Finding the sweet spot for pharmacotherapy in schizophrenia

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Over recent years, the goals in the management of patients with schizophrenia have evolved from simply symptom control to improving and managing functional recovery for the patient, with quality of life increasingly denoted as of paramount important to both patients and clinicians. However, only a small proportion of patients make a full recovery, despite the range of therapies available. Differences in side-effect profiles between treatments has therefore become an important consideration when selecting a treatment. Determining what clinicians can do in order to improve patient functioning in the short and long-term is an ongoing and important discussion.

Improved functioning is recognized in treatment guidelines as an important outcome of therapy in the management of schizophrenia, Sofia Brissos, Lisbon, Portugal, explained to an attentive audience during a satellite symposium at this year’s ECNP.  However, functioning is a complex and multifactorial phenomenon which makes it hard to assess and measure. What is known is that functional capacity declines as the patient’s illness progresses and with each subsequent relapse.

Functioning is recognized in treatment guidelines as an important outcome of therapy in the management of schizophrenia.

Recovery is attainable but requires a tailored, coordinated approach incorporating pharmacological, psychosocial and educational interventions in order to reduce overall disease burden.

 

A spoonful of sugar is just not enough

The problem is, as Greg Mattingly, Missouri, USA, told the audience following a straw poll, everyone hates taking medicines – especially medicines that make them feel bad.  And patients with schizophrenia are no different to the rest of us in this respect.

As with all medications, antipsychotic treatments are associated with a range of side effects, including – in some cases – metabolic issues. The potential for these issues must be addressed with the patient and clinicians must understand potential hesitations of patients in considering treatments that carry with them such potential side effects. Dr Mattingly noted, “would I choose an agent that made me feel hungry all of the time and out of control of my body for myself or someone I loved? No. So why do we do it for our patients?”

 

The active: sedative balance

Activating and sedating effects that are probably among the most ‘bothersome’ side effects experienced overall by patients. Fortunately, some antipsychotics are available that are neither activating nor sedating which may be helpful in overcoming this challenge.  As treatment side effects can have a negative effect on patient functioning and quality of life, striving to optimize symptom control while minimizing side effects is of paramount importance.

Striving to optimize symptom control while minimizing side effects is of paramount importance

The majority of second-generation antipsychotics exert their effects through D2 receptor antagonism and 5-HT2A antagonism. Antagonism at the D2 receptor reduces mesolimbic hyperactivity which reduces the positive symptoms of schizophrenia, but with the potential complication of extrapyramidal symptoms (EPS). Antagonism at the 5-HT2A receptor may reduce the risk of EPS by decreasing dopamine release in the striatum, and may limit excessive prolactin release from pituitary cells by countering the disinhibition by dopamine.

D2 receptor antagonism, however good its efficacy on positive symptoms, may not be the optimal approach towards addressing negative symptoms, cognition, quality of life and well-being – the things than help patients to feel and function better.

 

Finding the sweet spot of better receptor blockade

Ofer Agid, Ontario, Canada, proposed that perhaps there is a sweet spot that better balances receptor blockade for the patient in an effort to control positive symptoms and improve subjective well-being for the patient.

A key factor for D2 partial agonism is determining the optimal level of intrinsic activity at the receptor; too high and the activity is closer to that of an agonist with a potential lack of antipsychotic effect and presence of side-effects such as nausea, vomiting, insomnia and motor effects; too low, and the activity is too close to an antagonist with a potential increased risk of EPS and raised prolactin levels.

 

Partial agonists not only effective but also improve functioning in schizophrenia

As Christoph Correll, New York, USA, reported, all three available D2 partial agonists have been shown to be effective in short- and long-term clinical studies and improvements in patient functioning have been measured in two of the three. Maybe attainment of the sweet spot is closer than we think.

The report is from an ECNP satellite symposium sponsored by Lundbeck and Otsuka.

Symposium references
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