Problems with Treatment.

In my previous blog, I introduced and described Integrative Psychiatry. Conventional psychiatric treatment comes with pros and cons, benefits, and risks. In my book “A New Way Forward,” I analyze the clinical decision-making process leading up to treatment consideration in greater detail. In this blog, I’ll review some concerns with pharmaceuticals, therapy, and lifestyle modification in current practice. The Integrative Psychiatry approach poses a solution for the issues we face in current psychiatric practice.

Pharmaceuticals.

In this section, I’ll review issues of efficacy and tolerability related to pharmaceutical treatments.

Efficacy Concerns.

One derivative of a study used for the translation of evidence into the practice setting is an effect size, which tells us how large of an effect a treatment has on a population. Standard wisdom considers an effect size of 0.3 to be small, 0.5 to be moderate, and 0.8 to be large. So, if a treatment has an effect size of 0.8 or higher, it will provide its therapeutic effect to many of those who utilize it. However, exercise caution when interpreting these statistics. For example, selective serotonin reuptake inhibitors (SSRIs) carry a variable effect size for depression ranging from 0.3 to 1.75, with most studies hovering around 0.3. However, a Hamilton depression rating scale (HAM-D) change by two points leads to an effect size of 0.3. In contrast, a seven-point difference is clinically recognizable, corresponding to an effect size of 0.875 (Hengartner & Ploderl, 2018). For research translation, we should remain mindful of what statistically significant will mean and whether this will be clinically significant.

Another statistic utilized is the number needed to treat (NNT), which is the number of individuals needing to try the medication to achieve a beneficial outcome. This number varies among treatment options and populations. For instance, the NNT may be around 5 for antipsychotics used for psychosis, up to 6 for mood stabilizers for bipolar disorder, and as high as 10 for SSRIs for depression (Geddes et al., 2010; Leucht et al., 2017). In the worst-case scenario, this means that you would have to try the same antipsychotic with five individuals for one to achieve the benefit. With depression being the most significant psychiatric illness worldwide, prescribing a medication ten times to achieve one successful outcome is not ideal. Of course, the literature on specific agents should be examined, as the NNT will vary among specific options. Overall, more than 50% of those with depression do not respond to first-line therapy, and 30% remain “treatment resistant” after four drug trials (Sinyor et al., 2010). Depression is not the only condition with grim statistics regarding the effectiveness of pharmacologic agents.

With anxiety, there is about a 50% recurrence rate even while on appropriate pharmaceutical options (Angst et al., 2009; Yonkers et al., 1996). With bipolar disorder, there is a 50-70% relapse rate among those who have been deemed stabilized on a pharmaceutical regimen (Bowden et al., 2012). With ADHD, 65% have continued symptoms into adulthood when diagnosed as a child, regardless of the utilization of psychostimulant treatment in childhood (Faraone et al., 2006). With psychosis, there is evidence of publication bias that suppresses negative antipsychotic trials in favor of publishing studies with positive results. For example, the effect size for unpublished antipsychotic trials was only 0.23, less than half that for the published trials (0.47), which is a statistically significant difference (Turner et al., 2012). What is more, longitudinal data on antipsychotics indicates that in the majority of patients, long-term antipsychotics do not restore premorbid functional capacity (Harrow et al., 2017).

Tolerability Concerns.

Adverse drug reactions (ADRs) are among the leading causes of iatrogenic morbidity and mortality. In the outpatient or community setting, there are approximately 7,000 deaths per year attributed to ADRs (Homsted, 2000). In the inpatient or hospital setting, there are approximately 100,000 deaths per year attributed to ADRs (Lazarou et al., 1998). ADRs are potentially the fourth leading cause of death and are largely preventable.

Notably, one drug category with arguably the poorest tolerability is antipsychotics. According to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (Manschreck & Boshes, 2007), newer drugs were not demonstrably more effective than the older, cheaper ones (Leucht et al., 2009). In their assessment of what psychiatry learned from the CATIE study, Lieberman and Stroup (2011) conclude that to the extent that antipsychotics differ, it is more in their side effects than therapeutic effects. Almost 75% of individuals discontinue their antipsychotic regimen within 18 months of initiation (Lieberman et al., 2005). This discontinuation rate hinders the reliability of studies examining long-term treatment effects. One long-term follow-up study of MRI-based brain alterations in individuals with chronic psychosis receiving antipsychotics found that loss of brain tissue throughout antipsychotic treatment correlated with total antipsychotic exposure and length of untreated psychosis after controlling for other variables (Andreasen et al., 2013). Therefore, chronic antipsychotic use may damage the brain and perhaps, if used, should be used with the lowest possible dose with the shortest possible duration.

Beyond antipsychotics, many serotonergic agents (e.g., selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors) carry a significant risk of side effects that may outweigh the therapeutic benefit. Around 40-60% of individuals experience affective flattening or numbing with antidepressant use, which may be related to the preferential targeting of serotonin and subsequent lowering of reinforcement sensitivity (Langley et al., 2023; Ma et al., 2021). A common strategy to navigate this is to reduce the dose, switch to an alternative agent, or add something with dopaminergic properties like bupropion. However, one study found that bupropion does not alleviate the affective flattening caused by serotonergic drugs (Demyttenaere & Jaspers, 2008). Sexual dysfunction is a common side effect, which may be related to reduced nitric oxide availability caused by antidepressants (Ahn et al., 2005; Angulo et al., 2001). In one survey, 43% of psychiatrists surveyed reported that the most commonly used antidote to serotonergic agent-induced sexual dysfunction is bupropion (Dording et al., 2002). However, several trials have revealed that bupropion is not an effective antidote (Clayton et al., 2004; Debattista et al., 2005; Masand et al., 2001; Safarinejad, 2010; Safarinejad, 2011). Gastrointestinal side effects are also widespread among serotonergic agents. Gastrointestinal side effects are likely related to the fact that the gut synthesizes most of the body’s serotonin and is quite dense in serotonin receptors, modulating gastric motility. Finally, withdrawal is an issue that occurs in anywhere from 27% to 85% of individuals (an average of 55.4%) who stop antidepressants (Massabki & Abi-Jaoude, 2023). There is considerable debate about whether “withdrawal” should be called “discontinuation syndrome.” The push to label “withdrawal” as “discontinuation syndrome” shifts the burden from the drug to the patient. Regardless, this is common among many agents, the most notorious being venlafaxine. Serotonergic withdrawal syndrome is suspected to be due to the modulation of serotonin receptor affinity and the body’s ability to synthesize serotonin following psychotropic use. A novel approach to this is the repletion of serotonin vitamin and mineral co-factors, discussed in a later chapter, to repair the metabolism of serotonin and palliate the withdrawal response.

Psychotherapy.

A meta-analysis compiling the results of 375 controlled psychotherapy evaluations demonstrated that individuals who underwent therapy were overall better off than 75% of untreated individuals (Smith & Glass, 1977). Psychotherapy was a mainstay option before the development of several pharmaceutical agents. Now, it is uncommon for a prescribing clinician to incorporate psychotherapy. In a more recent meta-analysis of 102 studies comparing psychotherapies and pharmaceuticals, the effect size for psychotherapy was 0.36 versus 0.34 for pharmaceuticals (Leichsenring et al., 2022). However, when psychotherapy and psychopharmacology were combined, the effect size was 0.31 (Leichsenring et al., 2022). This is a curious finding indicating a ceiling effect. Remember, an effect size of 0.3 is small. There is certainly something that needs to be adjusted among the two first-line treatment options in psychiatry.

Interestingly, virtually no difference was observed between the modalities examined (Smith & Glass, 1977). Several treatment modalities exist, including psychoanalysis, cognitive-behavioral therapy, dialectical behavioral therapy, acceptance and commitment therapy, emotion-focused therapy, motivational interviewing, eye movement desensitization and reprocessing, hypnotherapy, and internal family systems therapy. Some modalities land better for some individuals compared with others. Also, some modality techniques are more robust for certain conditions than others. Head-to-head trials compare one modality versus another for a particular condition where a particular modality has outperformed another. What stands out among the crowd is the therapeutic relationship. Studies have demonstrated that the therapeutic relationship is the heart of psychotherapy and influences therapy outcomes more strongly than modality (Lambert & Barley, 2001; Luborsky et al., 2002; Wampold, 2012). These studies have led me to believe that relationships are the most critical ingredient for effective healing. Some even go to the extreme to assert that all problems are relational. Perhaps not only relational in the sense of self-other but also within a broader context of self-object relations. Regardless, when an effective therapeutic relationship is combined with a strong belief in a therapeutic modality, the therapist can effectively assist the individual in reaching mental health and wellness. Compared to pharmaceuticals and nutraceuticals, therapy does not come with a list of potential side effects.

Lifestyle.

A primary goal of psychiatric intervention is to assist an individual in re-engaging with life’s activities, organized into several domains. Despite functional impairment being the hallmark indicator drawing the line between normality and psychiatric illness, the domains of an individual’s lifestyle are uncommonly evaluated in conventional psychiatric practice. By extension, these areas do not always become the target of intervention. Introducing mindful engagement in the lifestyle domains is incredibly insightful. This breaks the spell of the automaton and sparks behavioral change. For instance, noticing that you eat thrice daily may bring your attention to what and how you eat. Noticing that when you reduce added sugar, the most inflammatory substance in American food, your energy level and joint pain improve. Noticing that when you take your time to eat, your gastrointestinal symptoms improve. Behavior transforms when changes are contextualized with the value structure (i.e., who and what is important). Curiosity may then carry an individual into other lifestyle domains such as relationships, leisure, occupation, academia, exercise, sleep, and spiritual practices.

The Solution.

Integrative Psychiatry conducts a more thorough analysis of the internal and external environment. This analysis provides a more effective or workable understanding of the individual’s experiences. With this in mind, we can develop more personalized treatment plans to target symptoms more effectively. In subsequent posts, I’ll review additional problems in conventional psychiatric practice and introduce you to some leading-edge considerations to revolutionize the care of your patients.

If you like the content of this blog, please check out my book, “A New Way Forward,” for a more in-depth analysis of some of these issues and solutions.

References.

Ahn, G. J., Kang, K. K., Kim, D. S., Ahn, B. O., Kim, W. B., Kang, S. K., Lee, B. C., & Hwang, W. S. (2005). DA-8159 reverses selective serotonin reuptake inhibitor-induced erectile dysfunction in rats. Urology, 65(1), 202-207. https://doi.org/10.1016/j.urology.2004.09.023

Andreasen, N. C., Liu, D., Ziebell, S., Vora, A., & Ho, B. C. (2013). Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: A prospective longitudinal MRI study. American Journal of Psychiatry, 170(6), 609-615.

Angst, J., Gamma, A., Baldwin, D. S., Ajdacic-Gross, V., & Rössler, W. (2009). The generalized anxiety spectrum: prevalence, onset, course and outcome. European archives of psychiatry and clinical neuroscience, 259(1), 37–45. https://doi.org/10.1007/s00406-008-0832-9

Angulo, J., Peiró, C., Sanchez-Ferrer, C. F., Gabancho, S., Cuevas, P., & Gupta, S. (2001). Differential effects of serotonin reuptake inhibitors on erectile responses, NO-production, and neuronal NO synthase expression in rat corpus cavernosum tissue. British Journal of Pharmacology, 134(6), 1190-1194. https://doi.org/10.1038/sj.bjp.0704351

Bowden, C. L., Perlis, R. H., Thase, M. E., Ketter, T. A., Ostacher, M. M., Calabrese, J. R., Reilly-Harrington, N. A., Gonzalez, J. M., Singh, V., Nierenberg, A. A., & Sachs, G. S. (2012). Aims and results of the NIMH systematic treatment enhancement program for bipolar disorder (STEP-BD). CNS neuroscience & therapeutics, 18(3), 243–249. https://doi.org/10.1111/j.1755-5949.2011.00257.x

Clayton, A. H., Warnock, J. K., Kornstein, S. G., Pinkerton, R., Sheldon-Keller, A., & McGarvey, E. L. (2004). A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction. The Journal of clinical psychiatry, 65(1), 62–67. https://doi.org/10.4088/jcp.v65n0110

DeBattista, C., Solvason, B., Poirier, J., Kendrick, E., & Loraas, E. (2005). A placebo-controlled, randomized, double-blind study of adjunctive bupropion sustained release in the treatment of SSRI-induced sexual dysfunction. The Journal of clinical psychiatry, 66(7), 844–848. https://doi.org/10.4088/jcp.v66n0706

Demyttenaere, K., & Jaspers, L. (2008). Review: Bupropion and SSRI-induced side effects. Journal of Psychopharmacology. https://doi.org/10.1177/0269881107083798

Dording C.M., Mischoulon D., Petersen T.J., Kornbluh R., Gordon J., Nierenberg A.A., Rosenbaum J.E., Fava M. ( 2002) The pharmacologic management of SSRI-induced side effects: a survey of psychiatrists. Ann Clin Psychiatry 14: 143-147

Faraone, S. V., Biederman, J., & Mick, E. (2006). The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychological medicine, 36(2), 159–165. https://doi.org/10.1017/S003329170500471X

Geddes, J. R., Carney, S. M., Davies, C., Furukawa, T. A., Kupfer, D. J., Frank, E., & Goodwin, G. M. (2010). Relapse prevention with antidepressant drug treatment in depressive disorders: A systematic review. The Lancet, 379(9834), 1045-1054.

Harrow, M., Jobe, T. H., Faull, R. N., & Yang, J. (2017). A 20-year multi-followup longitudinal study assessing whether antipsychotic medications contribute to work functioning in schizophrenia. Psychiatry Research, 256, 267-274.

Hengartner, M. P. & Ploderl, M. (2018). Statistically significant antidepressant-placebo differences on subjective symptom-rating scales do not prove that the drugs work: Effect size and method bias matter!. Frontiers in Psychiatry, 9, 157.

Homsted L. (2000). Institute of Medicine report: to err is human: building a safer health care system. The Florida nurse, 48(1), 6.

Lambert, M. J., & Barley, D. E. (2001). Research summary on the therapeutic relationship and psychotherapy outcome. Psychotherapy: Theory, Research, Practice, Training, 38(4), 357–361. https://doi.org/10.1037/0033-3204.38.4.357

Langley, C., Armand, S., Luo, Q., Savulich, G., Segerberg, T., Søndergaard, A., Pedersen, E. B., Svart, N., Johansen, A., Borgsted, C., Cardinal, R. N., Robbins, T. W., Stenbæk, D. S., Knudsen, G. M., & Sahakian, B. J. (2023). Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: A double-blind, placebo-controlled semi-randomised study. Neuropsychopharmacology, 48(4), 664-670. https://doi.org/10.1038/s41386-022-01523-x

Lazarou, J., Pomeranz, B. H., & Corey, P. N. (1998). Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA, 279(15), 1200–1205. https://doi.org/10.1001/jama.279.15.1200

Leichsenring, F., Steinert, C., Rabung, S., & Ioannidis, J. P. A. (2022). The efficacy of psychotherapies and pharmacotherapies for mental disorders in adults: an umbrella review and meta-analytic evaluation of recent meta-analyses. World psychiatry : official journal of the World Psychiatric Association (WPA), 21(1), 133–145. https://doi.org/10.1002/wps.20941

Leucht, S., Davis, J. M., & Engel, R. R. (2017). Equipercentile linking of the BPRS and the PANSS. European Neuropsychopharmacology, 27(11), 1077-1080.

Lieberman, J. A. & Stroup, T. S. (2011). The NIMH-CATIE schizophrenia study: What did we learn? American Journal of Psychiatry, 168(8), 770-775.

Lieberman, J. A., Stroup, T. S., McEvoy, J. P., Swartz, M. S., Rosenheck, R. A., Perkins, D. O., Keefe, R. S., Davis, S. M., Davis, C. E., Lebowitz, B. D., Severe, J., Hsiao, J. K., & Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators (2005). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. The New England journal of medicine, 353(12), 1209–1223. https://doi.org/10.1056/NEJMoa051688

Luborsky, L., Rosenthal, R., Diguer, L., Andrusyna, T. P., Berman, J. S., Levitt, J. T., Seligman, D. A., & Krause, E. D. (2002). The dodo bird verdict is alive and well–mostly. Clinical Psychology: Science and Practice, 9(1), 2–12. https://doi.org/10.1093/clipsy.9.1.2

Manschreck, T. C. & Boshes, R. A. (2007). The CATIE schizophrenia trial: Results, impact, controversy. Harvard Review of Psychiatry, 15(5), 245-258.

Masand, P. S., Ashton, A. K., Gupta, S., & Frank, B. (2001). Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. The American journal of psychiatry, 158(5), 805–807. https://doi.org/10.1176/appi.ajp.158.5.805

Massabki, I., & Abi-Jaoude, E. (2021). Selective serotonin reuptake inhibitor ‘discontinuation syndrome’ or withdrawal. The British Journal of Psychiatry, 218(3), 168–171. doi:10.1192/bjp.2019.269

Sinyor, M., Schaffer, A., & Levitt, A. (2010). The sequenced treatment alternatives to relieve depression (STAR*D) trial: a review. Canadian journal of psychiatry. Revue canadienne de psychiatrie, 55(3), 126–135. https://doi.org/10.1177/070674371005500303

Safarinejad M. R. (2010). The effects of the adjunctive bupropion on male sexual dysfunction induced by a selective serotonin reuptake inhibitor: a double-blind placebo-controlled and randomized study. BJU international, 106(6), 840–847. https://doi.org/10.1111/j.1464-410X.2009.09154.x (Retraction published Safarinejad MR. BJU Int. 2015 Mar;115(3):E11)

Safarinejad M. R. (2011). Reversal of SSRI-induced female sexual dysfunction by adjunctive bupropion in menstruating women: a double-blind, placebo-controlled and randomized study. Journal of psychopharmacology (Oxford, England), 25(3), 370–378. https://doi.org/10.1177/0269881109351966

Smith, M. L., & Glass, G. V. (1977). Meta-analysis of psychotherapy outcome studies. American Psychologist, 32(9), 752–760. https://doi.org/10.1037/0003-066X.32.9.752

Turner, E. H., Knoepflmacher, D., & Shapley, L. (2012). Publication bias in antipsychotic trials: an analysis of efficacy comparing the published literature to the US Food and Drug Administration database. PLOS Medicine, 9(3), e1001189.

Wampold, B. E. (2012). Humanism as a common factor in psychotherapy. Psychotherapy, 49(4), 445–449. https://doi.org/10.1037/a0027113

Yonkers, K. A., Warshaw, M. G., Massion, A. O., & Keller, M. B. (1996). Phenomenology and course of generalised anxiety disorder. The British journal of psychiatry : the journal of mental science, 168(3), 308–313. https://doi.org/10.1192/bjp.168.3.308