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<p class="ltrs-br-ltr-br-title">Adjuvant Metformin Worsens Psychosis in Schizophrenia: A Case Report</p>
<p class="ltrs-br-ltr-br-body-text"><span class="bold">To the Editor</span>: Metformin has been reported to be a useful add-on medication in reversing metabolic complications due to antipsychotic treatment in schizophrenia patients.<span class="superscript">1</span> However, treatment with metformin can reduce the levels of insulin-like growth factor-1 (IGF-1).<span class="superscript">2</span> Since IGF-1 deficiency might be associated with the pathogenesis of schizophrenia,<span class="superscript">3,4</span> it is possible that metformin treatment might result in worsening of psychosis.<span class="superscript">5</span> In this letter, we provide the first report of a patient with schizophrenia whose psychosis worsened after adjuvant treatment with metformin.</p>
<p class="ltrs-br-ltr-br-body-text"> </p>
<p class="ltrs-br-ltr-br-body-text"><span class="bold-italic">Case report</span>. Ms A, a 20-year-old woman with a diagnosis of schizophrenia (<span class="italic">ICD-10</span>), had experienced onset of symptoms in November 2007. She was treated with risperidone (4 mg/d) and trihexyphenidyl (2 mg/d). She had near total improvement in her symptoms in March 2008 and started attending her college regularly. Over a period of 5 months, she gained 12 kg. She had developed menstrual disturbances, acne, and hirsutism; her serum prolactin level was elevated (141.5 ng/mL); and ultrasonogram revealed polycystic changes in the ovary. In view of these side effects, her risperidone dose was reduced to 3 mg/d in April 2008, and regular physical exercises were advised. </p>
<p class="ltrs-br-ltr-br-body-text">Over the next 1-month period, Ms A maintained clinical improvement but was distressed about her weight gain. Hence, in May 2008, metformin 250 mg/d was added to her treatment. After 2 days, she started experiencing features suggestive of thought broadcast. Metformin treatment was stopped, and her risperidone dose was increased to 3.5 mg/d. Thought broadcast symptoms resolved completely. After 1 week, on repeated request by the patient as well as her family members, metformin was restarted at 250 mg/d and increased to 500 mg/d after a few days, as there was no initial worsening of psychosis. However, after 2 days of treatment with metformin 500 mg, thought broadcast symptoms reemerged, and metformin treatment was stopped. By the next day, these symptoms resolved completely. </p>
<p class="ltrs-br-ltr-br-body-text">Over the 6-month follow-up period (ie, up to December 2008), the patient maintained the clinical improvement with optimal functioning.</p>
<p class="ltrs-br-ltr-br-body-text"> </p>
<p class="ltrs-br-ltr-br-body-text">To the best of our knowledge, this is the first report of adjuvant metformin worsening psychotic symptoms in schizophrenia. Although one might argue that the worsening of symptoms could be a part of the illness course, the following factors make this explanation unlikely: (1) on both occasions, the symptoms were time-locked to either metformin initiation or dosage increase in metformin; (2) the symptoms disappeared completely after metformin treatment was stopped—importantly, during the second time, even with no increase in antipsychotic dosage; and (3) after metformin treatment was stopped, no further psychotic symptoms were observed over the follow-up period of 6 months.</p>
<p class="ltrs-br-ltr-br-body-text">Metformin can decrease IGF-1 level.<span class="superscript">2</span> Recently, antipsychotic-naive schizophrenia patients were demonstrated to have deficient IGF-1 levels, lower than those of healthy controls.<span class="superscript">4</span> Moreover, in that study, the lower the IGF-1 levels, the more severe were the positive symptoms.<span class="superscript">4</span> Although metformin-induced IGF-1 reduction might have played a role in the worsening of psychotic symptoms in this patient, confirmation of this is needed by concurrent assessment of serum IGF-1 in further studies.</p>
<p class="ltrs-br-ltr-br-references-head"><span class="smallcaps">References</span></p>
<p class="references-references-text-1-9"> 1. Wu RR, Zhao JP, Jin H, et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. <span class="italic">JAMA</span>. 2008;299(2):185–193. <span class="pubmed-crossref"><a href="
http://dx.doi.org/10.1001/jama.2007.56-b">doi:10.1001/jama.2007.56-b</a> <a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=18182600&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-1-9"> 2. Fruehwald-Schultes B, Oltmanns KM, Toschek B, et al. Short-term treatment with metformin decreases serum leptin concentration without affecting body weight and body fat content in normal-weight healthy men. <span class="italic">Metabolism</span>. 2002;51(4):531–536. <span class="pubmed-crossref"><a href="
http://dx.doi.org/10.1053/meta.2002.31332">doi:10.1053/meta.2002.31332</a> <a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11912566&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-1-9"> 3. Gunnell D, Holly JM. Hypothesis: do insulin-like growth factors underlie associations of birth complications, fetal and pre-adult growth with schizophrenia? <span class="italic">Schizophr Res</span>. 2004;71(1):191–193. <span class="pubmed-crossref"><a href="
http://dx.doi.org/10.1016/S0920-9964(03)00224-X">doi:10.1016/S0920-9964(03)00224-X</a> <a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15374587&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-1-9"> 4. Venkatasubramanian G, Chittiprol S, Neelakantachar N, et al. Insulin and insulin-like growth factor-1 abnormalities in antipsychotic-naive schizophrenia. <span class="italic">Am J Psychiatry</span>. 2007;164(10):1557–1560. <span class="pubmed-crossref"><a href="
http://dx.doi.org/10.1176/appi.ajp.2007.07020233">doi:10.1176/appi.ajp.2007.07020233</a> <a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17898347&dopt=Abstract">PubMed</a></span></p>
<p class="references-references-text-1-9"> 5. Venkatasubramanian G. Antipsychotic-induced weight gain in patients with schizophrenia. <span class="italic">JAMA</span>. 2008;299(16):1899–1900. <span class="pubmed-crossref"><a href="
http://dx.doi.org/10.1001/jama.299.16.1899-a">doi:10.1001/jama.299.16.1899-a</a> <a href="
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=18430906&dopt=Abstract">PubMed</a></span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Ganesan Venkatasubramanian, MBBS, MD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold"><a href="
mailto:venkat.nimhans@yahoo.com">
venkat.nimhans@yahoo.com</a></span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Rashmi Arasappa, MBBS, DPM</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Naren P. Rao, MBBS, MD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Rishikesh V. Behere, MBBS, MD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Bangalore N. Gangadhar, MBBS, MD</span></p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="bold-italic">Author affiliations:</span> Metabolic Clinic, Department of Psychiatry, National Institute of Mental Health & Neurosciences, Bangalore, India. </p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="bold-italic">Potential conflicts of interest:</span> None reported. </p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="bold-italic">Funding support: </span>None reported.</p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="bold-italic">Published online: </span>April 1, 2010 (<span class="doi">doi:10.4088/PCC.09l00801yel).</span></p>
<p class="ltrs-br-ltr-br-copyright-doi"><span class="italic">Prim Care Companion J Clin Psychiatry 2010;12(2):e1</span></p>
<p class="ltrs-br-ltr-br-copyright-doi"><span class="italic">© Copyright 2010 Physicians Postgraduate Press, Inc.</span></p>
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