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Akathisia: Problem of History or Concern of Today


Naveed Iqbal, MD, Tim Lambert, BSc, MBBS, PhD, FRANZCP, and Prakash Masand, MD


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CNS Spectr. 2007;12(9 Suppl 14):1-16

 

An expert panel review of clinical challenges in psychiatry

This expert roundtable supplement is based on
an i3 CME presentation held February 6, 2007, in
New York City. Both the presentation and this supplement are supported by an educational grant from Bristol-Myers Squibb.

 

Accreditation Statement/Credit Designation

i3 CME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. 

i3 CME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.TM Physicians should only claim credit commensurate with the extent of their participation in the activity.   

The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity is approved for 1 contact hour (0.1 CEU) in states that recognize ACPE. 

To receive enduring credit, you must pass the post test with a score of at least 70% and complete the evaluation form. Statements of CE Credit will be issued by the University of Florida College of Pharmacy upon proof of successful completion of the activity. (Enduring 012-999-06-184-L01).

i3 CME is an approved provider of continuing nursing education by the Utah Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. The participant will be awarded 1 contact hour of credit for attendance and completion of supplemental materials.

i3 CME is approved by the American Psychological Association to sponsor continuing education for psychologists. i3 CME maintains responsibility for this program and its content. The participant will be awarded 1 contact hour of credit for completion of the quiz and evaluation form.

This activity has been approved to provide 1 hour of CE for case managers by the Commission for Case Manager Certification (CCMC).

Target Audience

This activity is designed to meet the educational needs of physicians, pharmacists, nurses, psychologists, and case managers.

Learning Objectives

• Identify main points of the pathophysiology of drug-induced movement disorders with a focus on akathisia
• Recognize the signs and symptoms of drug-induced movement disorders, particularly drug-induced akathisia
• Select an appropriate strategy for preventing or alleviating movement disorders associated with neuroleptic treatment with a focus on akathisia

Faculty Affiliations and Disclosures

Dr. Iqbal is associate professor of clinical psychiatry at Albert Einstein College of Medicine in Bronx, New York, and director of research at Advanced Bio-Behavioral Sciences in Elmsford, New York. Dr. Iqbal is a consultant to and on the advisory boards of Bristol-Myers Squibb, Otsuka, and Janssen; is on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb, Janssen, and Otsuka; and receives grant/research support from AstraZeneca, Bristol-Myers Squibb, Janssen, Memory, Otsuka, and Pfizer.

Dr. Lambert is professor of psychological medicine at the University of Sydney and Head of Schizophrenia Treatments and Outcomes Research at the Brain and Mind Research Institute, Sydney. Dr. Lambert is a consultant to and is on the advisory boards and speaker’s bureaus of Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, AstraZeneca and Mayne Pharma; and receives grant/research support from Bristol-Myers Squibb and Janssen.

Dr. Masand is consulting professor of psychiatry at Duke University Medical Center in Durham, North Carolina. Dr. Masand is a consultant to Alkermes, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Jazz, Organon, Pfizer, Targacept, and Wyeth; is on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Janssen, Pfizer, and Wyeth; and receives grant/research support from AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest, GlaxoSmithKline, Ortho-McNeil, Janssen, and Wyeth.

Acknowledgment of Commercial Support

This activity has been supported by an educational grant to i3 CME from Bristol-Myers Squibb.

To Receive Credit for this Activity

Read this expert roundtable supplement, reflect on the information presented, and take the CME quiz on page 14. Complete the answer form and evaluation on page 15 and return it to: i3 CME, 180 Regent Court, Suite 50, State College, PA 16801.

To obtain credit, you should score 70% or better. Termination date: September 30, 2009. The estimated time to complete this activity is 1 hour.

Abstract

Akathisia is a neurological side effect of antipsychotic medications, which are used to treat various psychiatric disorders. Akathisia is characterized by physical restlessness and a subjective urge to move. Although side effects such as akathisia, dystonia, and dyskinesia are common with the use of conventional antipsychotics, they occur in reduced frequency with the use of new-generation antipsychotics. Despite a lowered incidence profile, akathisia and similar conditions continue to affect patients. Neuroleptic-induced akathisia can present as fidgety movements while seated, rocking in place while standing, pacing, inability to sit or stand still for an extended period of time, and an overwhelming urge to move. These symptoms can cause severe distress and an increased risk of suicide for affected patients. First-line treatment of akathisia includes benzodiazepines or ß-blockers for patients who do not have symptoms of Parkinson’s disease and anticholinergic medications for patients with Parkinson’s symptoms. Clinicians should ensure that an accurate diagnosis of akathisia is made and that target symptoms are decreasing due to treatment. At the same time, it must be ensured that the treatment used does not negatively affect the mental health of the patient. This expert roundtable supplement will address the diagnosis, pathophysiology, phenomenology, classification, and history of akathisia as well as discuss screening tools and treatment options for the condition.

Akathisia: Problem of History or Concern of Today

Introduction   

New-generation antipsychotics have largely replaced conventional medications for the treatment of various psychiatric disorders, largely due to their more favorable neurological side-effect profiles. Adverse events associated with older medications, such as akathisia, are less common with atypical antipsychotics, although they are not completely absent. All of the atypicals have the potential to cause akathisia. In addition, although newer medications are generally better tolerated, they come with their own set of specific side effects. While the focus of this discussion is largely on the neurological side effect akathisia, others of concern to clinicians include metabolic effects, hyperprolactinemia, sexual dysfunction, and extrapyramidal side effects (EPS).

FDA Indications for Atypical Antipsychotics

Atypical antipsychotics are approved by the United States Food and Drug Administration for various indications (Slide 1). For example, risperidone has indications for acute mania and mixed episodes of bipolar disorder, but is not indicated for maintenance treatment of bipolar disorder. Olanzapine and aripiprazole are approved for acute mania and mixed episodes as well as maintenance of bipolar disorder. Quetiapine is not approved for mixed episodes or maintenance, but is approved for acute mania and is the only atypical agent approved for acute depression. Because of their varied FDA indications, it is important for clinicians to understand the differences between these medications and their uses.



Clinicians also often use atypical antipsychotics for off-label purposes, including dementia with agitation and psychosis in the elderly population, a broad spectrum of childhood disorders, treatment-resistant mood disorders, major depressive disorder (MDD), and obsessive-compulsive disorder (OCD). In view of the significant off-label use of atypical antipsychotics for other conditions, many believe the term “antipsychotic” to be a misnomer. The term antipsychotic is also thought to cause patients to be reticent to use these agents for non-psychotic illnesses, such as MDD, OCD, or other treatment-refractory conditions.

Common Side Effects of Atypical Antipsychotics

Atypical antipsychotics have a more favorable side-effect profile than conventional antipsychotics, but they do possess side effects specific to their class. There are ~40 common antipsychotic-induced side effects, including psychic effects such as somnolence and fatigue, and cognitive effects such as neuroleptic-induced deficits. Some of the most well-known are akathisia, parkinsonism, dystonia, weight gain, dyslipidemias, cardiovascular problems, hyperprolactinemia, and sexual dysfunction (Slide 2).



EPS occurs less frequently with second-generation antipsychotics than with conventional antipsychotics: 60% to 65% of patients treated with conventional antipsychotics have experienced EPS.1,2 EPS can include akathisia, dystonia, akinesia, and/or tardive dyskinesia (TD). An analysis of 1-year studies examining second-generation antipsychotics and rates of TD demonstrated that conventional drugs were associated with a 5.2% rate of newly emergent TD symptoms within 1 year of treatment; this rate was 2.1% in patients taking second-generation antipsychotics.3

Confounding variables to these studies include use of non drug-naive patients, which defies the true prevalence of some of these side effects because of pretreatment or other issues. For example, withdrawal TD can occur anywhere from ~6 weeks to 6 months following the cessation of previous treatment, particularly if that treatment was a first-generation medication. While a side effect may be discovered over a 1-year period, it is quite difficult to determine if this incident was not due to prior TD that had been suppressed by previous medication use. The only way to determine true TD prevalence rates for a particular medication is by taking a cohort of first-episode, drug-naive patients and following their progress for 5 years. In the available studies, the rate of TD has been demonstrated to be lower with second-generation drugs—by how much less remains unknown.4

It has consistently been found that dosage—particularly with some of the second-generation antipsychotics—is related to an increased rate of akathisia. However, there are several variables that can significantly impact whether clinicians perceive akathisia to be a result of treatment with second-generation antipsychotics. Some factors clinicians consider is whether the presentation is true akathisia or pseudoakathisia, whether the medication switch occurred too quickly, and whether a psychotic anxiety is present together with the akathisia.

Current Confounds in Akathisia Research

In the past, Parkinsonism was established as a neuroleptic side effect, while clinicians paid little attention to akathisia. Today, many clinicians believe that akathisia is a motor phenomenon and that motor signs must be present for its diagnosis. This poses a problem because the majority of disability suffered by patients is subjective. Although estimation of the subjective components is essential for diagnosis, clinicians often do not ask their patients about it. Because diagnosis is driven by physical symptoms and not the mental problems caused by the desire to move, prevalence rates in studies are typically under-represented.

Another factor that confounds research concerns the point at which akathisia is measured. Many researchers have examined subjective and objective akathisia during an evaluation that generally occurs 2 weeks after establishing treatment with first-generation medications. The average rate at 2 weeks was 39%, which is typically slightly higher in the first week and reduces in severity over the next several weeks (T. Lambert, PhD, unpublished data, 1995). Clinical practice and reviewed studies indicate that 30% may be closer to the actual rate of akathisia measured over a treatment period.5

In addition, all atypical antipsychotics are not the same. Although all of them have the potential to cause akathisia, some may be more likely to cause akathisia and/or other EPS. Different drug classes, particularly serotonin-dopamine antagonists, have a more distinct dose-response curve because they are intensive dopamine blockers with their EPS partially modified at lower doses by serotonin (5-HT)2A blockade. For example, with risperidone, akathisia can be detected beginning at dosages of ~3 mg and increasing from that point. Although olanzapine appears to be relatively EPS-free, onset of akathisia is noted as patients take higher doses. Some of the other serotonin-dopamine antagonists, such as clozapine, are reported to be free of side effects, but clinicians demonstrate clear akathisia in ~7% of patients taking the drug. Side effects also exist with the second-generation antipsychotics, even with faster “on-off” drugs, such as clozapine and quetiapine.6 As doses increase, so does the likelihood of adverse effects.

History of Akathisia

It is thought that akathisia has been recognized in some form for more than a century (Slide 3). The term akathisia derives from the Greek term meaning “not to sit still.” Since the advent of the antipsychotics, the term akathisia is becoming more associated with the use of these medications, despite the fact that the syndrome exists with other drugs and in other neurological states. Theodore Van Putten was the first to identify subtle subjective akathisia as a behaviorally toxic component of psychosis treatment. The condition was identified as one that distresses the patient, causes morbidity, and leads to poor outcomes. This distinction is important because the concept of akathisia has developed over time from a condition of straightforward movement of the legs to a complicated intra-psychic and motor disorder that involves distress.7



While it is now known that subjective aspects may dominate without any motoric abnormality, the diagnosis is often missed because many clinicians still mistakenly believe that akathisia is not present unless the legs are moving. The psychological components of akathisia are often mistaken for other conditions. Clinicians tend to rely more on objective manifestations when it comes to movement disorders. This attitude may be related the narrow diagnostic criteria for akathisia depicted in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).8

Pathophysiology of Akathisia

The pathophysiology of akathisia may involve dopamine, acetylcholine, γ-aminobutyric acid (GABA), norepinephrine, serotonin, and neuropeptides (Slide 4). Dopamine antagonism impacts various neurotransmitters and directly correlates with EPS. For example, dopamine antagonism may affect GABA in the pallidus or norepinephrine in the locus ceruleus (Slide 5).9



Some have questioned whether akathisia is simply a dopamine blockade. While clinicians tend to examine neurotransmitters in isolation, medications often have indirect effects on other neurotransmitters. Therefore, when researchers search for new medications to treat psychosis or schizophrenia, they often focus on medications that do not predominantly produce dopamine blockade but may produce it indirectly through the glutamate system or the GABAergic system or the cholinergic system. For example, adding a 5-HT2A postsynaptic blocker improves negative symptoms, presumably by increasing dopamine in the prefrontal cortex. In this model, EPS defined strictly as rigidity due to Parkinson’s disease improves, although akathisia does not.10 The fact that akathisia prevalence has not changed in such studies suggests that there is an extradopaminergic mechanism involved (Slide 6).



Another factor to consider is that clozapine, a very weakly-bound agent, and quetiapine, which has virtually no features of Parkinsonism at normal doses, may also cause akathisia in the absence of other EPS.11 This suggests that there is another mechanism involved in akathisia.

In addition, tardive akathisia has been reported to improve with moclobemide treatment.12 This indicates that the mechanism involved may be inhibition of adrenergic function in the presence of supersensitive mesocortical dopaminergic systems.

Finally, in the elderly, akathisia can be completely divorced from the appearance of Parkinson’s disease.13 However, some of the treatments currently employed do tend to have an effect on the adrenergic system, rather than the dopamine cholinergic system. Researchers suspect that dopamine blockade is necessary in the development of akathisia but not sufficient to wholly explain this condition. Different areas of the brain and different circuits need to be examined.

Slide 7 illustrates the circuitry that is used to explain EPS.14 There are two pathways out of the basal ganglia—the direct pathway and the indirect pathway. Changes in the direct pathway typically involve consequences that are dyskinetic, while changes in the indirect pathway tend to have consequences related to symptoms of Parkinsonism disease. Unfortunately, there is no clear way of understanding where akathisia fits into this model. There are inputs into the system from 5-HT and the noradrenergic system. However, this model is driven as a GABA system, with dopamine and other neurotransmitters acting as modulators. Because the model offers no explanation for akathisia, many feel that investigators should move away from this model in their current akathisia research. 

Classification of Akathisia

The classification of akathisia continues to be problematic, and there is much disagreement among the experts. Slide 8 lists the symptoms of various classifications of akathisia, including neuroleptic-induced akathisias such as acute akathisia, pseudoakathisia, and chronic akathisias type 1 and 2 as well as other forms of the condition such as hysterial akathisia and spontaneous akathisia.15



Currently, clinicians classify akathisia based on a drug’s akathisic potential, or changing medications that have or do not have akathisic potential. This practice is problematic because clinicians often see chronic akathisia or persistent akathisia. It is difficult for the clinician to determine whether the patient has so-called chronic primary akathisia that was not detected initially but has been present, or late-appearing tardive akathisia that has appeared after some months of treatment.

This is also important because some cases of tardive akathisia may be a form of TD rather than akathisia. Symptoms may be due to withdrawal dyskinesia from previous treatment, or may represent a different type of entity than what clinicians understand akathisia to be in its acute form. There is much debate about the meaning of the tardive akathisic group of symptoms. The symptoms often to not respond like acute akathisia, which suggests involvement of a different mechanism and that these symptoms are from a related family of movement disorders (Slide 9).

Phenomenology of Akathisia

According to the DSM-IV, the essential features of neuroleptic-induced acute akathisia are subjective complaints of restlessness and at least one of the following observed movements: fidgety movements or swinging of the legs while seated, rocking from foot to foot or “walking on the spot” while standing, pacing to relieve the restlessness, or an inability to sit or stand still for at least several minutes.7

Akathisia is thought to consist of three tripartite components—subjective akathisia, distress, and motor phenomena. Subjective akathisia has been reported for a long period of time. An essential component is a subjective feeling of restlessness, which patients can often distinguish from agitation. Many times, patients are able to differentiate between the tremulousness caused by anxiety from that caused by akathisia based on the distinct quality of akathisia. This is similar to what many patients are able to do when they differentiate the feelings of everyday sadness secondary to life events from the distinct quality of the feeling of depression. These symptoms can also lead to severe distress or akathisic distress, which not uncommonly is associated with suicidality.

The motor phenomenon of akathisia may present as moving in the same spot, pacing up and down, and/or being fidgety.8 Depending on which definition a clinician adopts, either within the United States or outside, criteria for the full syndrome would include subjective akathisia plus either distress, motor phenomena, or both.

Some patients can repress their need to move around, which affects the akathisia diagnosis. Interestingly, patients with TD can suppress their movements for short periods if they are forced to do so, although they are involuntary movements. Another interesting aspect of akathisia, discovered in years past, is that patients often lie flat on the floor in hospitals and wards and press their hands and feet to the floor. The patients reported that this behavior was the only way they could cope with the restlessness. They described themselves as “grounding themselves.” Thus, motor phenomena may not always be the same, just as dystonia may fluctuate in presence. However, the subjective component is always present from the beginning (Slide 10, 11).



Akathisic distress is also variable. Some patients have become inured to the subjective feelings of needing to move and have stopped being distressed. These patients may even lose their motor movements to a degree. However, the subjective component stays. Patients who have the motor phenomena and express no subjective concern over the movements at all have pseudoakathisia. These patients may represent a different entity altogether, when compared to acute akathisia.

In severe cases and even moderate cases, patients report experiencing “a horrible feeling,” which causes agitation and spurs them to try to rid themselves of negative energy. Patients’ psychosis can appear to worsen because they are becoming agitated. Many patients begin to increase their substance use to suppress symptoms, which has been linked to increased risk of TD (Slide 12).16,17

Differential Diagnosis of Akathisia

There are various screening instruments available for clinicians to use in diagnosing akathisia. The Barnes Akathisia Rating Scale (BARS) is administered by physicians to assess the severity of drug-induced akathisia (Slide 13). BARS items consist of objective, subjective (awareness of restlessness, distress related to restlessness), and global clinical assessment of akathisia.18 While the BARS scale is probably the most widely used, the tool requires training prior to use. There are a variety of other scales that have also been developed. The large scale-screening tool, General Akathisia Tardive Phenomena and Extrapyramidal Scale (GATES), has two brief spin-off tools that deal with subjective and objective akathisia.19 Slide 14 features the objective component of this tool.



Tardive akathisia is characterized by longer-term akathisia manifestations, which develops after ≥3 months of treatment (Slide 15). It is occasionally confused with chronic akathisia, but the chronic form begins earlier and continues beyond 3 months. Tardive akathisia is accompanied by motor phenomena associated with dyskinesia (which is poorly responsive to anticholinergic treatments). It persists or in some cases, gets worse, when antipsychotic treatment is discontinued or reduced. Tardive akathisia may not be accompanied by subjective akathisia and in that case would be classified by the BARS as pseudo-akathisia.



Other conditions often confused with akathisia include the activation syndrome that clinicians occasionally see with use of atypical antipsychotics, particularly some new partial dopamine agonists. This is most likely not akathisia as patients often do not report subjective statements such as “my legs are pushing me to move around and I need to do this to make myself feel better.” In addition, ß-blockers have no effect for these patients and their responsiveness to benzodiazepines is a time-limited phenomena. The absence of Parkinson’s disease symptoms also suggests this condition is different from akathisia. Akathisia can be differentiated from activation by seeking information from patient about inner, pervasive restlessness, which is very characteristic of akathisia. Progressive restlessness and tremulousness while sitting can help clinicians separate between activation and akathisia.

Drug withdrawal states are common differential diagnoses. Withdrawal from substances such as opiates or cannabis can lead to akathisia-like movement and restlessness. Restless leg syndrome and TD are also mistaken for akathisia (Slide 16).

Treatment Options for Akathisia

Benzodiazepines or ß-blockers are first-line treatments for akathisia. If the clinician believes that the akathisia is a noradrenergic phenomena, a ß-blocker would be considered first. A second choice would be a benzodiazepine at the routine, clinical, standard dose. Careful dose reduction that does not compromise the treatment efficacy is encouraged.
Patients who have symptoms of Parkinsonism together with akathisia (approximately 65% of patients may have both presentations) may respond to anticholinergic medications (Slide 17). The same dose typically used of benztropine or similar medications, should be used for anticholinergic therapy in this situation.



The less common strategies include the 5-HT2 antagonists in the 10–30 mg dose range, 5-HT1 partial agonists, and dopamine reuptake inhibitors (Slide 18).

  

Conclusion

Akathisia has been such an elusive phenomena that a sharp focus on this condition is extremely important. Identifying and diagnosing akathisia can be quite difficult, and standardized scales can be very useful. It is also beneficial to distinguish between different types of akathisia, such as chronic versus spontaneous, in order to determine appropriate treatment. In addition, it is important to distinguish akathisia from activation or psychotic anxiety. Dopamine may not be the only neurotransmitter involved in akathisia. GABA, acetylcholine, and norepinephrine are involved as well. This must be considered in choosing treatment options (Slide 19).



From a clinical point of view, it is essential that clinicians feel comfortable measuring all three components of akathisia—subjective, distress, and motor. Both an interview and examination are necessary, rather than observation alone. Subjective akathisia is typically present before motor signs. A patient may have intense distress with no movements or no subjective distress with severe movement.

Lipophilic ß-blockers (eg, propranolol) are the best treatment for patients who do not have symptoms of Parkinsonism and anticholinergics are best when akathisia is accompanied by Parkinsonian symptoms. In patients with chronic, persistent akathisia or short-term acute akathisia, benzodiazepines are considered first-line treatment followed by clonidine. The treatment model must consider the risk-benefit ratio before undertaking dose reductions or concomitant treatment. The clinician should ensure that target symptoms are in fact decreasing with antidotes—consistent use of instruments is recommended.

References

1. Vieta E, Bourin M, Sanchez R, et al. Effectiveness of aripiprazole v. haloperidol in acute bipolar mania: double-blind, randomised, comparative 12-week trial. Br J Psychiatry. 2005;187:235-242.
2. McIntyre RS, Brecher M, Paulsson B, Huizar K, Mullen J. Quetiapine or haloperidol as monotherapy for bipolar mania--a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. Eur Neuropsychopharmacol. 2005;15(5):573-585.
3. Correl CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of  1-year studies. Am J Psychiatry. 2004;161(3):414-425.
4. Schooler N, et al. Risperdal and haloperidol in first episode psychosis: a long term randomized trial.  Am J Psychiatry. 2005;162:947-953.
5. Jano S, Holi M, Tuiso K, Wahlbeck K. Prevalence of neuroleptic-induced movement disorders in chronic schizophrenia inpatients. Am J Psychiatry. 2004;161:160-163.
6. Catalano G, et al. Acute akathasia associated with quetiapine. Psychosomatics. 2005;46(4): 291-301.
7. Sachdev P. The development of the concept of akathisia: a historical overview. Schizophr Res. 1995;16(1):33-45. 
8. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
9. Casey DE. Pathophysiology of antipsychotic drug-induced movement disorders. J Clin Psychiatry. 2004;65(suppl 9):25-28.
10. Wynchank D, Berk M. Efficacy of nefazodone in the treatment of neuroleptic induced extrapyramidal side effects: a double-blind randomised parallel group placebo-controlled trial. Hum Psychopharmacol. 2003;18(4):271-275.
11. Cohen BM, Keck PE, Satlin A, Cole JO. Prevalence and severity of akathisia in patients on clozapine. Biol Psychiatry. 1991;29(12):1215-1219.
12. Ebert D, Demling J. Successful treatment of tardive akathisia with moclobemide, a reversible and selective monoamine-oxidase-A inhibitor. A case study. Pharmacopsychiatry. 1991;24(6):229-231.
13. Sandyk R, Kay SR. The relationship of tardive dyskinesia to positive schizophrenia. Int J Neurosci. 1991;56(1-4):107-139.
14. Umbricht DS, Kane JM. Understanding the relationship between extrapyramidal side effects and tardive dyskinesia. In: Kane JM, Moller HJ, Awouters F, eds. Serotonin in Antipsychotic Treatment: Mechanisms and Clinical Practice. New York, NY: Marcel Dekker; 1996.
15. Barnes TR, Braude WM. Akathisia variants and tardive dyskinesia. Arch Gen Psychiatry. 1985;42(9):874-878.
16. Potvin S, Pampoulova T, Mancini-Marie A, Lipp O, Bouchard RH, Stip E. Increased extrapyramidal symptoms in patients with schizophrenia and a comorbid substance use disorder. J Neurol Neurosurg Psychiatry. 2006;77(6):796-798.
17. Miller DD, McEvoy JP, Davis SM. Clinical correlates of tardive dyskinesia in schizophrenia: baseline data from the CATIE schizophrenia trial. Schizophr Res. 2005;80(1):33-43.
18. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676.
19. Lambert T. GATES: a new instrument for the clinical and research assessment of neuroleptic-induced movement disorders. Schizophrenia Res. 1998;29(Special Edition):179.  

Question-and-Answer Session

Q: Is it a true statement that akathisia is a predictor of poor response to treatment?

Dr. Iqbal: I think it is very true today. Historically, akathisia was seen as a good prognostic indicator. Today, that pharmacodynamic model does not apply. Patients do not have to present with side effects to demonstrate drug efficacy. These side effects have the potential to increase distress to a level where suicide becomes a high risk. Therefore, akathisia is a poor prognostic indicator.

Q: Atypical antipsychotics are used for treatment-resistant major depression, as in augmentation therapy.  Selective serotonin reuptake inhibitors (SSRIs) are often the primary drug used in these patients, with augmentation of atypicals.  In adding an atypical, what are some of the clinical pearls that clinicians should be aware of in terms of trying to minimize akathisia and side effects?

Dr. Lambert: SSRI use in schizophrenia is very common, with 25% of patients taking an agent from this drug class. SSRIs are also used in the treatment of patients with resistant depression. Researchers have long known that a certain proportion of patients become affected with akathisia when taking SSRIs. Sometimes, the akathisia is mistaken as anxiety or acute anxiety. However, when questioned, patients report that they have an intense need to move. In actuality, these patients have classical akathisia. Then we add a drug (an atypical) that may have an individual small propensity to cause akathisia itself. Together, the synergism is such that they get incredibly distressed. The usual thing the doctor says is that the patient stopped taking the medication. In other words, they become overtly non-adherent.  When factors that can potentially lead to akathisia are noted, such as a patient’s history of akathisia with either drug, one can consider adding benzodiazepines for 10 days.

Dr. Masand:
The other key is that in major depression, the starting dose of the atypicals might need to be much lower than in schizophrenia.

Dr. Iqbal: And I think we should also look at the drug-drug interaction as a factor.  Because even with a smaller dose, a patient might actually have a much higher level of the drug in their blood.

Q: Which of the SSRIs are the most likely to cause the akathisia?

Dr. Iqbal: We do not know of any differences within the SSRIs. All SSRIs, including fluoxetine, paroxetine, sertraline, and citalopram, probably have equal potential to cause akathisia.

Q: I have found that clonidine works well for akathisia. Eighty-five percent of my patients are on clonidine or guanfacine. Yet, this was cited as second-line treatment in the presentation. Can you comment on that?

Dr. Lambert: I am a supporter of clonidine.  Some patients do not respond to anything else. The medication obviously affects the adrenergic system, and it should probably be used a lot more than it is. If a patient does not achieve success with the ß-blockers within a few days, one should move on to a second-line drug very quickly.



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