Recommendation Schizophrenia

Medication Guideline for Psychosis/Schizophrenia

This drug recommendation aims to address negative symptoms and, above all, cognitive symptoms through intermittent use of the antipsychotic. This is accompanied by a continuous intake of targeted antidepressants, which create a safe framework for intermittent intake of the antipsychotic. In contrast to conventional treatments, both positive symptoms, cognitive impairments and negative symptoms are effectively alleviated. This leads to a better course of the disease and a higher quality of life.


Medication Plan
Daily Intake:

• Bupropion (300–450 mg): Starting dose = 150 mg. Bupropion can help with mood swings such as irritability and inner restlessness, motivation problems, and cognitive impairments. It alleviates negative symptoms.
• Citalopram (10–40 mg): Citalopram can help with excessive emotionality or libido that may result from reduced use of the antipsychotic. It is also important to note that it counteracts side effects of bupropion, such as micturition dysfunction (weak bladder) and possible constipation symptoms.
• Trimipramine drops (40 mg/ml; approx. 10 drops in the evening): Optional for sleep disorders and addiction problems.

Interval Intake:

• Aripiprazole (5–10 mg): This atypical antipsychotic is the main active ingredient in the treatment of psychosis. Aripiprazole is effective against positive symptoms, severe depression, and sleep disorders. Intermittent use reduces negative symptoms and side effects.

The antidepressants work particularly well after stopping aripiprazole, although their effects wear off over the months and depressive as well as negative and positive symptoms reappear when it is time to take aripiprazole in interval form for 1–3 weeks. The antipsychotic, taken for a short period, reactivates the efficacy of the antidepressants so that they develop their full effect again for the next phase of discontinuing aripiprazole.

Intermittent intake of the antipsychotic is necessary because, otherwise, after significant improvement, symptoms would worsen again despite the antidepressants. Even at high doses, these would eventually be too weak, which is why intermittent intake of the antipsychotic is absolutely necessary. The need for interval intake can be recognized based on these early warning symptoms.

(Timeline: see table)

Combination of Active Ingredients and Interval Intake

The recommendation is based on monotherapy with aripiprazole, a well-tolerated antipsychotic, which is taken in a reduced interval form. The daily intake of antidepressants, particularly bupropion, enables this reduced intake form of the antipsychotic. This reduces side effects and effectively treats negative symptoms that are otherwise difficult to treat.

To take the three to four necessary active ingredients correctly and adjust to them, certain dosages and the order of medication changes must be observed:

1. Aripiprazole monotherapy in the smallest possible dose; effective from 5 mg.
   At the beginning of the change, aripiprazole should be taken daily. Intermittent use of aripiprazole is only possible once bupropion has been successfully introduced and ideally citalopram and doxepin are taken prophylactically in addition.
2. Add bupropion to aripiprazole, then add citalopram. The combination of citalopram and aripiprazole tends to cause restlessness and nervousness; bupropion reduces this restlessness due to its noradrenaline effect. Bupropion can also reduce mood swings like irritability.
3. Finally, add doxepin or trimipramine in a reduced dose to reduce sleep problems caused by bupropion. These older tricyclic antidepressants also alleviate addiction problems that can occur as part of psychosis; bupropion is more effective against nicotine addiction.

(Timeline: see table)

Once bupropion has been gradually introduced, you can start taking aripiprazole intermittently at the earliest. The withdrawal intervals are approximately 3–6 months. The right time to take it as needed can be recognized by the early warning symptoms. The effect of the antidepressants also wears off after 3–6 months, which can be a sign that you need to take aripiprazole intermittently. It is helpful to get to know your symptoms and get support from family members or therapists to better recognize your own symptoms.

If aripiprazole is stopped for too long, the effect of both antidepressants could eventually wear off. Depressive symptoms, negative symptoms, and positive symptoms could reappear, as could mood swings, paranoia, irritability, or shopping addiction. Sleep disorders can frequently occur if you start taking aripiprazole again. These and other early warning symptoms indicate the need for intermittent intake. By omitting aripiprazole for too long, bupropion can accelerate thinking, which can lead to delusions and mania and, in extreme cases, catatonia. Therefore, intermittent intake should not and must not serve as a guide to discontinuing antipsychotics.



Active Ingredients and Dosages

For interval intake:

• Aripiprazole 5 mg (daily – later in interval form 5–10 mg): Atypical antipsychotic.

Daily intake:

• Bupropion 300–450 mg (150 mg starting dose, slowly increasing; with doses from 300 mg, additional citalopram is important against side effects; up to max. 600 mg bupropion): SNDRI antidepressant, acts selectively on noradrenaline and dopamine.
• Citalopram 10–40 mg (prophylaxis for certain side effects like micturition dysfunction or constipation, which are favored by bupropion; suppression of emotions and libido, which can occur due to the interval intake of the antipsychotic): SSRI antidepressant, acts selectively on serotonin.
• Trimipramine drops 40 mg/ml; approx. 10 drops (optional for severe sleep disorders and addiction problems like alcohol addiction, gambling addiction, etc.): Tricyclic antidepressant, broad-spectrum effect.

Effect/Benefits by Color:

• Red: Against positive symptoms, in case of sleep disorders, also reliably acts as an antidepressant in psychosis and severe depression.
• Blue: Against negative symptoms, lack of motivation, and mild depression; against excessive libido and emotions, irritability, and mood swings.
• Green: Against sleep disorders.

Important Notes

You should always make medical decisions in consultation with professionals. This text is based on personal experiences and does not replace the advice of a qualified doctor or psychiatrist. Due to possible unknown interactions with additional or different active substances or significant dosage deviations, you should have each individual adjustment carefully examined. Bupropion is a strong inhibitor of the CYP2D6 enzyme, which increases the blood levels of medications primarily metabolized via CYP2D6 (this is broken down in more detail below).


Operating Machinery

Caution is advised when driving and operating machinery, especially during the intake of aripiprazole. Your ability to concentrate may be reduced, and negative symptoms can intensify. You should avoid long distances due to fatigue. In cases of restlessness, which can also occur with monotherapy using aripiprazole, bupropion can have an additional calming effect (against inner unrest) and increase alertness, making driving safer.

Trimipramine drops have a very strong sedative effect even in small doses; you should choose the dosage so that there is no residual drowsiness in the morning or daytime fatigue.

Regularly assessing your reaction ability can help minimize risks.


Adjustment of Antidepressants, Early Warning Symptoms, and Interval Intake of the Antipsychotic

The antidepressant bupropion improves your concentration and alertness and helps against inner unrest. Nicotine consumption and addictive tendencies are reduced. The effect on inner unrest, concentration, and alertness positively influences safe driving.

Regular interval intake (see diagram) of aripiprazole must be ensured so that the antidepressants work reliably and as desired. Discontinuation or the interval phase of aripiprazole initially leads to improved effectiveness of the antidepressants; months later, shortly before the next interval intake, the effectiveness of the antidepressants decreases. Taking the antipsychotic stabilizes the condition, allowing the antidepressants to work fully again in the next discontinuation interval. Bupropion serves as the constant, antipsychotically stabilizing antidepressant, which can be used consistently at a relatively high dosage. You should adjust citalopram and trimipramine drops more variably according to your needs, as citalopram regulates/dampens emotional states and trimipramine drops are important for sleep problems since bupropion, in effective dosages, makes you very alert.

Shortly before the interval intake, early warning symptoms such as inner unrest, anger, mistrust, and increased sleep disturbances can occur. Bupropion also causes sleep disturbances, so you need to differentiate here, and it may take time to get used to bupropion.


Only with a Specialist and Precise Background Information

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The medication combination can only be prescribed by a trained doctor or psychiatrist. They should have time beforehand to read up, as this is not standard therapy and several factors need to be considered. Especially if other active substances than the recommended ones need to be used or supplemented, any changes should be made with the utmost care. It is advisable to build upon monotherapy with aripiprazole and take time step by step to better reflect on the changes brought about by the respective active substances.

Bupropion is recommended in the current S3 guidelines for schizophrenia by the DGPPN, for example, in cases of psychoses with nicotine addiction (Recommendation 109). Broader access to this form of treatment could be beneficial for affected individuals.


Order of Introducing Active Ingredients

1. Aripiprazole
2. Bupropion
3. Citalopram
   • Trimipramine can be taken later as a supplement.

Studies:

• The Effects of Bupropion on Negative Symptoms in Schizophrenia
• Antidepressants for Patients with Schizophrenia and Depression
• Antidepressants for the Negative Symptoms of Schizophrenia
• Risks and Benefits of Bupropion Treatment in Schizophrenia

Quote:
"In schizophrenic patients treated with bupropion in addition to antipsychotics, the risk of bupropion-induced psychosis appears to be negligible. The efficacy of a combined dopamine and noradrenaline agonist in schizophrenia is biologically plausible. Further studies with bupropion should integrate neurobiological methods and focus on negative symptoms and cognitive deficits in schizophrenia."

Study Situation on Bupropion + SSRI Antidepressants (Citalopram)

Spoiler: Bupropion + SSRI Antidepressants

Clinical studies and meta-analyses have investigated the safety of the combination:

• Weisler et al. (2005) conducted a study examining the combination of Bupropion SR with patients taking SSRIs. They found no significant increase in seizures or serious adverse events.
• Patkar et al. (2006) analyzed the efficacy and safety of combination therapy in patients with major depression. The risk of seizures remained low, and the combination was well tolerated.

Conclusion of the studies:

• The combination therapy of Bupropion with SSRIs is safe and effective when used under medical supervision and at recommended dosages.
• There is no significant increase in the risk of seizures due to the combination.

Clinical Practice​

Application of the combination:

• The combination of Bupropion with an SSRI is frequently used to enhance the antidepressant effect, especially in treatment-resistant depression.
• Bupropion can also improve sexual dysfunctions caused by SSRIs.

Advantages of the combination:

• Improved mood control through different mechanisms of action.
• Reduction of side effects by balancing the respective profiles.

Supplementary Notes on Aripiprazole Interval Intake + Bupropion + SSRI​

• An additional SSRI alongside Bupropion counteracts depressive moods during the discontinuation phase of Aripiprazole, as Bupropion alone is rather weakly antidepressant. SSRIs dampen emotions, thereby improving the antidepressant effect.
• The additional SSRI moderately dampens libido and emotions, which can be desirable during the interval phase, as emotions and feelings can return intensified.
• Bupropion acts against irritability and restlessness, which significantly improves concentration and safe driving behavior, for example, when driving a car.
• An SSRI additionally reduces side effects of Bupropion such as urinary disorders and constipation.

Spoiler: Metabolism of Aripiprazole

Metabolism of Aripiprazole​

Aripiprazole is an atypical antipsychotic medication primarily metabolized in the liver. The main enzymes involved in its breakdown are:

• CYP2D6
• CYP3A4

Details of Metabolism:​

1. CYP2D6:

• Role: Responsible for part of the metabolism of aripiprazole.
• Genetic Variations:Lead to different rates of metabolism among individuals.
  • Extensive (Rapid) Metabolizers: Have more active CYP2D6 enzymes.
  • Poor (Slow) Metabolizers: Have fewer active enzymes, resulting in higher plasma levels of aripiprazole.

2. CYP3A4:

• Primary Metabolic Pathway: CYP3A4 is the main enzyme metabolizing aripiprazole.
• Conversion: Transforms aripiprazole into its main metabolite, dehydroaripiprazole.
• Activity: Dehydroaripiprazole has pharmacological effects similar to aripiprazole itself.

Influence of Bupropion on the Metabolism of Aripiprazole​

Bupropion is an antidepressant that acts as a strong inhibitor of the CYP2D6 enzyme. This means:

1. Inhibition of CYP2D6:

• Effect: Bupropion can reduce or block the activity of CYP2D6.
• Consequence: Leads to decreased metabolism of substances processed by CYP2D6.

2. Consequences for Aripiprazole:

• Increased Plasma Levels of Aripiprazole:
  • The inhibition by bupropion can result in higher concentrations of aripiprazole in the blood.
• Enhanced Effects and Side Effects:
  • Potential for intensified therapeutic effects.
  • Increased risk of side effects such as restlessness, agitation, or movement disorders.

Dosage Interval and Administration Pattern:

• Lower Dosage or Interval Dosing:
  • Using a reduced dose or dosing at intervals may lower interaction risks.
• Caution Remains Important:
  • Even with dose adjustments, vigilance is necessary.
  • Medical Supervision:
    • Regular monitoring by a healthcare professional is crucial to ensure safety and effectiveness.

Cariprazine as an Alternative:

• About Cariprazine:
  • An atypical antipsychotic similar to aripiprazole.
• Metabolism:
  • Primarily metabolized via CYP3A4.
  • Less influenced by CYP2D6 inhibition.
• Potential Benefits:
  • Could minimize drug interactions when taken with bupropion.
• Considerations:
  • Individual efficacy and tolerability must be evaluated.
  • Not automatically a suitable replacement; clinical judgment is essential.

References:​

1. Analysis of CYP450 Interactions: Small Effort, Big Impact
   • Discusses the significance of understanding cytochrome P450 enzyme interactions in clinical practice.
2. Phenoconversion of CYP2D6 by Inhibitors Modifies Aripiprazole Exposure
   • European Archives of Psychiatry and Clinical Neuroscience
   • Examines how CYP2D6 inhibition affects aripiprazole levels in the body.
3. Dose-Dependent Inhibition of CYP2D6 by Bupropion in Clinical Settings
   • Journal of Clinical Psychopharmacology
   • Explores the extent to which bupropion inhibits CYP2D6 and implications for drug interactions.

Possible drug interactions

Spoiler: Interactions and Precautions

Summary of Interactions Considering Low-Dose Trimipramine​

Medications:​

Bupropion

• Mechanism of Action: Norepinephrine and dopamine reuptake inhibitor (NDRI).
• Metabolism: Primarily via the enzyme CYP2B6.
• Special Considerations: Strong inhibitor of CYP2D6.

Citalopram

• Mechanism of Action: Selective serotonin reuptake inhibitor (SSRI).
• Metabolism: Primarily via CYP2C19; to a lesser extent via CYP3A4 and CYP2D6.
• Special Considerations: Low dependence on CYP2D6.

Aripiprazole

• Mechanism of Action: Atypical antipsychotic; partial agonist at D₂ and 5-HT₁A receptors, antagonist at 5-HT₂A receptors.
• Metabolism: Via CYP3A4 (main pathway) and CYP2D6.
• Special Considerations: Metabolism can be affected by CYP2D6 inhibitors.

Trimipramine (in low dosage as drops)

• Mechanism of Action: Tricyclic antidepressant (TCA); inhibits the reuptake of norepinephrine and serotonin, with strong sedative effect.
• Metabolism: Mainly via CYP2D6; also via CYP2C19 and CYP1A2.
• Special Considerations: At low dosages, the risks of interactions are reduced.

Possible Interactions Between the Medications Considering Low-Dose Trimipramine​

A. Bupropion and Trimipramine (Low Dosage)​

• CYP2D6 Inhibition by Bupropion:
  • Can increase plasma levels of Trimipramine.
  • Impact: Due to the low dose of Trimipramine, the increase in plasma levels is likely minimal.
• Risks:
  • Slight enhancement of the sedative effect.
  • Mild anticholinergic side effects (e.g., dry mouth, mild constipation).
• Conclusion: The risk of side effects is reduced but should still be monitored.

B. Trimipramine (Low Dosage) and Citalopram​

• Additive Serotonergic Effects
  • Both medications increase serotonin levels.
  • Serotonin Syndrome: Risk is low with low-dose Trimipramine but not entirely excluded.
• QT Prolongation:
  • Both can affect the QT interval on an ECG.
  • Impact: Risk of cardiac arrhythmias is reduced at low doses.
• Conclusion: Regular monitoring may be advisable, especially if existing heart conditions are present.

C. Bupropion and Citalopram​

• CYP2D6 Inhibition:
  • Citalopram is only minimally metabolized via CYP2D6.
  • Impact: Low risk of increased Citalopram levels.
• Conclusion: Interaction is likely clinically irrelevant, but monitoring for side effects is advisable.

D. Bupropion and Aripiprazole​

• CYP2D6 Inhibition by Bupropion:
  • Can lead to increased plasma levels of Aripiprazole.
• Risks:
  • Enhanced side effects of Aripiprazole, such as restlessness or movement disorders.
• Conclusion: Medical supervision and potential dose adjustment of Aripiprazole are recommended.

E. Trimipramine (Low Dosage) and Aripiprazole​

• Additive Sedative Effects:
  • Both can cause drowsiness.
  • Impact: With low-dose Trimipramine, the increased sedation is less pronounced.
• Conclusion: Be mindful of your ability to react, especially when operating machinery or driving.

Overall Assessment Considering Low-Dose Trimipramine​

• Reduced Risk Due to Low Trimipramine Dose:
  • Using low-dose Trimipramine reduces the likelihood of significant interactions.
• Important Monitoring Points:
  • Sedation: Mild, but watch for excessive drowsiness.
  • Anticholinergic Effects: Likely minimal, but be aware of symptoms like dry mouth.
  • Heart Rhythm: When taken with Citalopram, the QT interval should be monitored, especially if other risk factors are present.
• Individual Response:
  • Everyone reacts differently; despite low dosage, some individuals may be more sensitive.

Recommendations and Precautions​

Consultation with Your Doctor:​

• Inform your doctor about all medications being taken and the exact dosages.
• Discuss the potential risks and benefits of the combination together.

Monitoring Symptoms:​

• Sedation: Watch for signs of excessive sleepiness or dizziness.
• Anticholinergic Symptoms: Such as dry mouth, blurred vision, or mild constipation.
• Heart Rhythm: If you experience symptoms like palpitations or dizziness, inform your doctor immediately.

Regular Check-Ups:​

• Therapeutic Drug Monitoring (TDM): Blood level measurements can be helpful if necessary.
• ECG Examinations: To monitor the QT interval, especially if taking higher doses of Citalopram.

Dose Adjustments:​

• Trimipramine: The dose can be further adjusted if needed.
• Aripiprazole: A dose reduction may be necessary to balance increased plasma levels.

Avoiding Additional Risks:​

• Alcohol: Can enhance sedative effects; consumption should be minimized.
• Other Medications: Avoid additional substances that affect CYP2D6 without consulting your doctor.

Final Thoughts​

The addition of low-dose Trimipramine to your medication regimen can be safe when considering the points mentioned and working closely with your doctor. The low dose helps minimize the risk of interactions and side effects, but vigilance remains important.

Open communication with your doctor and careful monitoring of your symptoms are crucial to achieving the best therapeutic effect while ensuring safety.

Spoiler: Choosing a Suitable SSRI

Supplement: Selection of Suitable SSRIs in Combination with Bupropion and Consideration of QT Prolongation

SSRIs and Their Metabolism When Combined with Bupropion
When choosing an appropriate SSRI to combine with Bupropion, it's important to consider the metabolic pathways and potential CYP450 interactions. Since Bupropion is a strong inhibitor of CYP2D6, SSRIs that are primarily metabolized via this enzyme may exhibit increased plasma levels, thus raising the risk of side effects.


Overview of SSRIs and Their Metabolic Pathways:

Citalopram and Escitalopram​

• Metabolism: Primarily via CYP2C19 and CYP3A4.
• Low dependence on CYP2D6, therefore less affected by CYP2D6 inhibition from Bupropion.

Advantages:

• Lower risk of interactions with Bupropion.
• Escitalopram tends to have fewer effects on the QT interval compared to Citalopram.

Considerations:

• Citalopram can dose-dependently prolong the QT interval, especially at dosages above 20 mg daily.
• Escitalopram is often preferred due to its lower impact on QT prolongation and better tolerability.

Sertraline​

• Metabolism: Via CYP2C19, CYP2B6, CYP2C9, and CYP3A4; minimal influence from CYP2D6.

Interactions with Bupropion:

• Moderate interaction, as Sertraline is minimally metabolized by CYP2D6.
• Can still lead to moderate increases in Sertraline levels.

Advantages:

• Lower risk of QT prolongation compared to Citalopram.
• Well-tolerated and flexible in dosing.

Recommendation:

• Sertraline is a good option in combination with Bupropion.
• Monitoring and potential dosage adjustments may be advisable.

Fluoxetine and Paroxetine​

• Metabolism: Primarily via CYP2D6.

Interactions with Bupropion:

• Increased risk of significant interactions, as both medications inhibit CYP2D6.
• Can lead to elevated levels and enhanced side effects.

Recommendation:

• Use caution when co-administering.
• Consider dose reduction or alternative SSRIs.

Fluvoxamine​

• Metabolism: Via CYP1A2 and CYP2D6.

Interactions:

• Inhibits multiple CYP enzymes, which can lead to numerous interactions.

Recommendation:

• Less suitable in combination with Bupropion.
• Alternative options should be considered.

QT Prolongation and Selection of SSRIs

Citalopram​

• Higher risk for QT prolongation, especially at dosages above 20 mg.
• Regular ECG monitoring may be necessary.

Escitalopram​

• Lower risk compared to Citalopram.
• Offers similar efficacy at lower dosages.

Sertraline​

• Lowest risk for QT prolongation among SSRIs.
• Good option for patients with cardiovascular risk factors.

Recommendations for Selecting Suitable SSRIs

• Preferred SSRIs in Combination with Bupropion:
  • Escitalopram and Sertraline due to their low risk of CYP2D6 interactions and QT prolongation.
• Use SSRIs with Caution:
  • Citalopram can be used, but dosage should be kept low, and the QT interval should be monitored.
• SSRIs to Avoid or Use with Caution:
  • Fluoxetine and Paroxetine due to their high potential for CYP2D6 interactions.

Dose Adjustment of SSRIs with CYP2D6 Inhibition

Need for Dose Reduction:

• For SSRIs metabolized via CYP2D6, inhibition by Bupropion can lead to increased medication levels.
• Fluoxetine and Paroxetine may require dose adjustments.

Sertraline:

• Low dependence on CYP2D6.
• Dose adjustment may still be necessary in individual cases.

Recommendation:

• Regular monitoring of side effects.
• Adjust dosage based on clinical evaluation.

Summary and Recommendation

• Best Options:
  • Escitalopram and Sertraline are preferred when combining with Bupropion.
  • Low risk of interactions and QT prolongation.
• Monitoring Required:
  • ECG checks when using Citalopram.
  • Observation of side effects and regular consultation with a doctor.
• Individual Adjustment:
  • Therapy should be tailored to individual needs and risk factors.

Critique and Cautionary Notes:
Treatment Recommendation: Summary and Criticism

Treatment Recommendation: Summary and Critique

• It's crucial to consider individual patient factors and consult healthcare professionals when selecting medications.
• The information provided should not replace professional medical advice.

Additional Complementary Therapies:

• Psychotherapy: Cognitive Behavioral Therapy (CBT) and other forms of psychotherapy can help manage symptoms and improve quality of life.
• Exercise: Regular physical activity can reduce oxidative stress and promote overall health.
• Nutrition: A balanced diet with sufficient vitamins and minerals can play a supportive role.
• Supplements: Vitamins and minerals can be helpful as additional support.

Status: As of 02.02.25

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