4.4.2 Dose ranges, treatment resistance and switching/cross tapering
Knowledge of Dose Ranges, Minimum Effective Doses, and Time Scales for Evaluating Efficacy
In pharmacology, the dose of a drug refers to the amount of medication given at a certain time. The effective dose range is the range of doses that produce a therapeutic effect.
The minimum effective dose (MED) is the smallest dose of a drug that produces a therapeutic effect in a patient. This means that taking a higher dose will not necessarily result in a greater therapeutic effect, and may instead cause adverse side effects or toxicity. MED is an important concept in pharmacology and is used to optimize the balance between therapeutic benefit and risk of harm. The MED may vary between individuals and can be influenced by factors such as age, weight, genetics, and other medications being taken. It is important to always follow the recommended dosage guidelines and consult with a healthcare provider before adjusting the dose of any medication.
The time scale for evaluating efficacy varies depending on the type of drug and the condition being treated. Some drugs may show their therapeutic effect within hours, while others may take days or weeks to show a noticeable improvement. The time scale for evaluating efficacy is also influenced by the half-life of the drug, which is the time it takes for half of the drug to be eliminated from the body.
It is important to note that the dose range, minimum effective dose, and time scale for evaluating efficacy can vary between individuals and may need to be adjusted based on factors such as age, weight, medical history, and other medications being taken.
Strategies for Managing Non-/Poor-Response
Strategies for managing non-response or poor response in medication-taking include:
- Education: Educate patients about the importance of taking their medication as prescribed, and the potential consequences of not doing so.
- Simplification: Simplify the medication regimen by reducing the number of pills, or the frequency of dosing.
- Reminders: Use reminder systems, such as pill boxes, phone alarms, or text messages, to help patients remember to take their medication.
- Involvement of caregivers: Involve a caregiver, such as a family member or a home health aide, to ensure the patient takes their medication as prescribed.
- Adherence monitoring: Use technology, such as wearable devices or smartphone apps, to monitor medication adherence and provide real-time feedback to patients.
- Collaboration with healthcare providers: Collaborate with healthcare providers, such as pharmacists or nurses, to monitor medication adherence and provide support.
- Personalized support: Provide personalized support, such as one-on-one counselling or support groups, to help patients overcome barriers to medication adherence.
- Medication review: Regularly review the patient’s medication regimen to ensure it is still appropriate and make changes if needed.
‘Treatment resistance’ (schizophrenia/major depression):
Treatment resistance in schizophrenia and major depression is a persistent challenge in the field of psychiatry. Despite the availability of various pharmacological and psychotherapeutic treatments, a significant proportion of individuals with these mental health disorders continue to experience symptoms and impairments that negatively impact their daily functioning. In the case of schizophrenia, treatment resistance is estimated to occur in approximately 20-30% of patients, while in major depression, it is estimated to occur in 30-50% of patients (Malhi, 2014), (Velligan, 2010).
The exact causes of treatment resistance in these disorders are still not well understood, but it is likely that a complex interplay of multiple factors is involved. Some of the commonly suggested contributing factors include:
- Inadequate treatment dosing: A common reason for treatment resistance is that the individual may not be receiving a therapeutic dose of medication, or the dose may be adjusted too slowly or too quickly.
- Incorrect diagnosis: In some cases, individuals may be diagnosed with schizophrenia or major depression when in fact they have a different mental health condition. This incorrect diagnosis can result in the wrong type of treatment being prescribed, leading to a lack of response.
- Co-occurring substance abuse: Substance abuse is a common problem among individuals with schizophrenia and major depression. This can interfere with treatment response and exacerbate symptoms, making it difficult to determine whether the individual is resistant to treatment or if their symptoms are being exacerbated by substance abuse.
- Biological and genetic factors: There is increasing evidence that genetic and biological factors play a role in treatment resistance. For example, some studies have suggested that certain genetic variations may affect an individual’s response to certain medications. Additionally, changes in the brain and other physiological systems can also contribute to treatment resistance.
Given the complex nature of treatment resistance in schizophrenia and major depression, it is essential to take an individualized approach to treatment. This may involve a combination of pharmacological and psychotherapeutic interventions, as well as the consideration of factors such as the person’s lifestyle, environment, and personal preferences. In some cases, treatment may also involve the use of novel therapies, such as transcranial magnetic stimulation or ketamine-assisted psychotherapy.
Systematic strategies for managing ‘treatment resistance’:
There are several systematic strategies for managing treatment resistance in individuals with schizophrenia and major depression:
| Management for treatment resistance: | Description: |
| Comprehensive assessment | A comprehensive assessment that includes a thorough medical, psychiatric, and psychosocial evaluation can help determine the root cause of treatment resistance and inform the development of an individualized treatment plan. |
| Medication optimization | This may involve adjusting the dose of the individual’s current medication, switching to a different medication, or adding a second medication to enhance the efficacy of the current treatment. |
| Psychological therapies | In addition to pharmacological interventions, psychological therapies such as cognitive behavioural therapy (CBT), dialectical behaviour therapy (DBT), and psychodynamic therapy can be beneficial in managing treatment resistance. These therapies can help individuals manage symptoms, develop coping skills, and improve their overall quality of life. |
| Electroconvulsive therapy (ECT) | ECT has been shown to be an effective treatment for individuals with treatment-resistant depression. This procedure involves applying electrical stimulation to the brain while the individual is under general anaesthesia. |
| Transcranial magnetic stimulation (TMS) | TMS is a non-invasive brain stimulation procedure that has been shown to be effective in treating treatment-resistant depression. It works by applying a magnetic field to specific areas of the brain to stimulate nerve cells and improve mood. |
| Collaborative care | Collaborative care is an approach that involves a team of healthcare providers, including psychiatrists, primary care physicians, and mental health specialists, who work together to manage treatment resistance. This approach is based on the idea that a coordinated, integrated approach to treatment can result in better outcomes for individuals with treatment-resistant mental health disorders. |
| Lifestyle modifications | Simple lifestyle modifications such as regular exercise, a healthy diet, and adequate sleep can help improve overall mental health and reduce symptoms of treatment resistance. |
| Novel treatments | In some cases, treatment resistance may be managed using novel treatments such as ketamine-assisted psychotherapy or deep brain stimulation (DBS). These treatments are still in the early stages of development and research and are typically only used as a last resort for individuals who have not responded to other forms of treatment. |
Recommendations for Switching within Major Classes and across Compounds
The Maudsley Prescribing Guidelines, published by the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, provide recommendations for switching between major psychiatric classes and major compounds in the treatment of mental health disorders. Here are some of the key recommendations:
- Antidepressants: The Maudsley Guidelines recommend considering a switch to a different class of antidepressant if a patient has not responded to an adequate trial of a first-line antidepressant. Options for switching include switching to a different type of selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), or a monoamine oxidase inhibitor (MAOI).
- Antipsychotics: The guidelines recommend considering a switch to a different antipsychotic if a patient has not responded to an adequate trial of a first-line antipsychotic. Options for switching include switching to a different type of typical antipsychotic, an atypical antipsychotic, or clozapine.
- Mood stabilizers: The guidelines recommend considering a switch to a different mood stabilizer if a patient has not responded to an adequate trial of a first-line mood stabilizer. Options for switching include switching to a different type of anticonvulsant, such as carbamazepine or valproate, or a different type of lithium compound.
It is important to note that these recommendations are based on the best available evidence and clinical experience and may vary depending on the individual patient’s needs and circumstances.
Antidepressant switching:
The tapering and switching time frames for antidepressant medications can vary depending on the individual patient’s needs and the specific medications being used. It is important to follow the guidance of a healthcare professional when tapering and switching antidepressant medications.
As for the clinical examples of UK medications, here are some commonly used antidepressants and their recommended tapering and switching time frames:
- SSRIs: For individuals taking SSRIs, such as fluoxetine or sertraline, a tapering period of several weeks to a few months is typically recommended. For example, the Maudsley Guidelines recommend tapering fluoxetine over a period of 4-6 weeks.
- SNRIs: For individuals taking SNRIs, such as venlafaxine or duloxetine, a tapering period of several weeks to a few months is typically recommended. The specific tapering schedule will depend on the individual patient and the dose of the medication being used.
- TCAs: For individuals taking TCAs, such as amitriptyline or imipramine, a tapering period of several weeks to a few months is typically recommended. The specific tapering schedule will depend on the individual patient and the dose of the medication being used.
When switching between antidepressant medications, it is important to consider the half-life of the medications being used. For example, switching from a medication with a short half-life, such as paroxetine, to a medication with a longer half-life, such as fluoxetine, may require a longer tapering period (Maudsley, 2018).
Switching to: | |||||||
|---|---|---|---|---|---|---|---|
| Switching from: | TCA (except clomipramine) | SSRI ( citalopram, escitalopram, paroxetine or sertraline) | SNRI (duloxetine, venlafaxine) | Fluoxetine | Mirtazapine | Reboxetine | Trazodone |
| TCA (except clomipramine) | Direct switch possible | Gradually reduce the dose of TCA to 25–50 mg daily or half the usual dose. Start SSRI then slowly withdraw TCA over the next 5–7 days | Cross-taper cautiously starting with low-dose SNRI | Halve the dose of TCA, add fluoxetine and then slowly withdraw TCA | Cross-taper cautiously | Cross-taper cautiously | Halve the dose of TCA, add trazodone and then slowly withdraw TCA |
| SSRIs ( citalopram, escitalopram, paroxetine or sertraline) | Cross-taper cautiously with a low dose of TCA | Direct switch possible | Direct switch possible (caution if paroxetine used) | Direct switch possible | Cross-taper cautiously | Cross-taper cautiously | Cross-taper cautiously |
| SNRIs (duloxetine, venlafaxine) | Cross-taper cautiously with a low dose of TCA | Direct switch possible | Direct switch possible | Direct switch possible | Cross-taper cautiously | Cross-taper cautiously | Cross-taper cautiously |
| Fluoxetine | Stop fluoxetine, start TCA at a low dose 4–7 days later and increase the dose very slowly | Stop fluoxetine, and start SSRI at a low dose 4–7 days later | Stop fluoxetine, and start SNRI at a low dose 4–7 days later | — | Cross-taper cautiously | Cross-taper cautiously | Cross-taper cautiously |
| Mirtazapine | Cross-taper cautiously | Cross-taper cautiously | Cross-taper cautiously | Cross-taper cautiously | — | Cross-taper cautiously | Cross-taper cautiously |
| Reboxetine | Cross-taper cautiously | Cross-taper cautiously | Cross-taper cautiously | Cross-taper cautiously | Cross-taper cautiously | — | Cross-taper cautiously |
| Trazodone | Cross-taper cautiously with a low dose of TCA | Cross-taper cautiously | Cross-taper cautiously | Cross-taper cautiously | Cross-taper cautiously | Cross-taper cautiously | — |
(Taylor, 2021)
Antipsychotic switching:
The tapering and switching time frames for antipsychotic medications can vary depending on the individual patient’s needs and the specific medications being used. It is important to follow the guidance of a healthcare professional when tapering and switching antipsychotic medications.
As for the clinical examples of UK medications, here are some commonly used antipsychotics and their recommended tapering and switching time frames:
- Typical antipsychotics: For individuals taking typical antipsychotics, such as chlorpromazine or haloperidol, a tapering period of several weeks to a few months is typically recommended. The specific tapering schedule will depend on the individual patient and the dose of the medication being used.
- Atypical antipsychotics: For individuals taking atypical antipsychotics, such as olanzapine or quetiapine, a tapering period of several weeks to a few months is typically recommended. The specific tapering schedule will depend on the individual patient and the dose of the medication being used.
When switching between antipsychotic medications, it is important to consider the half-life of the medications being used. For example, switching from a medication with a short half-life, such as risperidone, to a medication with a longer half-life, such as olanzapine, may require a longer tapering period.
It is also important to consider the potential for withdrawal symptoms and the need for a gradual tapering process. Some antipsychotics, such as clozapine, may have a higher risk of withdrawal symptoms and may require a slower tapering schedule (Maudsley, 2018).
| Oral first-generation (typical) | Oral second-generation (atypical) | Antipsychotic depot injections |
|---|---|---|
| Benperidol Chlorpromazine Flupentixol Haloperidol Levomepromazine Pericyazine Perphenazine Pimozide Prochlorperazine Promazine Sulpiride Trifluoperazine Zuclopenthixol | Amisulpride Aripiprazole Clozapine Olanzapine Paliperidone Quetiapine Risperidone | Aripiprazole Flupentixol decanoate Fluphenazine decanoate Haloperidol Olanzapine embonate Paliperidone Pipotiazine palmitate Risperidone Zuclopenthixol decanoate |
References:
(1) Malhi, G. S., Bassett, D., Boyce, P., Bryant, R., Fitzgerald, P. B., Fritz, K., … & Mitchell, P. B. (2014). Treatment-resistant depression: a review. The Lancet Psychiatry, 1(2), 149-164.
(2) Maudsley Prescribing Guidelines in Psychiatry. 12th ed. Cambridge University Press; 2018.
(3) Taylor, D.M., Barnes, T.R.E. and Young, A.H. (Eds.) (2021) The Maudsley Prescribing Guidelines in Psychiatry. 14th edn. Chichester: Wiley Blackwell.
(4) Velligan, D. I., Bow-Thomas, C. C., & Miller, A. L. (2010). Treatment-resistant schizophrenia. Journal of Psychiatric Practice, 16(3), 175-184.