Concurrent Treatment of Depression and Auditory Hallucinations in a Patient with Schizophrenia

An increasing number of studies are exploring the use of repetitive transcranial magnetic stimulation (rTMS) in the treatment of patients with schizophrenia [1,2]. The major focus of this research has been on the use of low frequency rTMS applied to the temporoparietal cortex of patients who experience treatment refractory auditory hallucinations. Although there are some negative studies, this application of rTMS is supported by a number of positive trials and meta-analyses (for example Freitas et al. [3]). Clearly the most investigated application of rTMS, however, is in the treatment of patients with depressive disorders. There is a considerable body of evidence supporting the use of rTMS in depression (see reviews by Fitzgerald and Daskalakis, and Schonfeldt-Lecuona et al. [4,5]), although these studies have typically excluded patients with comorbidities such as schizophrenia.

This report describes the concurrent treatment of both auditory hallucinations and depression in a patient with refractory schizoaffective disorder.

A 37-year-old female with a long history of psychiatric illness first experienced psychiatric symptoms at the age of eight with the initial onset of her depression. During her teenage years she experienced several prolonged depressive episodes, as well as several episodes of hypomania. During this period she also developed a number of psychotic symptoms at a time when she was not depressed. These included persecutory delusions, passivity delusions and auditory and olfactory hallucinations.

Over a 20 year period since the onset of her psychiatric symptoms, the patient has experienced frequent exacerbations of her illness, and the persistence of residual symptoms without full inter-episodic recovery. She has received treatment with a range of antidepressant, mood stabilizing and antipsychotic medications. Eight months prior to this initial assessment the patient received five ultra-brief right-sided ECT treatments. This resulted in a substantial mood improvement but marked confusion and memory impairment. Her mood relapsed within one month of the cessation of ECT.

At the time of assessment for rTMS the patient was receiving treatment with olanzapine (40 mg per day), lithium (1250 mg per day), venlafaxine (300 mg per day) and thyroxine (50 μg per day). At this point she described marked depressed mood with anhedonia, reduced motivation, energy and concentration, persistent suicidal ideation, hopelessness and insomnia. She described some persecutory beliefs in relation to the possibility others were poisoning her food, and the ongoing experience of second person auditory hallucinations. Although the diagnosis was not clear, the patient described a history of several seizures that occurred in early childhood. These appeared most likely to be febrile convulsions. There was a positive family history of epilepsy. She had undergone several normal EEGs as an adult.

The initial referral was for treatment of her depression. Because of the history of childhood convulsions, the patient was treated with right-sided stimulation using a ‘priming’ protocol [6] rather than high frequency stimulation, as high frequency is more likely to be seizure inducing. The treatment involved the initial application of twenty trains at 6 Hz (5 s duration and 90% of the resting motor threshold), followed by a single 15 min 1 Hz train at 110% of the resting motor threshold. These stimuli were applied to the right dorsolateral prefrontal cortex located 6 cm anterior to the site of maximal stimulation of the contralateral abductor pollicis brevis muscle. She received 25 treatments on consecutive week days as an inpatient. This course of rTMS produced a moderate improvement in her mood, with a reduction in her 17-item Hamilton Depression rating scale (HAMD) [7] score from 18 to 9.

Following discharge, the patient's mood deteriorated relatively quickly. It was notable that in this time frame she was particularly troubled by her auditory hallucinations, which appeared to contribute to the rapid deterioration. A decision was therefore made to provide a repeat course of right-sided low frequency stimulation in conjunction with low frequency stimulation to the left temporoparietal cortex, in an attempt to alleviate the patient's ongoing hallucinations. Prefrontal rTMS for her depression was applied in the same way as the previous course. rTMS was applied to the temporoparietal cortex in a single 15 min 1 Hz train at 100% of her left resting motor threshold. The temporoparietal cortex was identified as the TP3 EEG point as per previous studies (for example Hoffman < et al. [8]).

During the second course of treatment there was clearly dissociation in the response to rTMS of the patient's auditory hallucinations and her depression. After four days of treatment she noticed a dramatic reduction in the frequency and intensity of her hallucinations. These remained almost completely absent throughout the subsequent three weeks of treatment. However, there was no change in mood until approximately 10 days after her voices had almost totally resolved. Mrs CC reported an improvement in her mood which began during the third week and progressively escalated until the end of treatment. At the conclusion of rTMS her scores had decreased on the HAMD from 16 to 8, on the Beck Depression Inventory (II) [9] from 52 to 31, and the Beck Anxiety Inventory [10] from 47 to 22.

The development of therapeutic applications of rTMS has almost exclusively involved the consideration of single cortical targets aimed at alleviating specific syndromes or symptoms. However, psychiatric disorders often present with a variety of concurrent problematic symptoms which frequently do not respond to standard treatments. Patients with schizoaffective disorder often experience problematic mood disturbance as well as ongoing psychosis. These symptoms can be difficult to treat even with optimal antipsychotic and mood altering treatments. This report demonstrates that it is potentially feasible to combine different forms of rTMS, targeted at different symptoms or symptom clusters, in a way that may have overall therapeutic benefit.

One of the most striking aspects of this case was the clear dissociation in the times at which her auditory hallucinations and her depression responded to treatment. It is possible that the earlier response of auditory hallucinations reflected the initial improvement of a psychotic depression, with later mood effects. Both responses may therefore have arisen from prefrontal mood relevant changes. However, given the clear gap between the resolution of psychosis and improvement in mood it seems more likely that the temporoparietal stimulation had a relatively rapid beneficial effect on the patient's hallucinations, independent of the stimulation resulting in mood improvement. This conclusion is supported by the observation that the patient's hallucinations remained severe during her initial course of prefrontal stimulation.

It is also notable that auditory hallucinations were the first symptom to respond. The vast majority of investigations into rTMS for hallucinations have provided only short treatment courses (often 10 sessions; for example [8]) but have relatively consistently shown amelioration of symptoms. In contrast, mood improvement associated with rTMS treatment appears to take longer. This is reflected in the greater effect size seen in more recent clinical trials utilizing longer treatment durations [11].

Whilst these are interesting observations, the clinical application of rTMS for schizophrenia or schizoaffective disorder clearly needs to consider the chronicity of these conditions, which are often characterized by persistent symptoms or frequent relapse. If brain stimulation approaches are to contribute substantively to the treatment of schizophrenia spectrum disorders, longer term maintenance protocols need to be systematically developed and investigated.