Drs McGlashan and Woods Respond to Dr Feinberg

June 28, 2011

Dr Feinberg takes exception to much of what we wrote, or what he thinks we wrote, in our article “Early Antecedents and Detection in Schizophrenia”. We will do our best to reply to his criticisms of what we did write and try to point out where he is shadowboxing at issues that he has created but that we do not hold or endorse.

Dr Feinberg takes exception to much of what we wrote, or what he thinks we wrote, in our article “Early Antecedents and Detection in Schizophrenia”(Psychiatric Times, March 2011, page 48). We will do our best to reply to his criticisms of what we did write and try to point out where he is shadowboxing at issues that he has created but that we do not hold or endorse.

In his seminal 1982 paper on adolescent synaptic pruning, Dr Feinberg1 states that he noted schizophrenia could result from the elimination of “too many, too few, or the wrong synapses” during adolescence. Since that paper, we feel the evidence from multiple sources has substantially endorsed the direction of eliminating “too many” synapses.2 Dr Feinberg did not address this review of the literature, but he challenges the Hoffman/McGlashan2 computer simulation, which illustrates that schizophrenic symptoms can arise from the reduction of too many synapses. Dr Feinberg writes, “However, we could devise other simulations in which the elimination of too few or of the wrong synapses would give rise to these symptoms.” We appreciate that this could be a fair statement if Dr Feinberg had indeed created such “other simulations.” If not, his dismissal of the work of Hoffman and McGlashan that has been done is disingenuous to say the least.3,4

Dr Feinberg criticizes our “suggestion that the early administration of neuroleptics might forestall schizophrenia or diminish its severity” and contends “there are no data showing that these drugs can protect synaptic anatomy or ‘hardware.’” Here Dr Feinberg criticizes a straw man by suggesting that we singularly endorse neuroleptics for people in the prodromal phase of the disorder. That is simply not the case. In our prodromal clinic at Yale, “treatment” consists of the following:

• Having regular meetings with clients and their families

• Tracking the severity of prodromal symptoms over time

• Developing psychotherapeutic and psychoeducational relationships to inform the client and his or her family about the signs and symptoms of risk and to train them in stress management techniques for dealing with risk burdens and pressures

• Providing nonneuroleptic pharmacotherapy for symptoms of anxiety and/or depression

• Choreographing in advance a plan of care in the event of conversion to psychosis (eg, hospitalization, antipsychotic medication)

In short, our treatment package is not “early administration of neuroleptics,” and Dr Feinberg’s truncating it to this level is uninformed, if not inflammatory.

In our clinic, we endorse a treatment strategy of active engagement and carefully following patients who meet risk criteria, for as long as they meet these criteria. Depending on the patient’s degree of distress, his functional disorganization, and the apparent imminence of “conversion” to psychosis, this may or may not include neuroleptics. From Dr Feinberg’s perspective, this may be doing harm, but we maintain that from the long-term risk to benefit perspective, it is better to risk exposing the prodromal patient to stigma and unnecessary treatment than it is to deny risk. Why? Because in false-positive cases, the negative effects of stigma and unnecessary treatment are reversible with time, but in true-positive cases, the onset of psychosis and many of its consequences are not.

Being overly cautious with patients who manifest risk criteria, the adage “first do no harm” can lead to tragic first-psychosis outcomes (witness the recent Tucson shootings). In our clinic, when an antipsychotic prescription is recommended, it is almost always in the context of a clinical trial so that we can generate evidence about the balance of benefits and risks.

Finally, we take issue with what appears to be Dr Feinberg’s overall nihilistic view about the preventive potential of early detection and intervention. His statement about there being no data showing that neuroleptics can protect synaptic anatomy or “hardware” may be correct for “neuroleptics” per se, but it is incorrect for treatment packages that include individual psychotherapeutic and family intervention services in addition to antipsychotic medication.

The Treatment and Intervention in Psychosis (TIPS) project in Norway and Denmark has demonstrated that reducing the duration of untreated psychosis in first-episode schizophrenia with multimodal treatment significantly reduces positive symptoms, negative symptoms, and functional incapacities in the patients who are identified and treated earlier compared with first-episode patients receiving the same treatment only later in the course of the episode. Furthermore, these advantages appear to be permanent. They are apparent at first treatment and at 1 year, 2 years, and 5 years.5-8 It does appear that earlier treatment in the first episode of psychosis may actually “correct synaptic anatomy or hardware.” Given this, there is every reason to believe that still earlier, broad-based interventions during the prodrome may correct or preserve brain hardware even more.

References:

References

1. Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res. 1982-1983;17:319-334.
2. McGlashan TH, Hoffman RE. Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Arch Gen Psychiatry. 2000;57:637-648.
3. Hoffman RE, McGlashan TH. Synaptic elimination, neurodevelopment and the mechanism of hallucinated “voices” in schizophrenia. Am J Psychiatry. 1997;154:1683-1689.
4. Hoffman RE, McGlashan TH. Reduced corticocortical connectivity can induce speech perception pathology and hallucinated “voices.” Schizophr Res. 1998;30:137-141.
5. Melle I, Larsen TK, Haahr U, et al. Reducing the duration of untreated first-episode psychosis: effects on clinical presentation. Arch Gen Psychiatry. 2004;61:143-150.
6. Larsen TK, Melle I, Auestad B, et al. Early detection of first-episode psychosis: the effect on 1-year outcome. Schizophr Bull. 2006;32:758-764.
7. Melle I, Larsen TK, Haahr U, et al. Prevention of negative symptom psychopathologies in first-episode schizophrenia: two-year effects of reducing the duration of untreated psychosis. Arch Gen Psychiatry. 2008;65:634-640.
8. Larsen TK, Melle I, Auestad B, et al. Early detec-tion of psychosis: positive effects on 5-year out-come. Psychol Med. 2010 Oct 14:1-9; [Epub ahead of print].