Sadock et al.1 define akinetic mutism as an absence of voluntary motor movement or speech in a patient who is apparently alert. They describe the clinical features as mutism accompanied with limited movement in patients who have their eyes open, will track visual stimuli, and withdraw from painful stimuli.
Since its initial description, numerous cases have been reported in a wide variety of clinical settings.2,3 The common pathophysiology of akinetic mutism appears to be involvement of the mesocortical dopaminergic system, with successful reports of treatment involving dopamine agonists.4
While not completely understood, the main clinical effects of olanzapine appear to be due to dopamine type 2 (D2) receptor blockade in the mesolimbic pathway and serotonin receptor type 2A (5HT2A) blockade with enhanced dopamine release in the mesocortical pathway. In the following three cases, acute onset akinetic mutism was successfully treated with intramuscular olanzapine. We propose that through its indirect elevation of dopamine in the mesocortical pathway, olanzapine represents a novel treatment of akinetic mutism.
Our patient is a 76-year-old Caucasian female who has received multiple treatments of ECT for melancholic depression, with well-sustained remission. Her medical history was significant for pulmonary emboli.
She was admitted to the medicine service with a chief complaint of "failure to thrive," complicated by a urinary tract infection. Treated without incident, she was again diagnosed with major depression, when she began experiencing shortness of breath and tachypnea. Medical evaluation was remarkable for pulmonary emboli and she received an inferior vena caval filter.
A computerized tomography (CT) scan of the brain showed no acute pathology. Over the next 2 days she was oriented to person only. The latency of her speech progressed to the point of being absent. Her face appeared expressionless and she showed extensive psychomotor slowing. Utilizing the Scale for the Assessment of Negative Symptoms (SANS)5 to objectify the degree of affective flattening, this patient’s initial score was 27/35. EEG showed diffuse background slowing suggestive of a mild encephalopathy of undetermined etiology. At this point, her akinetically mute state was treated with olanzapine 2.5 mg h.s. i.m. Within 2 days she was conversant, her affect brightened, and she was no longer akinetic or hypokinetic. She now scored 2/35 on the SANS. Within 5 days her level of cognition had returned to baseline and intramuscular olanzapine was discontinued.
Our patient is a 67-year-old African American male who was admitted after experiencing a grand mal seizure. The relevant history provided by family was that he "abused alcohol."
A CT scan of the head revealed only chronic changes. An EEG on admission was significant for severe slowing with background waves at 2 Hz and isolated sharp waves in the left hemisphere.
Further investigation revealed a reactive serum rapid plasma reagin and CSF VDRL. He was diagnosed and treated for neurosyphilis with intravenous penicillin followed by benzathine penicillin.
We were consulted on day 21 of this admission for management and evaluation of our patient’s "altered mental status." On initial interview, he was found to be awake, tracking visual stimuli, and withdrawing from painful stimuli. However, he remained mute throughout the exam and there was an extreme lack of volitional movement. On initial evaluation, our patient scored 31 out of 35 the SANS. At this point, olanzapine 2.5 mg i.m. t.i.d. was initiated. Forty-eight hours later, while still demonstrating symptoms of delirium, there was a marked increase in volitional movement and he became communicative. At this time, he scored 10 out of 35 on the SANS. Seven days later, olanzapine therapy was discontinued without development of akinetic mutism.
Our third patient is a 54-year-old African American male who we evaluated to assess cognitive ability after a motor vehicle accident. The patient was found unconscious at the scene of the accident but had a Glasgow Coma Scale score of 12 on admission. Limited information was available as to the patient’s baseline cognitive function. Despite multiple fractures and a pneumothorax, the patient was ultimately admitted to the physical medicine unit for impaired mobility. It was during this time that psychiatry was consulted to evaluate his cognition.
Upon initial evaluation, the patient was found to be apathetic and avolitional. While he did not describe his mood as depressed, he would be content to remain seated in his wheelchair, essentially disinterested or unmotivated to do any type of rehabilitation activity. He had an initial SANS score of 30.
Additional laboratory studies revealed no other metabolic causes of akinetic mutism, however, MRI of the head showed two small subdural hematomas over the right anterior frontal lobe. At this point in the hospitalization, the patient was started on 2.5 mg of i.m. olanzapine at bedtime. Two to 3 days later, the patient’s avolition and disinterest improved. He would socialize regularly with the nursing staff, actively sought activities, and demonstrated more goal-directed behavior. His SANS score at this time was 6. Seven days later, olanzapine was discontinued, again without the return of akinetic mutism.
Spontaneity of behavior has been shown to be reproduced in a variety of lesional studies involving the anterior cingulate cortex.6 Thus, the treatment for akinetic mutism can be readily aimed at dysfunction in this region of the brain. When a causative lesion is located in the frontal lobe, favorable responses to L-dopa or dopamine agonists such as bromocriptine have been reported.4,7
In the case of the first patient, it is postulated that the akinetic mute state was caused by infection or pulmonary emboli/hypoxia, although profound depression could not be ruled out as a confounding variable. The exact etiology of our second patient’s akinetic mutism also remains unclear, although it appears that tertiary syphilis and, less likely, a postictal state, might have been involved. In our third patient, a closed head injury was deemed to be related to the symptoms of akinetic mutism. The frontal lobes are extremely vulnerable to injury due to their location at the front of the cranium, proximity to the sphenoid wing, and their large size. MRI studies have shown that the frontal area is the most common region of injury following mild to moderate traumatic brain injury.8
Despite seemingly various possible etiologies and several confounding clinical factors, these cases represent rapid resolution of the symptoms of akinetic mutism (in association with "hypokinetic delirium") with intramuscular olanzapine. Breitbart et al. report efficacy in the treatment of delirium with olanzapine, albeit, the hypokinetic subtype responded less robustly than the hyperkinetic variant (N=79, 43% and 83%, respectively).9 Despite this, underrecognition and misdiagnosis in patients with hypokinetic delirium is not uncommon, possibly resulting in poorer outcomes compared to patients with its hyperactive counterpart.10 The detection and treatment of akinetic mutism as a symptom of delirium could potentially result in lower mortality rates and higher rates of full recovery. It should be stated, though, that given the recent nature of the insults in patients one and three, it is possible that spontaneous resolution of akinetic mutism occurred; Lee et al.11 reported, however, that resolution of similar symptoms typically occurs 3 weeks after the initial insult.
While akinesis and mutism are symptoms of catatonia, our patients did not demonstrate any other signs of motor dysregulation of catatonia. As such, we are admittedly diagnosing akinetic mutism independent of catatonia.8
Olanzapine is indicated for schizophrenia and the manic/maintenance phases of bipolar I disorder.12 It has also been shown to be efficacious in the treatment of negative symptoms involved in schizophrenia which could lie along the continuum of akinetic mutism to include avolition, alogia, and affective flattening. As for its anatomic manifestations, olanzapine increases the levels of dopamine in the medial prefrontal cortex.13 With a broad range of targeted receptors, the mechanism by which this occurs has not been definitively ascertained. One such explanation deals with the interaction of D2 and 5HT2 receptors. Selective blocking of 5HT2 receptors leads to the disinhibition of D2 receptors. If the relative concentration of receptors favors 5HT2, then dopamine levels would rise in such a region of the brain as is postulated in the mesocortical pathway.1 This increase in mesocortical dopamine, especially in the anterior cingulate cortex, could effectively attenuate akinesia and mutism.
In fact, transient mutism has also been reported post resection of cerebellar (astrocytomas) tumors in children. Additionally, Steinlin et al.14 noted that there is a tendency for vermal lesions to produce this neuropsychological symptom. As executive function deficits are also noted in these patients, the authors postulate this pathophysiology involves disruption of fronto-cerebellar pathways, which also could potentially respond to the increase in mesocortical dopamine provided by olanzapine.14 We thus propose that olanzapine and other 5HT2/D2 antagonists may represent novel therapies for akinetic mutism.