Low Dose Risperidone Every 3.8 Hours: Superior Ecacy In Treatment of Bipolar Disorders

Background: This paper presents a previously unpublished Bipolar Disorder treatment using low-dose Risperidone that gives superior-ecacy, prevents overmedication, and prevents medication-induced anxiety and irritability. Standardized other Bipolar Disorder treatments have a failure rate of 82% to 87.1%. When dropouts and poor adherence are combined, only 12.9% to 18% of Bipolar patients adhere to medications within three years. Self-defensive providers primarily blame Bipolar patients for treatment failures. When that bias is removed, failure is due to overmedication and anxiety and irritability caused by medications. This paper shows the neurobiochemical processes that cause those problems. Published prescription-guidelines recommend Risperidone in high amounts that intentionally activate its 9-Hydroxyrisperidone metabolite under auspices that it is virtually the same as Risperidone and lasts for 24 hours. In truth, however, the benecial Risperidone chemical lasts for four hours and 9-Hydroxyrisperidone agonizes Bipolar-toxic Serotonin. Low-dose Risperidone neutralizes 9-Hydroxyrisperidone. Methods: Low doses of Risperidone were calculated to be therapeutic amounts without causing overmedication, anxiety, and irritability. Doses were calculated to metabolize low plasma concentrations of 9-Hydroxyrisperidone that stay below the neural-activation threshold level. Four-hour-duration low doses of Risperidone were administered every 3.8 hours. Results: 3.8-hour dosing sustained steady benets by overlapping 15-minute ecacy-onset with the 15-minute termination of each previous dose. Steady transitions between doses and ve administrations per day gave therapeutic ecacy for 16 hours. Taking dose #5 at bedtime gave improved sleep. Conclusions: Low doses of Risperidone activate its therapeutic benets while neutralizing Bipolar-toxic Paliperidone. Low-dose Risperidone every 3.8 hours maintains stability with room for adding occasional extra doses to control exacerbations of symptoms. This study provides a new biochemistry-based Bipolar Disorder treatment that is vitally needed because the failure rate of traditional treatments is too high. Traditional treatments and research are guided by commercial drug manufacturers’ recommendations and data. Traditional treatment dropout and non-adherence


Background
This paper presents a groundbreaking and vastly superior new paradigm for treating Bipolar Disorders.
This author is unaware of any other studies of the neurobiochemistry processes and Bipolar Disorder treatment methods presented in this paper. Risperidone is used in the Mental Health profession as a major mood stabilizer and as an antipsychotic. Risperidone has two main components: (1) a chemical with the scienti c name Risperidone and (2) 9-Hydroxyrisperidone, an antipsychotic-metabolite of Risperidone also known as Paliperidone. Risperidone was FDA approved for Bipolar Disorder treatment in 1993 under the brand name Risperdal. Paliperidone is not FDA-approved for Bipolar Disorder treatment. The FDA rejected Paliperidone-Invega for Bipolar treatment in 2006, 2009, and 2011. This is the rst paper known to this author to analyze the Bipolar-toxic properties of Paliperidone. This is the rst paper known to this author to present a vastly superior method of Bipolar Disorder treatment that uses low-dose Risperidone every 3.8 hours and neutralizes Bipolar-toxic Paliperidone. 51.5 million adults in the United States (20.6%) reportedly experienced Mental Health problems during 2019. Forty-six million people worldwide reportedly had Bipolar Disorders during 2018 with a reported 2.8% prevalence of Bipolar Disorders in the USA during 2019. Common Bipolar Disorder treatments combine antiepileptics such as Valproic Acid and antipsychotics such as Risperidone. Risperidone is a 4hour chemical that metabolizes into 24-hour Paliperidone. This is the rst research paper to strictly differentiate between Risperidone, Paliperidone, and an ostensive active moiety. Standard daily Risperidone of 2mg to 8mg or more metabolizes activation-amounts of Paliperidone. Little known laboratory studies show Paliperidone increases Prolactin and Serotonin. Standard-dose Risperidone exceeds effective small amounts by 400% to 1600%, causing unnecessary Risperidone overmedication for four hours followed by 21 hours of harmful Serotonin agonism by Paliperidone.
To the best knowledge of this author this is the rst research paper to address those issues. To the best knowledge of this author this is the rst research paper to overcome those issues by developing a superior new Bipolar-treatment with low-dose Risperidone every 3.8 hours. Low doses of 0.25 mg, 0.5mg, 0.75mg, and 1.0 mg activate the bene ts of Risperidone without activating Paliperidone. Administration every 3.8 hours sustains e cacy by overlapping 15-20-minute e cacy-termination of one dose and 15-20-minute onset of the next dose. This new method is overtly superior to the universally accepted 30-year standard. Neurobiochemistry data in this paper is from a review of scienti c literature. Case study information is from the author's outpatient treatment experiences with Bipolar Disorder patients. Drugmanufacturer information is from a review of history literature.

Risperidone reduces Dopamine and Serotonin
Bipolar Disorders have a neurobiochemical trait of receptor-synapses that absorb excessive amounts of Dopamine and Serotonin. This over-activates the nervous system, e.g., the brain. Medications that reduce synaptic-absorption of Serotonin and Dopamine can calm and stabilize Bipolar nerves and brains.
Reductions can occur through antagonism of receptors, antagonism of natural production of Dopamine and Serotonin, antagonism of transporter-cell bonding and production, and increased reuptake. Low serum concentrations of Risperidone can reduce synaptic absorption of Dopamine and Serotonin.
Increased serum concentrations can further decrease absorption of Dopamine and Serotonin.
Two de nitions of "Risperidone" The word "Risperidone" has two de nitions: 1) In scienti c chemistry "Risperidone" is the scienti c name, or chemical name , of a speci c 4-hour duration chemical. Its unique chemical-identi cation number (CID) is 5073. Its unique chemical structure is C 23 H 27 FN 4 O 2 . In scienti c chemistry it is distinctly differentiated from its metabolite chemicals. 2) In commercial drug marketing "Risperidone" is the generic name of the brand name medication "Risperdal" that is marketed as an inextricable combination (active-moiety) of the name-ingredient and it's 23-to-26-hour duration metabolite Paliperidone (9-Hydroxyrisperidone). This paper avoids confusion by using "chemical-Risperidone" as a topic or paragraph lead-in for the scienti c chemistry de nition.
Onset-time, half-life, and e cacy-duration Chemical-Risperidone has a short half-life of 2.8 to 3.5-hours depending on which source is being cited 1,2,3,4 . A study with 19 pediatric inpatients [2] showed a half-life of 3.0 hours. The study showed Risperidone plasma levels dropped to dose-administration levels (horizontal red line in Figure 1 below) at 4 hours then dropped below dose-administration levels. Adult patients at this author's Mental Health clinic consistently reported the effects of Risperidone fade noticeably between 3.9 and 4 hours and end at about 4 hours. Patients' reports were consistent with household members' reports, this author's clinical observations, and the above study. The plasma concentration drops below the dose-administration level and e cacy ends at about 4 hours. This author's patients also consistently reported that bene cial effects of Risperidone are noticeable 15 to 20 minutes after ingestion. This was also consistently reported by patients' household members and was consistently observed by this author hundreds of times.
E cacy duration is independent of dose-amount, length of use, and adjunctive medications Participants in the above study were 19 pediatric inpatients ages 4 to 16 of several diagnostic categories.
All were on established maintenance Risperidone therapy twice per day prior to and during the study. Doses ranged from 0.25 mg BID to 2.5 mg BID. Four participants were on Risperidone monotherapy. Fifteen participants were taking concurrent medications with a wide range of amounts wherein some took 10 times more than others. Among the participants the half-life and duration of Risperidone were constant regardless of dose-amount, length of use, type and amount of co-medication, diagnosis, age, and gender. Research studies consistently show that among the vast majority of people Risperidone metabolizes completely into other chemicals at or very near the 4-hour mark.
15-20-minute onset-time, moot half-life, and 4-hour duration Onset: Several research studies report a median T-max of 1-hour and a dose dependent C-max [8]. This is the rst paper this author knows of that includes patient-reported e cacy onset time of chemical-Risperidone. This author's Bipolar Disorder treatment patients and their participating household members consistently reported an onset-time of 15 to 20 minutes after pill ingestion. The author also consistently observed the 15-to-20-minute onset-time during clinical therapy sessions. The short onset time is an important component of the Bipolar Disorder treatment method presented in this paper.
Half-life: The traditional de nition of "half-life" states that after ve half-lives a chemical is 94% eliminated and after six half-lives it is 98% eliminated. The half-life of Risperidone is reportedly 2.8 hours, 3 hours, 3.2 hours, or 3.4-hours (the mean among these reports is 3.1 hours) depending on which source is cited (4,6,7,8). On one hand, given the reported the shortness of the half-life, a 36-minute difference among reports is considerable. One the other hand, this is the rst research paper that the author knows of to show that the traditional concept of "half-life" is moot for Risperidone. The median reported half-life is 3.1 hours, whereby it would be 98% eliminated only after 18.6 hours. However, what actually happens is this: 1. On one hand, a 3.1-hour "half-life" is too long. Four hours after intake the chemical structure of Risperidone metabolizes into several other chemicals whereby the chemical structure of Risperidone becomes disassembled and no longer exists. Risperidone has a 4-hour duration, not a 3.1-hour "halflife".
2. On the other hand, a 3.1-hour "half-life" is too short. The manufacturer has cleverly convinced everyone (other than this author) that Risperidone is combined with a metabolite with a half-life of 20 to 25 hours. Everyone (except this author) dogmatically believes "Risperidone and Paliperidone" are 98% eliminated at 120 to 180 hours although everyone also believes Risperidone has a 3. to the initial intake level. When an intake level is above zero due to a previous dose, the level drops below intake to zero about 10 minutes after hour-4 (8). All of the author's Bipolar Disorder patients reported that noticeable effects begin 15-20 minutes after dose-intake and effects start fading about ve minutes before they end at about hour-4 (see Figure 2 below).

Superior responses from a lower blood level
Oral tablet Risperidone is more clinically potent than Paliperidone. This is partially due to bioavailability of 68% versus 28% respectively. The difference in bioavailabilities is largely due to a higher Paliperidone a nity for e ux protein Pgp (ABCB1). This a nity decreases brain exposure to medications by reducing brain tissue permeability [11]. A signi cantly higher percent of blood-borne Risperidone passes through the blood-brain barrier tissues to enter the brain. The brain-absorption of higher quantities of Risperidone enables lesser amounts of medication to induce superior e cacy. The good bioavailability of Risperidone might be advantageous for any diagnostic category of patients who use antipsychotics. It is particularly advantageous for patients with Bipolar Disorders. Bipolar Disorders cause Dopamine and Serotonin to over-activate the brain and the nervous system. Effective antipsychotics calm the brain and nerves by reducing Dopamine and Serotonin absorption. Reduction is done by receptor inhibition, transporter-cell inhibition, and inhibition of production.
Risperidone is a benzisoxazole derivative. It is a selective monoaminergic antagonist with a high a nity for binding to and occupying Serotonin and Dopamine synaptic receptors. It has a ten to twenty times higher a nity for 5-HT 2A receptors than for D 2 receptors (8). It signi cantly decreases both Dopamine and Serotonin absorption. It also inhibits absorption in other ways. A laboratory investigation of Risperidone vs. Paliperidone neural-activation functions and neural-responses spoke of "concentrations of paliperidone (3 μM) and risperidone (1 μM)" that were "obtained from concentration-response curves for signaling responses at 5-HT 2A and 5-HT 2C receptors." The investigation found that three times less Risperidone than Paliperidone induced neural responses [6].
In the laboratory investigation serum concentrations for neural responses had a 1-to-3 ratio of Risperidone-to-Paliperidone. Neural responses to Paliperidone differed from responses to Risperidone. 1 μM of Risperidone signi cantly reduced the release and functions of Serotonin transporter Arachidonicacid (AA). A three times higher amount of 3 μM Paliperidone increased AA sensitivity causing AA transporter cells to gather increased amounts of Serotonin and carry it to receptors. Researchers found that the differing effects on AA signi cantly impacted the amounts of Serotonin that were absorbed by 5-HT 2A and 5-HT 2C receptors. Risperidone reduced the number of AA transporters and decreased the amount of Serotonin that transporter cells brought to synaptic receptors. By allowing less incoming Serotonin the amount of Serotonin that was absorbed by receptors decreased. Paliperidone made AA transporters more e cient. By not reducing their number an increased amount of Serotonin was brought to synaptic receptors. Thereby the amount of Serotonin that was absorbed by synaptic receptors increased (see Figure 3 and Figure 4 below).
Odou, et al found that in a response in 5-HT 2C receptors, Risperidone was an inverse agonist and reduced basal AA release by 14 ± 2%. By contrast, Paliperidone reduced basal AA release by only 0.5 ± 8% and behaved as an agonist. In 5-HT 2A receptors only Risperidone signi cantly reduced AA release (17 ± 4%).
Another comparative study found Risperidone occupied 17% more D 2 -Dopamine receptors and 28.2% more 5-HT 2A -Serotonin receptors. The reported D 2 -receptor a nity of Paliperidone was three times lower than that of Risperidone. Risperidone occupied a greater number of D 2 and 5-HT 2A receptors. The occupied receptors were less able to absorb Dopamine and Serotonin. [12]. Activation of neural response requires three times higher serum concentrations of Paliperidone and the resulting Paliperidone responses are harmful to Bipolar Disorders.

1) Aim of this study
This paper is an independent Humanitarian work that brings the world a critically needed paradigm of scienti c neurobiochemistry to safely and effectively help people who have a Bipolar Disorder.

2) Design of this study
This paper is based on data found online in approximately 120 existing documents (see Description of Materials Used in This Study below).

3) Setting of this study
This author owns and operates a one-person private practice Mental Health clinic that is not used for experimental research. This author's research consists of extensively gathering and analyzing information documents and research studies found on the internet.

4) Characteristics of study participants
Four of this author's Bipolar Disorder clinical patients and two of their household family members signed consent forms allowing medication-pertinent treatment information to be mentioned in this paper. These were not experiment subjects. They did not actively participate in this study.

5) Description of materials used in this study
Internet searches gathered a wide range of scienti c research documents, prescription guidelines, drug product package inserts, letters and other documents exchanged back and forth between the FDA and the manufacturer, FDA documents evaluating the manufacturer's Approval Application research reports, clinical e cacy research studies, laboratory in-vivo investigations of chemical properties and interactions.

6) Description of the processes used in this study
See #5 above

7) Interventions used in this study
No experimental interventions were used in this study.

8) Comparisons used in this study
Risperidone was compared to Paliperidone vis á vis review and analysis of data in existing documents found online regarding dose-related clinical e cacy, duration of clinical e cacy, chemical structure, duration of chemical structure, neurobiochemical properties, neurobiochemical actions and potentials, histories of product development, and histories of FDA approvals 9) Type of statistical analysis used in this study Basic Algebra was used for calculating Risperidone dose-amounts, plasma concentrations, and activation thresholds.

Differential-activation: Activating Risperidone while neutralizing Paliperidone
The neuropsychiatric bene ts of Risperidone can be activated without neural responses to Paliperidone. To the best knowledge of this author this is the rst research paper regarding differential-activation of Risperidone and Paliperidone. This is the rst research paper to show differential-activation is possible. This research paper also is the rst to present a treatment method that activates the bene ts of Risperidone without activating responses to Paliperidone. This topic is new and critically important for the treatment for Bipolar Disorders.
Many people in the Medical and Research Communities are aware that Serotonin destabilizes Bipolar Disorders and that Risperidone is a Serotonin antagonist. The vast majority of Medical and Research people are unaware that metabolite Paliperidone is a Serotonin agonist that needs to be neutralized for safe and effective treatment of Bipolar Disorders. Key factors for accomplishing this critically necessary differential-activation include: A) At about 4-hours Risperidone metabolizes into other chemicals including Paliperidone. B) Risperidone e cacy occurs at low serum concentrations [12] that metabolize inactive small amounts of Paliperidone [6]. C) Risperidone metabolizes into 77.35% of its volume in Paliperidone, yielding 22.65% less Paliperidone than Risperidone [9].
D) The activation-threshold serum concentration of Paliperidone is three times higher than activationthreshold of Risperidone [6].
To the best awareness of this author, this is the rst paper to show that it is bene cial to activate the psychoactive properties of chemical-Risperidone while not activating the psychoactive properties of Paliperidone. To the best awareness of this author, this is the rst paper to show that it is possible to activate to activate the psychoactive properties of chemical-Risperidone while not activating the psychoactive properties of Paliperidone. To the best awareness of this author, this is the rst paper to show how to activate the psychoactive properties of chemical-Risperidone while not activating the psychoactive properties of Paliperidone. When providing clinical treatment for Bipolar Disorders it is critical to differentially activate the former and not the latter. Chemical-Risperidone is a powerful Serotonin and Dopamine antagonist. Paliperidone is a harmful Serotonin agonist and a weak Dopamine antagonist. Key factors for calculating a differential-activation regimen include: 1) E cacy of Risperidone occurs at low serum concentrations.
2) At about 4-hours Risperidone metabolizes into other chemicals.
3) The metabolites are inert other than Paliperidone.
An active-moiety research article by Odou et al studied Paliperidone serum concentrations in relationship to clinical-e cacy. The authors wrote, "Statistical analysis revealed a signi cant increase in e cacy when the serum concentration of active drug was between 25 and 150 µg/L…" This author marked the level of clinical e cacy from Paliperidone 25 µg/L with vertical red line in Figure 5 below. Figure 6 below shows "active-moiety" (Paliperidone) plasma concentration levels and corresponding Risperidone dose-amounts per day.
On Graph F this author marked 25 µg/L with a horizontal green line that intersects the Curve-1 e cacymean at the 0.051 mg/kg point. This is equivalent to 4.627 mg for a 200-pound person, 3.933 mg for 170pounds, 3.47 mg for 150-lbs, 3.0073 mg for 130-lbs, 2.6603 mg for 115-lbs, or 2.3133 mg for 100-lbs. This yields Paliperidone 25 µg/L and the above-mentioned signi cant increase in clinical e cacy [13].
The phrase "signi cant increase in e cacy" said minimal e cacy occurred at a lower concentration than 25 µg/L. This author re-analyzed the data and found minimal Paliperidone e cacy occurred at 23.9 µg/L (see Figure 7 below). This corresponds with Risperidone .05 mg/kg, equivalent to 4.5 mg for a 200-lb person, 3.75 mg for 170-lbs, 3.5 mg for 150-lbs, 3 mg for 130-lbs, 2.5 mg for 115-lbs, or 2.25 mg for a 100-lb person (see Figure 8 below) [13].
The above study listed mg/kg dosages per body weight. The average weight of USA males is 197.9 pounds [14] and 170.6 pounds for females [15] (see Figure 9 and Figure 10 below). According to data from the above study, minimum clinical e cacy of Paliperidone requires a Paliperidone serum concentration of 23.9 µg/L. That requires Risperidone daily dose-amounts of 4.48 mg for average-weight males and 3.87 mg for average-weight females [16] (see Figure 9a and Figure10a below). The 4.48 mg and 3.87 mg dose-amounts were for average-weight USA Americans. Such persons are signi cantly overweight. Their dose-amounts may be too high for persons of healthier weight. In order to nd dose-amounts for persons of healthier weight, this author used the weight-range means for average height males (5'9", 156.66 pounds) and females (5'4", 131.33 pounds). The calculated daily dose-amount for healthier-weight men is 3.55 mg and 2.98 mg for healthier-weight women (see Figure11, Figure11a, Figure 12, and Figure 12a below) [12,13].
The calculated dose-amounts for healthier-weight and average-weight USA Americans correspond to the Paliperidone serum concentration that was associated with minimal clinical e cacy on CGI 2 test-scores.
The clinical e cacy dose-amounts and serum concentration seem to a rm a synaptic-activation threshold but biochemical data is needed in order to correctly identify a synaptic threshold and dosage parameters.
Factors for calculating dose-amounts that activate Risperidone without activating Paliperidone Factors for calculating appropriate dose-amounts include but are not limited to: 1. The appropriate Risperdal/Risperidone doses are 3.2265 times less than doses that activate Paliperidone. This is a biochemical ratio with two inherent properties: 1. The needed amount of Risperidone serum concentration is three times less than the amount of Paliperidone serum concentration that affects synaptic functions 6 .
2. Risperidone has an onset time of 15-20 minutes, a half-life of 3.2-3.5 hours, and its clinical e cacy and chemical-structure end at 4 hours [2].
Steady e cacy requires a steady serum concentration that requires taking Risperidone every 3.8 hours.
Due to the frequency, routine small doses plus small extra doses taken as needed provide steady e cacy without overmedicating the patient and without activating Paliperidone. When a patient is starting Risperidone (or any psychoactive medication), introduce it slowly in a way that minimizes and/or prevents grogginess. Keep in mind that medication-grogginess is a tiredness of the body, muddied/slow thinking, and at or irritable emotions. Medication-grogginess is the leading cause of poor adherence and quitting treatment among Bipolar Disorder patients. The new treatment paradigm in this paper prevents medication-grogginess.
Calculating differential-activation dose-amounts Differential-activation is de ned herein as an induction of neural responses to Risperidone without an induction of neural responses to Paliperidone. Differential-activation requires maintaining Paliperidone at below the serum concentration that induces neural responses to Paliperidone. The preceding re-analyses of clinical data calculated the threshold concentration of Paliperidone and the threshold doses of Risperidone. In addition to clinical data, differential-activation incorporates laboratory ndings and biochemical variables such as 1) Risperidone metabolizes into a 22.65% lesser amount of Palideridone, and 2) Neural responses to Paliperidone require a serum concentration that is three times higher (a 3/1 ratio) than the Risperidone response-threshold.
The calculated Risperidone serum concentration clinical e cacy threshold is 6.5 µg/L (see Table 1 below). This is 27.2% of the Paliperidone e cacy-threshold. Thus, differential-activation occurs when a Risperidone serum concentration is below 27.2% of the Paliperidone threshold. Dose amounts for differential-activation vary according to body weight and severity of symptoms, and the severity of Bipolar symptoms uctuates over time. Body weight is a useful constant factor in calculating doseamounts and it can useful for preliminary calculations of ve-times-per-day low doses. Computations for dosages per body weights [14,15,16,17] and serum concentrations are provided in Table 1 and Table 2.

Results
Guidelines for titration of adjunctive Valproic acid and low dose Risperidone Adjunctive therapy with Valproic acid and Risperidone is more effective than Valproic acid monotherapy or Risperidone monotherapy. Each of these medications has a set of unique bene ts that are therapeutically enhanced by the unique bene ts of the other medication. One of the combined bene ts is that Valproic acid increases digestive absorption of Risperidone into the blood stream, whereby lower doses of Risperidone achieve therapeutic plasma concentrations with Valproic acid adjunctive therapy. Conversely, Risperidone does not affect the plasma concentration of Valproic acid [3]. Starting therapy with just Valproic acid allows it to be titrated to its optimal e cacy without confusing its effects with effects of concurrent Risperidone titration. This eliminates the risk of cross-reaction overmedication during Valproic acid titration.

Titration of Valproic acid ER
a) The therapeutic blood-level of Valproic acid for Bipolar treatment is typically 85 to 125 mcg/mL [20].  j) It is valuable for a patient to set cell phone reminder-alarms to ring every 3.8 hours at medication-time.
k) It is valuable for a patient to not turn off the alarm sound until the scheduled pill is taken. The roller coaster is unnecessary and can be foregone by taking a second dose 10 minutes before the rst dose loses effect. The serum concentration of a dose (Dose-1) wanes as it nears the termination of its 4-hour duration. A next dose (Dose-2) brings more concentration in a slope of increase that adds a bit to the Dose-1waning-amount at the time when the waning would otherwise drop to an amount below the e cacy-threshold. The waning amount simultaneously adds a bit to the increasing amount at a time when the increasing amount would otherwise not yet be at the e cacy-threshold amount. The two amounts cumulatively keep the serum concentration above the e cacy-threshold. Dose-2 increases on a slope at the same pace as the decrease-slope of Dose-1. They combine to sustain serum concentration threshold equilibrium during the transition from Dose-1 to Dose-2. This occurs when Dose-2 is taken 10 minutes before Dose-1 wanes below the threshold. The diminishing e cacy of one dose is offset by the increasing e cacy of the next dose. The patient remains stable. There is no e cacy roller coaster with low doses of Risperidone every 3.8-hours (see Figure-13

below).
A Risperidone 1 mg dose that corresponds with .01-mg/kg to .02-mg/kg does not meet or exceed the Paliperidone-activation threshold. A 1 mg low dose does not activate Paliperidone. It does, however, induce bene cial Risperidone responses.
An added bene t of low-dose treatment is that routine maintenance doses can be augmented with small extra doses during symptom exacerbations. This is possible because low doses metabolize 22.65% less Paliperidone than their own volume and because Paliperidone activation requires three times more serum volume than Risperidone activation requires. With low dose Risperidone, Paliperidone cannot be activated by small extra doses.
The treatment-paradigm in this paper differs from other Bipolar regimens in that it relies on accurate biochemistry and also ts patient-oriented perspectives. The new paradigm precludes 1) overmedication, 2) Paliperidone-increases of Serotonin and Prolactin, 3) false claims of active moiety, and 4) thirty-years of inaccurate research based on false active moiety. This new paradigm encourages treatment and minimizes dropout rates by providing markedly superior bene ts without overmedication. This author has implemented the superior method in this paper successfully for 14 years at a private practice Mental Health clinic that he owns and operates as a sole-proprietor single-providership since 1997. Four current patients use the method in this paper. They gave written consent to include their pertinent treatment and case history information in this paper. This paper is not a Multiple-Case-Study but some pertinent patient-information is valuable. One of the patients is a male 58-year-old Medical Doctor in treatment with this author for 13 years since 2008. Another patient is a 22 year-old woman in treatment with this author for six years since 2015. Another patient is a 21 year-old woman in treatment with this author for four years since 2017. The other patient is a male 45 year-old schoolteacher in treatment with this author for seven months since early-2021.
The superior bene ts of the treatment method in this paper are evidenced by this author's clinical caseobservations, patient self-reports, and patient household-member reports. Patient self-reports of e cacy were positive and consistent within each patient across time. Individual patient self-reports were consistent with reports by other patients across all patients. Household members said the same things as patients and members of other households. Reports by patients and household members were consistent with this author's clinical case-observations. The information from patients and household members is reliable evidence that the method in this paper overcame the above-mentioned treatment-dropout rates and family fears of treatment.
Across all patients, household members participated in treatment at home in the similar ways. Notably: a) They could sense when a patient forgot to take medications. b) They used supportive tones and words in pointing out that medications were missed and should be taken now. c) They quickly sensed exacerbations of Bipolar-symptoms. d) They used supportive tones and words to calm the patient during exacerbations. e) They sensed when an extra "booster" tab of low dose medication was the best thing for resolving an exacerbation. f) They encouraged patients to take medications on time and attend regularly scheduled Therapy sessions. g) They supportively got the patient to page the Therapist (or page on behalf of the patient) for an emergency session when exacerbated symptoms were too severe to handle at home. h) They brought the patient to the clinic when exacerbated symptoms were too severe for the patient to drive safely.
Patients reported reliable treatment information that validates the bene ts of the treatment method in this paper. Some key points that validate the method are: 2. The 3.8-hour dose-frequency sustained stability during transitions between doses 3. The x5 per day dosage sustained stability through the day 4. Sustained stability through the day contributed to better quality sleep at night 5. Consistent medication administration made symptom exacerbations less frequent and less severe . Use of extra doses as-needed enabled patient-control of symptom exacerbations 7. Flexible patient-control is a patient-oriented approach that engendered patient self-con dence and trust toward professional care All of the involved patients have histories of quitting two to six or more other treatments in the past All of the patients and household members reported to this author, "You are the only one who knows what he's doing with medications and you're the only one who has actually helped." That says about everything that can be said to validate the bene ts and superiority of the new paradigm presented in this paper. This paper presents a method of treating Bipolar Disorders with standard Valproic acid plus low-dose Risperidone every 3.8 hours. The purpose of this method is to optimize patients' therapeutic bene ts. A part of this optimization is prevention of overmedication. Another part is differential-activation of Risperidone that neutralizes counter-therapeutic Paliperidone. Bipolar Disorder treatment using adjunctive Valporic acid and differential-activation-Risperidone yields signi cantly superior results of safety and e cacy.

Discussion
We can't change the past but we can make a better future for 46-million Bipolar sufferers and their communities worldwide. When a person with a Bipolar Disorder starts Risperidone and Valproic acid it is important to maintain patient-comfort by preventing initial overmedication and grogginess. This can be done easily by introducing low doses and slow titration. Medication-grogginess is a tiredness of the body and slow/muddy thinking that often brings attened or irritable emotions. Bipolar patients sense the slow grogginess more acutely than most other people because they are accustomed to hyperactive nerves and racing thoughts. Bipolar illness runs in family bloodlines. Many Bipolar families have a staunch fear of overmedication and of "all of that mental health crap". The fear is not false or delusional. The words "zombied" and "zombi ed" describe a reality that besets Bipolar patients more often than other people due to the sedation-factor in Bipolar medications. Bipolar families fear bad/excessive medications because the reality of bad/excessive medications induces well-justi ed and appropriate fear in Bipolar families.

Conclusions
When Bipolar-medication grogginess occurs, it is real and it is not the patient's fault. It usually leads to "poor adherence" and quitting treatment. "Poor adherence" happens by true necessity because a person should discontinue treatments that induce harm. Quitting therapy also happens by true necessity because providers who overmedicate people are inept and patients should leave rather than rely on them. Every incident of side effects reinforces a Bipolar-family's fears and they deride members who "get help." Fearful families are highly unlikely to encourage treatment for America's 2,840,000 people with untreated severe Bipolar Disorders. A study in Korea reported a rapid increase in treatment dropout rates from month-1 (10.9%) to month-3 (24.7%) and it was 50.2% at month-36 [21]. Treatment providers told the researchers that the main reasons for quitting treatment were patients' denial of need, lack of e cacy, and patients' poor understanding of treatment effects. The providers were correct about "lack of e cacy" but they wrongly blamed patients' "denial" and "poor understanding of treatment effects." This paper showed that widely accepted treatments for Bipolar Disorders are actually harmful to patients.
Harmful treatments certainly "lack e cacy". Patients who quit harmful treatments are actually showing "good understanding of harmful treatment effects." Their awareness that they are being harmed is awareness that treatment "lacks e cacy." Providers wrongly say patients deny that they need help but patients quit treatment because it does not help.

Availability of data and materials
All data generated or analyzed during this study are included in this published article and its supplementary information les.

Competing interests
The author declares he has no competing interests.

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