Can typical and atypical antipsychotics show differential effectiveness in treating paranoia and hallucinations in schizophrenia?

Abstract

A dopamine excess is thought to be involved in positive psychotic symptoms in schizophrenia. All current antipsychotics show a degree of dopamine receptor antagonism. Little is known about the differential effectiveness of different antipsychotics in treating specific sets of symptoms. We report the case of a 35-year-old man with schizophrenia who presented with prominent hallucinatory symptoms (Positive and Negative Syndrome Scale [PANSS] P1=5, P3=5, P6=5) resistant to high doses of a dopamine, serotonin receptor antagonist, olanzapine. Switching from olanzapine to zuclopenthixol, a dopamine D2 receptor antagonist, led to a complete shift of his symptomatology: his hallucinations abated, however, he presented as very highly paranoid (PANSS P1=6, P3=2, P6=7). On a combination of both antipsychotics, his symptoms subsided (PANSS P1=3, P3=2, P6=2). We discuss the potential for differential effectiveness of different antipsychotic medications in treating hallucinations and paranoia. We argue that future studies could address this question by stratifying patients based on symptoms.

Background

Dopamine dysfunction is thought to be the core biological mechanism of positive psychotic symptoms.¹ Acutely psychotic patients on average show elevated presynaptic striatal dopamine availability on positron emission tomography scanning.^{2 3} All currently licensed antipsychotic drugs block striatal D2 receptors at clinical doses, and a threshold striatal D2 blockade is required for most antipsychotics’ effectiveness, however not sufficient—some patients show little improvement despite high D2 receptor occupancy.⁴ Despite the clear relationship that exists between dopamine receptor occupancy and overall effectiveness in treating positive psychotic symptoms, little is known about the differential effectiveness of different antipsychotics in treating specific sets of symptoms. We report of a case which might suggest differential effectiveness of a dopamine D2 receptor antagonist (typical antipsychotic) and of a dopamine D2, serotonin 5-HT2 receptor antagonist (atypical antipsychotic) medication in treating hallucinations or paranoia.

Case presentation

A 35-year-old man of Romani background presented to our clinic following multiple attendances to the emergency department in the last few months. He had been feeling distressed with paranoid thoughts and auditory hallucinations. Our patient presented a strong genetic loading for schizophrenia, as both his brother and his father had died of suicide in the last 3 years following this same diagnosis. He also presented a personal history of high early life stress, having witnessed domestic violence, and having been emotionally, physically and sexually abused in the past. He had a history of severe alcohol and opiate abuse, currently on a detox regimen, and had also been in jail >20 times in his youth for various offences. He was now living with his wife and five children, and had had a few happy and settled years before the death of his close family members.

For the last 9 months, he had been supported by his family while experiencing severe psychotic symptoms. He had attended the emergency services and his general practitioner, where he had been started on olanzapine. While his paranoia had been helped by olanzapine, he was still troubled by hallucinations, and he had himself decided to increase the dose of this medication up to 60 mg per day, a dose that is double the recommended maximum daily dose in the UK.

At this point, he presented to our early intervention in psychosis team clinic complaining of prominent hallucinations, such as seeing his name on number plates followed by ‘X’, which he explained had the meaning of a death threat directed to him; he could also see ‘flashes’, or vivid images of putative future events. He also explained with difficulty that he was hearing unknown male voices ‘showing’ him the flashes. He described hearing a growl that he explained was the Devil. These visions and voices appeared to be the main source of distress at the time. He also presented with paranoid ideation, such as thinking of being watched and followed everywhere he went; the paranoia was not as distressing to him as the hallucinations. He was also distressed by the ‘speed’ of his thoughts, described as racing and not allowing him to rest, even at night. He presented a good degree of insight into his condition, as he recognised the voices as foreign, he accepted that he had a mental health problem and that he needed help. At the time, he scored 24/49 on the positive symptoms sub-scale of the Positive and Negative Syndrome Scale (PANSS), with a score of 5 on the delusions subscale (P1), 5 on Hallucinatory behaviour (P3) and 5 on suspiciousness/persecution (P6).

We recommend that the patient reduce olanzapine and augment it with a dopamine D2 receptor antagonist (typical antipsychotic) medication, in order to harness the sedative potential of such medication to alleviate his racing thoughts, as well as aiming to treat the hallucinations. The patient found it very difficult to follow our recommendations, given his inability to read or write. Therefore, he started oral zuclopenthixol 30 mg twice daily as prescribed but mistakenly stopped olanzapine. He came back to our clinic after 2 weeks, and his presentation had substantially changed: his hallucinations had dwindled, but he was severely paranoid. He interpreted previous medical ailments as a sign of having been poisoned, he was hyperalert as, in his words, ‘everybody is watching me. As soon as I make the wrong move, they will get me and my family. I have been drugged. I am constantly waiting for it to happen’. He was physically preparing to defend himself and his family from an attack and had completely lost insight. Scoring on the PANSS revealed an increased positive symptom score of 29 (P1=6, P3=2, P6=7).

The patient at this point was offered, and agreed, to have zuclopenthixol decanoate in the form of a long-acting depot intramuscular injection (200 mg fortnightly) and to take olanzapine orally 15 mg once daily, dispensed in a dosette box. The subsequent follow-up showed great improvement. He was mildly sedated in the day, but had been sleeping well, had started accepting his wife cook for him as he was not worried about being poisoned anymore and denied experiencing any hallucinations in any form. The PANSS positive symptom score was 12 (P1=3, P3=2, P6=2).

Outcome and follow-up

The patient is now being titrated down to the minimum possible dose of a combination of a typical and an atypical antipsychotic, zuclopenthixol decanoate and olanzapine, in order to maintain clinical effectiveness and reduce sedation.

Discussion

In this case, we report that a patient with prominent positive psychotic symptoms showed differential response to a dopamine D2 receptor antagonist (typical antipsychotic) and a dopamine D2, serotonin 5-HT2 receptor antagonist (atypical antipsychotic) medication. In particular, while his paranoia responded to olanzapine, his hallucinations only showed a good response to zuclopenthixol. This finding is novel to our knowledge and would need to be tested in future studies, to ascertain whether it is just the consequence of the individual biology of this patient or if it can be generalised. In this case, due to the sudden changes in medication over a short period of time, we cannot exclude that the changes we noted could be at least in part mediated by withdrawal effects.

Medicine is now aspiring to offer personalised treatments, therefore potentially the knowledge of differential effectiveness of antipsychotics towards specific sets of symptoms might in future improve patient care.^{5 6}

This case also highlights the challenges in treating patients who, despite their best efforts and a supportive family, struggle to take treatments as prescribed because of illiteracy or chaotic lifestyle. These issues require creative solutions, in our case, the use of injectable long-acting medication and dosette boxes/pill organisers, as provided by our inpatient pharmacy.

A final point concerns the nature of hallucinations. Our patient, despite his illiteracy, reported being able to ‘read’ his name followed by an ‘X’ sign on number plates. This is despite his inability to read or write in his daily life. While he was very concerned by the ominous nature of this sign, he accepted his new-found ability to read without question. The authors note a resemblance between this acceptance of breaking the usual rules of reality in his psychosis and that commonly observed in dreams.

Patient’s perspective.

The patient reported that zuclopenthixol ‘calms me right down, makes it bearable. I do not hear any of the voices any more’. However, when not olanzapine he felt he had ‘eyes on him all the time, burning into me’. When on both medications, he reported feeling ‘better in myself, a lot calmer, not paranoid anymore. The medication is working, I’m doing well’. Regarding compliance, he reported that the dossette box ‘really helps me to know what I’m taking when I open the cupboard’.

Learning points.

• A dopamine D2, serotonin 5-HT2 receptor antagonist (olanzapine), showed partial effectiveness in treating paranoid delusions, which were resistant to zuclopenthixol.

• A dopamine D2 receptor antagonist (zuclopenthixol) showed effectiveness in treating hallucinatory symptoms, which were resistant to olanzapine.

• The combination of zuclopenthixol and olanzapine was effective on both symptoms.

• Trials are needed to ascertain the differential effectiveness of typical and atypical antipsychotic medication in treating different positive symptoms of psychosis.