Treatment of schizophrenia always involves anti-psychotic medications.  No alternatives have been found which has a positive impact without these.  It is possible that a healthy diet is beneficial, although there is almost no research to this effect.  One international study did report that people with schizophrenia in countries with less meat in their diets recovered much faster than in countries with high levels of meat in the diet.  

I do recommend that all patients with schizophrenia take folic acid (800 mcg), vitamin D (1000-2000 IU), magnesium (250-500 mg), and fish oil (2-4 capsules/day).  I have recently added melatonin (6-12 mg) to the list. Each of these is very good for general health with a total cost of about $7/month.  Folic acid has five double-blind study showing benefit with depression and one with schizophrenia.  Both vitamin D and magnesium help prevent diabetes, which a recent VA study of 50,000 patients with schizophrenia found had a 600% higher risk of onset compared to normal adults (4.4% vs. 0.63% annual rate).  Whether diabetes is a medication side-effect or a natural consequence of the disease is unknown.  Magnesium protects against heart arrhythmias.  Several atypical anti-psychotics have reports of prolonged QTc intervals which may cause arrhythmias and anti-psychotics in general have a small, but significantly higher rate of sudden death due to heart arrhythmias.  Fish oil is good for the brain and might help.  All four of these supplements lower heart disease as well as many other beneficial effects.  Melatonin is a powerful anti-oxidant, protective of the brain, and reduces the weight gain effects of some anti-psychotics in animal studies.

Anti-Psychotic Medications

There has been a massive change in the prescribing practices for schizophrenia in the past 12 years with a huge shift from traditional anti-psychotics to what are called the atypical anti-psychotics.  According to more unbiased reviews on the topic, there is either no overall benefit or quite small benefit to the atypicals other than a lower rate of the long-term side-effect of tardive dyskinesia.  The atypicals are much, much more expensive since all traditionals are now available as generics.

In my experience with the traditional anti-psychotics, each patient is unique and finding the right medication can minimize side-effects.  Thioridazine (Mellaril) is rarely used because of a higher rate of a rare heart conduction side-effect.  Thus, the most popular traditionals would be chlorpromazine (Thorazine), perphenazine (Trilafon), loxapine (Loxitane), thiothixene (Navane), haloperidol (Haldol), and fluphenazine (Prolixin).  Most psychiatrists have virtually abandoned all but haloperidol, although there seems to logic to this exclusion of the others.  Because so few patients are now on traditionals, the prices have increased to around $50 per month except for haloperidol at $5 per month.  This said, because I would be viewed as too radical, I don't use these traditional anti-psychotics very much.

Atypical anti-psychotics include clozapine (Clozaril), olanzepine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), zipraxidone (Geodon), aripiprazole (Abilify), and amisulpride.  Clozapine may be somewhat more effective, but it is much more cumbersome to use in view of the danger of serious blood disorder side-effects requiring blood testing every one to two weeks.  Thus, it seems most reasonable to reserve it for patients not responding to the others.  Amisulpride has a long and excellent track record but is not available in the United States.  It can be legally obtained with physician approval via the internet.

My favorite atypical is ziprasidone (Geodon).  It has few side-effects and is the least expensive, especially when given as a once a day dose after initial twice a day treatment.  My other preferences are quetiapine, aripiprazole, and amisulpride because these have fewer serious side-effects.  Both clozapine and olanzepine cause considerable weight gain and sedation in many patients, although they have good effectiveness against psychotic symptoms.  Risperidone causes frequent tremors, although it too is a good medication.  Ziprasidone is the least expensive costing $120/month for the treatment of most patients.  Aripiprazole is definitely not cheap at $270-$370 per month.  The manufacturer of aripiprazole touts its medicine as unique and without the cardiac conduction side-effect of ziprasidone.  However, I have yet to find a report of any patient ever suffering any harmful health outcome from the ziprasidone conduction side-effect and aripiprazole is not all that unique.

The cost of clozapine is $350/month, risperidone $350-550/month, and olanzepine an incredible $350-700/month.  For patients needing these medications, I can help considerably decrease the cost.  I can arrange free medication for indigent patients for some atypicals and I can help obtain inexpensive risperidone and olanzepine from abroad.  Actually, these two are the least expensive at the moment of any atypicals from overseas and can cost as little as $15 a month.  While the big pharmaceutical giants have been quite successful at getting the Republican Bush administration to crack down on Americans buying medications from abroad. And with the new Medicare law, the giants will have the taxpayers to pay top dollar for Medicare and Medicaid patients and employers with drug benefits will also pay top dollar.  Many fewer patients will be trying to import medications, since Uncle Sam (you and I) will be footing the bill.  The drug industry is very happy.

Psychiatric Medication Studies Strongly Rigged in Favor of the Sponsor: In an analysis of 42 head-to-head comparison studies of second-generation antipsychotics, 33 were sponsored by a pharmaceutical company. In 90% of the company studies, the reported overall outcome was in favor of the sponsor's drug. This pattern resulted in contradictory conclusions across studies when the findings of studies of the same drugs but with different sponsors were compared, e.g. Drug A did better than Drug B when the drug was sponsored by Company A, but worse when the study was funded by Company B. Potential sources of bias occurred in the areas of doses and dose escalation, study entry criteria and study populations, statistics and methods, and reporting of results and wording of findings. Why Olanzapine Beats Risperidone, Risperidone Beats Quetiapine, and Quetiapine Beats Olanzapine: An Exploratory Analysis of Head-to-Head Comparison Studies of Second-Generation Antipsychotics. Heres S, et al. Technischen Universitat Munchen, Germany. . Am J Psychiatry 2006 Feb;163(2):185-94. Ed: Corruption is rampant in even prestigious academic centers. 

Early Treatment Helps: Research suggests that the longer the period of time before treatment, the worse off the patients are not only when they come into treatment, but how they respond to treatment. 281 patients were studied in four Scandanavian areas with equivalent treatment programs, but only two of the four areas had early detection programs. These two educated residents, school counselors, and health workers about psychotic symptoms such as increasing isolation, responding to voices no one else hears, delusional thinking, irritability, difficulty sleeping, and overall marked reduction in the ability to cope. The duration of untreated patient psychosis in the two health sectors with early detection programs was shorter -- one month vs. four months. Patients who began treatment earlier were younger, less symptomatic, and more responsive to treatment. Follow-up is ongoing. Thomas McGlashan, et al. Yale, Arch Gen Psychiatry, 2/2004, 61:143-150.

Potency: In Chlorpromazine equivalents: olanzepine = 25, risperidone = 80, quetiapine = 0.5, perphenazine = 14, clozapine = 1.5, haloperidol = 50, thioridazine = 1, fluphenazine = 40, thiothixene = 25, loxapine = 12. In 1998, Boston inpatients rx atypicals 72% of time. Polypharmacy has increased as has average dose although it is still low around 300 CE/d. Harvard, Am J Psychiatry 11/02;159:1932. Ziprasidone = 5

Treatment Guideline for Dosage: 300-1000 chlorpromazine equivalents is the recommended range. Am J Med Qual. 2003 Jul-Aug;18(4):140-6.

Differing Side-Effects: June ’98 survey of NAMI and NMHA affiliated schizophrenic patients surveyed. Of 253 patients, 71% were on atypicals. Traditionals had more tremors (12% vs. 7%) and distress (16% vs. 7%) but atypicals more weight gain (34% vs. 16%), sedation (29% vs. 8%), and sex dysfunction (19% vs. 14%). Peter Weiden, St Luke’s, APA 5/99

Traditional Meds Better Lipid Profile: Atypicals cause higher triglycerides and lower HDLs. Sherley Millet, Bronx, APA 5/99

Traditional vs. Atypical Short-Term: No Difference: A small 20 patient study of acute schizophrenia, half treated with each found no diff at 3 month on BPRS. Neuropsychobiology 2002;45(2):74-80. Hannover Germany

Traditional vs. Atypicals: Meta-Analysis Says Atypicals a Little Better: Strong evidence that risperidone and olanzepine are better but the difference is small, e.g. 59% respond to risperidone but only 52% to conventional neuroleptics. Says superiority of quetiapine, sertindole, and ziprasidone not yet demonstrated.

Traditionals More Cost-Effective in VA Study: study of the cost effectiveness of Zyprexa in treating patients at 17 Veterans Affairs medical centers. Robert Rosenheck, Yale, Zyprexa cost the V.A. $3,000 to $9,000 more per patient, with no benefit to symptoms, Parkinson's-like side effects or overall quality of life. Zyprexa was less likely to produce the physical restlessness called akisthesia, the study found, and was associated with slightly better memory and motor skills. The study was financed by Eli Lilly. APA 5/23/03

Traditionals vs. Atypicals: Review Says Traditional Just as Good: The British Medical Journal says there is no advantage atypicals other than they cause less EPS although both groups were equally in overall side-effects. BMJ 12/2/01 Researchers reviewed 52 DB studies with 12,600 pts. Says traditionals should be 1^st line of treatment

Traditionals vs. Atypicals: Review Finds No Atypical Advantage: A review of the FDA database reports an average decrease of 16.6% of symptoms with atypicals, 17.3% with traditionals, and 40% with anti-depressants (for depression). Khan 2001

Atypicals Better But No Miracle: Atypical anti-psychotics had significantly fewer symptoms of cognitive impairment and hostility/excitement than the traditional group (p < .05). However, self-reported adverse events were similar in the two medication groups, and the groups did not differ significantly on work status. IUPUI rehab patients with 5 year history. J Clin Psychiatry 2002 Feb;63(2):108-16

Atypicals Clozapine, Amisulpride, Risperidone, Olanzepine Said Better: A review of 126 studies comparing traditionals to atypicals through May, 2002, was completed by Univ Illinois psychiatrists. The effect sizes of clozapine, amisulpride, risperidone, and olanzapine were 0.49, 0.29, 0.25, and 0.21 greater than those of FGAs. A meta-analysis of the efficacy of second-generation antipsychotics. Davis JM, Chen N, Glick ID. Arch Gen Psychiatry. 2003 Jun;60(6):553-64

Atypical Somewhat Better than Low Potency Traditionals: As a group, new generation drugs were moderately more efficacious than low-potency antipsychotics, largely irrespective of the comparator doses used. Meta-Analysis found no advantage on EPS except with clozapine. Univ Munich. New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Leucht S, Wahlbeck K, Hamann J, Kissling W. Lancet. 2003 May 10;361(9369):1581-9

Haldol, Olanzapine, Risperidone Did Better than Others in Acute Study: In a 3-week randomized, open-label study of 327 newly admitted patients with schizophrenia, improvement occurred in haloperidol (89%), olanzapine (92%) and risperidone (88%) significantly more effective than aripiprazole (64%), quetiapine (64%) and ziprasidone (64%). However, changes in BPRS ratings were not significant among treatments. Comparative effectiveness of second-generation antipsychotics and haloperidol in acute schizophrenia. McCue RE, et al. Brooklyn, New York. . Br J Psychiatry 2006 Nov;189:433-40.

Schizophrenia First-Episode with Drug Abuse Slower to Improve: Study of 49 1^st episode schizoophrenics without drug abuse vs. 12 with alcohol or drug abuse found 13 week median to rx response without and 24 weeks with alcohol or drug abuse. Rosalind Hoffman, Hillside, APA 5/99. Also, substance abusing schizophrenics had their 1^st hospitalization at earlier age (21 vs. 25) and more hospitalizations (15 vs. 11) and were 80% male in study by Paul Kettl. APA 5/99

Bedtime Dosing OK with a Short-Acting Atypical Quetiapine (Seroquel): A study of 21 stable schizophrenics on 400-600mg/d found only 15% of patients had an increase in symptoms or problems with hypotension when switched to HS dosing. A random-assignment, double-blind, clinical trial of once- vs. twice-daily administration of quetiapine fumarate in patients with schizophrenia or schizoaffective disorder: a pilot study. Chengappa KN, Parepally H, Brar JS, Mullen J, Shilling A, Goldstein JM. Can J Psychiatry. 2003 Apr;48(3):187-94

What Helps: All standard anti-psychotics including amisulpride. Also, allopurinol, folate, fish oil, glycine, gingko, clonidine, ECT, serine, and possibly low mammal and bird fat diet.

Delayed Treatment of Psychosis Hurts Outcome:In a review of 26 studies involving 4490 participants, there was a significant association between the duration of untreated psychosis (DUP) and several outcomes at 6 and 12 months (including total symptoms, depression/anxiety, negative symptoms, overall functioning, positive symptoms, and social functioning). Long vs short DUP data showed an association between longer DUP and worse outcome at 6 months in terms of total symptoms, overall functioning, positive symptoms, and quality of life. Patients with a long DUP were significantly less likely to achieve remission. The observed association between DUP and outcome was not explained by premorbid adjustment.  Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Marshall M, et al.  University of Manchesterr. . Arch Gen Psychiatry. 2005 Sep;62(9):975-83.

Polypharmany Common in Schizophrenia Treatment Although Not Recommended: In a 1-year follow-up study of 796 adults with schizophrenia-spectrum disorders, only 35.7% of the patients were treated predominately with monotherapy (>300 days). Most patients (57.7%) had at least one prolonged period of antipsychotic polypharmacy (>60 consecutive days). Patients averaged 195.5 days on monotherapy, 155.7 days on polypharmacy, and 13.9 days without antipsychotic therapy. Olanzapine-initiated patients were significantly more likely to be on monotherapy with the initiating antipsychotic during the 1-year post initiation compared to risperidone (p = .043) or quetiapine (p = .002). The number of monotherapy days was significantly greater for olanzapine than quetiapine (p < .001), but not for olanzapine versus risperidone, or for risperidone versus quetiapine-initiated patients. Antipsychotic monotherapy and polypharmacy in the naturalistic treatment of schizophrenia with atypical antipsychotics. Douglas Faries et al. Eli Lilly. BMC Psychiatry 2005:5:26. Free access: http://www.biomedcentral.com/1471-244X/5/26 

Prolactin: High Levels Not Found Associated with Bone Loss: Small 14 pt study 12 months olanzapine or risperidone found no association between high prolactin levels and bone loss although was associated with higher bone activity. Effects of elevated serum prolactin on bone mineral density and bone metabolism in female patients with schizophrenia: a prospective study. Abraham G, Paing WW, Kaminski J, Joseph A, Kohegyi E, Josiassen RC. Am J Psychiatry. 2003 Sep;160(9):1618-20

Prolactin: High Levels in Parkinson's Disease Not Associated with Breast Cancer: A study of 12,000,000 deaths, of whom 144,000 had Parkinson's Disease found a lower, not a higher, rate of breast cancer. Parkinson's Disease has low dopamine and traditional anti-psychotics block dopamine and frequently cause Parkinson's-like side-effects. Are dopamine antagonists a risk factor for breast cancer? An answer from Parkinson's disease. Lalonde FM, Myslobodsky M. Breast. 2003 Aug;12(4):280-2

Prolactin & Risperidone Associated Bone Problems: "Hyperprolactinemia induced by conventional antipsychotics often leads to osteoporosis. Risperidone (N = 12) or olanzapine (N = 14) females f/u for at least 2 years. Dual energy X-ray absorptiometry evaluated bone mineral density, and multisite quantitative ultrasound measured bone speed of sound. In addition, profiles of urinary excretion of deoxypyridinoline and circulating levels of hormones and lipids were assessed. Prolactin levels were higher in the risperidone- (123 vs. 25.9). Bone mineral density was similar. Bone speed of sound was lower in the risperidone. The bone speed of sound in the risperidone-treated patients inversely correlated with urinary deoxypyridinoline excretion (r = 0.73, p <.05). Calculated relative risk for fragility fracture of women treated with risperidone as compared to those treated with olanzapine is 1.78 when bone speed of sound was measured at the phalanx and 1.23 when measured at the radius. Risperidone, but not olanzapine, decreases bone mineral density in female premenopausal schizophrenia patients. Becker D, Liver O, Mester R, Rapoport M, Weizman A, Weiss M. J Clin Psychiatry. 2003 Jul;64(7):761-6

Prolactin & Amenorrhea: J Neuropsychiatry Clin Neurosci. 2003 Summer;15(3):375-7 reports haldol or risperidone amenorrhea resolved in 71% with a switch to quetiapine.; Quetiapine has no effect on prolactin or HPA axis hormones. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Aug;27(5):875-8

D4 Antagonist Fananserin Did Not Work: A potent D4 and serotonin A2 receptor antagonist was of minimal benefit in DB PC of paranoid schizophrenic. Tamminga, Am J Psych 3/99;156:419

D3 Antagonist Worsens Psychosis: A D3 favoring antagonist (4:1 vs. D2) in a single dose caused a worsening, not an improvement, in schizophrenic patients. Lahti, U Maryld, J Neural Trans ’98;105:719

Anti-depressants Common Cause of Exacerbation: 11% of 207 consecutive admissions at Yale were due to psychosis precipitated by an anti-depressant. All had previous psychosis diagnoses. All did well with stopping the antidepressant and increasing the anti-psychotic. MacLean, APA 5/30/98 Toronto.

16% Higher Breast Cancer: Anti-psychotics increase prolactin which tends to promote malignant transformation of breast cells. Impact dose related in study. No increase in colon cancer was found. 52,819 on antipsychotics vs. 55,289 controls in study in New Jersey using medicaid/medicare records only. Wang PS, Arch Gen Psyc 12/02;59:1147-54

Anti-psychotics, Especially Haldol Have Higher Rate of Sudden Death: 250,000 Dutch patients from 1995-2001 experience 582 cases of sudden cardiac death or 1 per 1000 person-years per year. Current use of antipsychotics was associated with a threefold risk increase (OR, 3.3) but not past use. Risk was highest for haloperidol. The risk increased significantly with higher doses (P < .001). For current users (OR, 4.7 compared with 2.4); men vs. women (OR, 4.9 vs. 2.9); those younger than 65 years (OR, 5.5 vs. 3.1 for those older than 65 years). Sabine M.J. M. Straus, Erasmus University, Rotterdam. Arch Intern Med. 6/28/2004;164:1293-1297

Avoid Metabolife with Anti-Psychotics, Especially Ziprasidone: In a small study of healthy volunteers, a single Metabolife 356 tablet was associated with a 24 millisecond increase in QTc interval on electrocardiogram, an increase that investigators said was associated with a 3.5-fold increase in risk for torsade de pointes. Nov. 9, 2003 at the American Heart Association (AHA) Scientific Sessions, Brian F. McBride, University of Connecticut.  Moreover, a single Metabolife tablet — which is just a third of the recommended daily dose — also significantly increased both systolic and diastolic blood pressure. Metabolife 356 currently controls about 49% of the world market in diet supplements. Metabolife 356 contains ephedra as well as 17 other ingredients. Other studies have suggested an increased cardiac event risk associated with ephedra.  Ephedra has resulted in many deaths and is banned in several states. Anti-psychotics increase the QTc interval and Metabolife would likely be additive.

Adherence: Medications Often Not Taken and Clinicians Unaware: Antipsychotic medication adherence was determined over 3 consecutive months with (1) the Medication Event Monitoring System (MEMS(R)) cap and (2) the Clinician Rating Scale. Non-adherence was defined as daily adherence of <70% during any one of three monthly evaluations for MEMS(R) and ratings of </=4 (scale of 1-7) on the Clinician Rating Scale. Non-adherence was detected in 12 of 25 patients (48%) by MEMS(R) and 0% by the Clinician Rating Scale. Clinician assessment dramatically underestimated antipsychotic non-adherence. A comparison of electronic monitoring vs. clinician rating of antipsychotic adherence in outpatients with schizophrenia. Byerly M, Fisher R, et al. University of Texas Southwestern. Psychiatry Res. 2005 Feb 28;133(2-3):129-33.

Adherence Appears Important: In a study of 1906 patients with schizophrenia or schizoaffective disorder in a multi-site, 3-year, prospective, naturalistic study, nonadherence was associated with poorer functional outcomes, including greater risks of psychiatric hospitalizations, use of emergency psychiatric services, arrests, violence, victimizations, poorer mental functioning, poorer life satisfaction, greater substance use, and more alcohol-related problems (all p < .001). Adherence was relatively stable, with 77.3% of patients maintaining the same adherence status from the first year to the second year. Nonadherence in the first year predicted significantly poorer outcomes in the following 2 years. J Clin Psychiatry 2006 Mar;67(3):453-60. This was not a controlled study.

Adherence: Patient and Family Education Sessions Help: In a randomized study of 236 inpatients with schizophrenia or schizoaffective disorder, patients and their relatives were encouraged to attend psychoeducational groups over a period of 4 to 5 months. The patients' and relatives' psychoeducational programs were separate, and each consisted of 8 sessions. Patients in the other treatment condition received routine care. Psychoeducation significantly reduced the rehospitalization rate after 12 and 24 months in patients (p < .05). Patients who attended psychoeducational groups showed better compliance than patients under routine care without psycho-education. J Clin Psychiatry 2006 Mar;67(3):443-52.

Active and Low-Dose Controlled Studies Biased; Placebo-Controlled Best: In 32 studies comprising 66 risperidone, olanzapine, quetiapine, and ziprasidone arms including 7,264 patients, researchers found that in atypical antipsychotic medication arms, the degree of improvement was nearly double in active-controlled trials than that seen with the same drugs and dosages in placebo-controlled studies. An effect of design was also observed in low dose-controlled studies vs placebo-controlled studies in ineffective and intermediate antipsychotic medication dose ranges. Therfore, caution is indicated when considering active- or low dose-controlled studies requiring comparisons with external placebo as alternatives to placebo-controlled trials for establishing efficacy of new medications for schizophrenia. Control group bias in randomized atypical antipsychotic medication trials for schizophrenia. Woods SW, et al. Yale University. Arch Gen Psychiatry. 2005 Sep;62(9):961-70.

Early Treatment May Help: In the 1-year DB PC Prevention Through Risk Identification, Management, and Education project, outpatients with very early symptoms of schizophrenia received olanzapine (5-15 mg/day, N=31) or placebo (N=29). 16% of olanzapine patients and 38% of placebo patients experienced a conversion to psychosis, a nearly significant difference. The olanzapine patients gained 19 more pounds. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. McGlashan TH, et al. Yale University. . Am J Psychiatry 2006 May;163(5):790-9.

Thomas E. Radecki, M.D., J.D.

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