagnoses of other substance use problems among veterans treated at US Department of Veterans Affairs (VA) medical centers in recent years, with alcohol and cocaine use disorders being the most common. Part of the increase in numbers is accounted for by an overall increase in numbers of veterans seen at VA medical centers, but some of the increase stems from higher proportions of veterans with substance use disorders in the overall VA population. In addition, Table 1 documents the high co-occurrence rates of PTSD among veterans being treated for substance use disorders.

Examining this co-occurrence from a slightly different perspective, Fontana and Rosenheck¹³ used administrative data to examine rates of substance use among veterans enrolled in 86 VA outpatient PTSD programs between 2004 and 2006. They compared veterans of the Iraq and Afghanistan wars with veterans of the first Persian Gulf War and with veterans of the Vietnam War (Table 2). They also compared these groups with cohorts of Persian Gulf War veterans and Vietnam War veterans seen in 105 VA programs from 1992 to 1994 (Table 3).

Consistent with findings from other studies noted above, veterans from the Iraq and Afghanistan wars who seek treatment for PTSD do have high rates of alcohol use disorders compared with the general population, although combat veterans from earlier eras who seek treatment for PTSD have even higher rates of alcohol use disorders and drug use disorders. These findings raise the possibility that Iraq and Afghanistan veterans, like veterans before them, are at risk for an increasing incidence of substance use disorders over the coming years and that aggressive early intervention is warranted now.

Co-occurrence of substance abuse, PTSD, TBI, and pain

It appears that 20% to 30% of military members returning from Iraq or Afghanistan may have a TBI.^14,15 A study of discharges from the active duty military in 1992 found 2243 cases of head injuries in 1,879,724 active duty members. Compared with the non–head-injured military population, discharge rates for alcoholism or drug use were 2.6 times greater for mild TBI and 5.4 times greater for moderate TBI.¹⁶ Subtle frontal lobe impairments with decrements in executive function certainly could make TBI patients more vulnerable to substance abuse.

A systematic review of the association between TBI and pain noted 3 studies of 917 combat veterans with head injury, with 43.1% who complained of pain.¹⁷ One of these studies that examined the relationships between TBI, PTSD, and pain found that among soldiers recently deployed to Iraq, those with mild TBI were significantly more likely to also have PTSD and headache than were soldiers without TBI.¹⁸ In veterans receiving substance abuse treatment, there were high rates of pain complaints, mostly related to musculoskeletal conditions. Pain in this cohort was associated with poorer treatment outcomes and higher health care utilization and costs.¹⁹

Assessment

Ultimately, diagnosis of a substance use disorder or PTSD relies on clinical assessment using DSM criteria. Screening instruments exist that can help uncover or point the way toward a potential diagnosis. For alcohol use disorders, the Alcohol Use Disorders Identification Test (AUDIT) and the AUDIT-Consumption (AUDIT-C) have been widely validated as self-report screening measures.^20,21 A single-item screening measure was recently validated for drug use disorders consisting of the single question, “How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?” A response of 1 time or more yields a positive screen.²²

The PTSD Checklist has well-supported validity as a self-report screening instrument for PTSD.²³ The Clinician-Administered PTSD Scale provides a comprehensive diagnostic assessment of PTSD according to DSM criteria but requires a trained clinician to administer it.²⁴

Screening for and diagnosis of milder forms of TBI use somewhat complex algorithms, and optimal approaches are still being studied.²⁵

Treatment

Overall, military members and veterans with uncomplicated substance use disorders would be expected to respond to the typical behavioral and pharmacological interventions demonstrated to have general effectiveness. In the behavioral realm, various forms of cognitive-behavioral therapy (CBT),²⁶ 12-step facilitation therapy, and contingency management have all been effective in treating veterans.^26,27

Naltrexone and disulfiram(Drug information on disulfiram) have been shown to be beneficial for the treatment of alcohol dependence, as have methadone maintenance and buprenorphine(Drug information on buprenorphine) for opioid dependence.^28-30 Naltrexone(Drug information on naltrexone), particularly the long-acting injectable formulation, warrants further exploration for opioid dependence in veteran populations. Nicotine(Drug information on nicotine) replacement therapy, bupropion, and varenicline(Drug information on varenicline) have also been used successfully for the treatment of nicotine dependence in veterans.^31,32

There is less evidence for the efficacy of these treatments when PTSD complicates the picture of substance use disorder. In regard to behavioral treatments, a common clinical practice has been to provide sequential treatment for both disorders, with the substance abuse treatment coming first. The rationale behind this sequencing relates to the fact that treatments for PTSD, such as prolonged exposure, can be emotionally evocative and distressing and could increase substance abuse as a coping mechanism if stable substance abuse recovery has not already been achieved. However, some developing evidence among civilians with co-occurring PTSD and substance use disorders suggests the opposite, that initial reduction in PTSD symptoms facilitates substance abuse recovery.³³

This finding supports the idea of integrating treatment for co-occurring PTSD and substance abuse in a single package. A form of group CBT, Seeking Safety, was developed to treat the two disorders simultaneously in women.³⁴ Although there is little evidence for its efficacy above what would be obtained with separated treatments, its concept has sufficient appeal to both providers and patients that its clinical application has rapidly expanded to include both female and male veterans.³⁵

McFall and colleagues³¹ recently demonstrated that integrating smoking cessation treatment with mental health care for veterans with PTSD produced significantly better smoking quit rates without any negative impact on PTSD outcomes. The success of this model warrants adapting and testing it for veterans with other substance use disorders.

The FDA-approved medications for PTSD, sertraline(Drug information on sertraline) and paroxetine(Drug information on paroxetine), have shown little benefit for treatment of substance use disorders. Similarly, the FDA-approved pharmacotherapies for alcohol dependence, naltrexone and disulfiram, have been shown to reduce alcohol use compared with placebo in veterans with PTSD and alcohol dependence without causing any adverse effects on PTSD symptoms but also not exhibiting any particular benefit for PTSD.³⁶ Sertraline combined with naltrexone has been found to be effective for co-occurring depression and alcohol dependence, which raises the question of what this combination might do for co-occurring PTSD and alcohol dependence.³⁷

Recent work also provides encouragement that some medications can simultaneously treat substance abuse and PTSD. The antihypertensive medication prazosin(Drug information on prazosin), which blocks a1-adrenergic receptors, has been studied for more than a decade by Raskind and colleagues³⁸ as a treatment for PTSD-related nightmares and other symptoms and has come into fairly widespread use.³⁹ Recently, in a small, double-blind, placebo-controlled trial, prazosin significantly reduced alcohol use in alcohol-dependent men without PTSD, which suggests that it may have independent efficacy for alcohol dependence.⁴⁰ Trials are now under way to explore the efficacy of prazosin for patients with co-occurring alcohol dependence and PTSD.

Topiramate, an anticonvulsant that enhances function of γ-aminobutyric acid, is effective for reducing alcohol use in alcohol-dependent persons.⁴¹ Preliminary work suggests that topiramate(Drug information on topiramate) might also be effective for PTSD.⁴² Should this hypothesis be verified, topiramate could be explored as a single pharmacotherapy for co-occurrence of both disorders. As a cautionary note, topiramate can cause memory impairment so it would have to be used with extreme caution in patients who also have TBI.

Substance abuse treatment for patients with co-occurring TBI and/or pain has not been sufficiently studied. It seems probable that subtle deficits in memory, attention, and impulse control frequently seen in TBI patients would render them less amenable to treatments such as CBT that rely on assimilation of verbal material.¹⁴ Early evidence suggests that patients with TBI and substance use disorders respond well to contingency management.⁴³ It remains to be determined whether integrated treatment for pain and substance abuse would improve outcomes for active troops and veterans who have both problems.

Summary

High rates of substance use problems among active troops and veterans certainly warrant attention, particularly for the younger cohorts of these populations. Intervention now could prevent a lifetime of worsening impairment and disability. The co-occurrence of PTSD, TBI, and pain in active troops and veterans with substance use problems will require future innovations for optimum treatment, since it is not entirely clear that standard treatments for substance use disorders will have sufficient efficacy in persons with this constellation of problems. Careful and complete diagnosis is essential before treatment is initiated.

Although it is time-consuming, is burdensome to patients, is costly, and requires expertise in neuropsychology, assessment and understanding of cognitive deficits present in patients may enhance outcomes and ultimately improve treatment efficiency. Further investigation and implementation of behavioral treatments that address this constellation of disorders simultaneously seems warranted. The additional study of pharmacological interventions that have simultaneous efficacy across these disorders is needed.

References

1. Bray RM, Hourani LL. Substance use trends among active duty military personnel: findings from the United States Department of Defense Health Related Behavior Surveys, 1980-2005. Addiction. 2007;102:1092-1101.
2. Milliken CS, Auchterlonie JL, Hoge CW. Longitudinal assessment of mental health problems among active and reserve component soldiers returning from the Iraq war. JAMA. 2007;298:2141-2148.
3. Jacobson IG, Ryan MA, Hooper TI, et al. Alcohol use and alcohol-related problems before and after military combat deployment. JAMA. 2008;300:663-675.

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